User login
-
My inspiration
Kobe Bryant knew me. Not personally, of course. I never received an autograph or shook his hand. But once in a while if I was up early enough, I’d run into Kobe at the gym in Newport Beach where he and I both worked out. As he did for all his fans at the gym, he’d make eye contact with me and nod hello. He was always focused on his workout – working with a trainer, never with headphones on. In person, he appeared enormous. Unlike most retired professional athletes, he still was in great shape. No doubt he could have suited up in purple and gold, and played against the Clippers that night if needed.
Being from New England, I never was a Laker fan. But I thought, if Kobe can head to the gym after midnight and take a 1,000 shots to prepare for a game, then I could set my alarm for 4 a.m. and take a few dozen more questions from my First Aid books. Head down, “Kryptonite” cranked on my iPod, I wasn’t going to let anyone in that test room outwork me. Neither did he. I put in the time and, like Kobe in the 2002 conference finals against Sacramento, I crushed it.*
When we moved to California, I followed Kobe and the Lakers until he retired. To be clear, I didn’t aspire to be like him, firstly because I’m slightly shorter than Michael Bloomberg, but also because although accomplished, Kobe made some poor choices at times. Indeed, it seems he might have been kinder and more considerate when he was at the top. But in his retirement he looked to be toiling to make reparations, refocusing his prodigious energy and talent for the benefit of others rather than for just for scoring 81 points. His Rolls Royce was there before mine at the gym, and I was there early. He was still getting up early and now preparing to be a great venture capitalist, podcaster, author, and father to his girls.
Watching him carry kettle bells across the floor one morning, I wondered, do people like Kobe Bryant look to others for inspiration? Or are they are born with an endless supply of it? For me, I seemed to push harder and faster when watching idols pass by. Whether it was Kobe or Clayton Christensen (author of “The Innovator’s Dilemma”), Joe Jorizzo, or Barack Obama, I found I could do just a bit more if I had them in mind.
On game days, Kobe spoke of arriving at the arena early, long before anyone. He would use the silent, solo time to reflect on what he needed to do perform that night. I tried this last week, arriving at our clinic early, before any patients or staff. I turned the lights on and took a few minutes to think about what we needed to accomplish that day. I previewed patients on my schedule, searched Up to Date for the latest recommendations on a difficult case. I didn’t know Kobe, but I felt like I did.
When I received the text that Kobe Bryant had died, I was actually working on this column. So I decided to change the topic to write about people who inspire me, ironically inspired by him again. May he rest in peace.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
*This article was updated 2/19/2020.
Kobe Bryant knew me. Not personally, of course. I never received an autograph or shook his hand. But once in a while if I was up early enough, I’d run into Kobe at the gym in Newport Beach where he and I both worked out. As he did for all his fans at the gym, he’d make eye contact with me and nod hello. He was always focused on his workout – working with a trainer, never with headphones on. In person, he appeared enormous. Unlike most retired professional athletes, he still was in great shape. No doubt he could have suited up in purple and gold, and played against the Clippers that night if needed.
Being from New England, I never was a Laker fan. But I thought, if Kobe can head to the gym after midnight and take a 1,000 shots to prepare for a game, then I could set my alarm for 4 a.m. and take a few dozen more questions from my First Aid books. Head down, “Kryptonite” cranked on my iPod, I wasn’t going to let anyone in that test room outwork me. Neither did he. I put in the time and, like Kobe in the 2002 conference finals against Sacramento, I crushed it.*
When we moved to California, I followed Kobe and the Lakers until he retired. To be clear, I didn’t aspire to be like him, firstly because I’m slightly shorter than Michael Bloomberg, but also because although accomplished, Kobe made some poor choices at times. Indeed, it seems he might have been kinder and more considerate when he was at the top. But in his retirement he looked to be toiling to make reparations, refocusing his prodigious energy and talent for the benefit of others rather than for just for scoring 81 points. His Rolls Royce was there before mine at the gym, and I was there early. He was still getting up early and now preparing to be a great venture capitalist, podcaster, author, and father to his girls.
Watching him carry kettle bells across the floor one morning, I wondered, do people like Kobe Bryant look to others for inspiration? Or are they are born with an endless supply of it? For me, I seemed to push harder and faster when watching idols pass by. Whether it was Kobe or Clayton Christensen (author of “The Innovator’s Dilemma”), Joe Jorizzo, or Barack Obama, I found I could do just a bit more if I had them in mind.
On game days, Kobe spoke of arriving at the arena early, long before anyone. He would use the silent, solo time to reflect on what he needed to do perform that night. I tried this last week, arriving at our clinic early, before any patients or staff. I turned the lights on and took a few minutes to think about what we needed to accomplish that day. I previewed patients on my schedule, searched Up to Date for the latest recommendations on a difficult case. I didn’t know Kobe, but I felt like I did.
When I received the text that Kobe Bryant had died, I was actually working on this column. So I decided to change the topic to write about people who inspire me, ironically inspired by him again. May he rest in peace.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
*This article was updated 2/19/2020.
Kobe Bryant knew me. Not personally, of course. I never received an autograph or shook his hand. But once in a while if I was up early enough, I’d run into Kobe at the gym in Newport Beach where he and I both worked out. As he did for all his fans at the gym, he’d make eye contact with me and nod hello. He was always focused on his workout – working with a trainer, never with headphones on. In person, he appeared enormous. Unlike most retired professional athletes, he still was in great shape. No doubt he could have suited up in purple and gold, and played against the Clippers that night if needed.
Being from New England, I never was a Laker fan. But I thought, if Kobe can head to the gym after midnight and take a 1,000 shots to prepare for a game, then I could set my alarm for 4 a.m. and take a few dozen more questions from my First Aid books. Head down, “Kryptonite” cranked on my iPod, I wasn’t going to let anyone in that test room outwork me. Neither did he. I put in the time and, like Kobe in the 2002 conference finals against Sacramento, I crushed it.*
When we moved to California, I followed Kobe and the Lakers until he retired. To be clear, I didn’t aspire to be like him, firstly because I’m slightly shorter than Michael Bloomberg, but also because although accomplished, Kobe made some poor choices at times. Indeed, it seems he might have been kinder and more considerate when he was at the top. But in his retirement he looked to be toiling to make reparations, refocusing his prodigious energy and talent for the benefit of others rather than for just for scoring 81 points. His Rolls Royce was there before mine at the gym, and I was there early. He was still getting up early and now preparing to be a great venture capitalist, podcaster, author, and father to his girls.
Watching him carry kettle bells across the floor one morning, I wondered, do people like Kobe Bryant look to others for inspiration? Or are they are born with an endless supply of it? For me, I seemed to push harder and faster when watching idols pass by. Whether it was Kobe or Clayton Christensen (author of “The Innovator’s Dilemma”), Joe Jorizzo, or Barack Obama, I found I could do just a bit more if I had them in mind.
On game days, Kobe spoke of arriving at the arena early, long before anyone. He would use the silent, solo time to reflect on what he needed to do perform that night. I tried this last week, arriving at our clinic early, before any patients or staff. I turned the lights on and took a few minutes to think about what we needed to accomplish that day. I previewed patients on my schedule, searched Up to Date for the latest recommendations on a difficult case. I didn’t know Kobe, but I felt like I did.
When I received the text that Kobe Bryant had died, I was actually working on this column. So I decided to change the topic to write about people who inspire me, ironically inspired by him again. May he rest in peace.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
*This article was updated 2/19/2020.
Private equity firms acquiring more physician group practices
Lead author Jane M. Zhu, MD, of Oregon Health & Science University, Portland, and colleagues examined physician group practice acquisitions by private equity firms using the Irving Levin Associates Health Care M&A data set, which includes manually collected and verified transactional information on health care mergers and acquisitions. Investigators linked acquisitions to the SK&A data set, a commercial data set of verified physicians and practice-level characteristics of U.S. office-based practices.
Of about 18,000 unique group medical practices, private equity firms acquired 355 physician practice acquisitions from 2013 to 2016, a trend that rose from 59 practices in 2013 to 136 practices in 2016, Dr. Zhu and colleagues reported on Feb. 18 , 2020, in a research letter published in JAMA.
Acquired practices had a mean of four sites, 16 physicians in each practice, and 6 physicians affiliated with each site, the data found. Overall, 81% of these medical practices reported accepting new patients, 83% accepted Medicare, and 60% accepted Medicaid. The majority of acquired practices were in the South (44%).
Anesthesiology (19%) and multispecialty (19%) were the most commonly represented medical groups in the acquisitions, followed by emergency medicine (12%), family practice (11%), and dermatology (10%). In addition, from 2015 to 2016, the number of acquired cardiology, ophthalmology, radiology, and ob.gyn. practices increased. Within acquired practices, anesthesiologists represented the majority of all physicians, followed by emergency medicine specialists, family physicians, and dermatologists.
Dr. Zhu and colleagues cited a key limitation: Because the data are based on transactions that have been publicly announced, the acquisition of smaller practices might have been underestimated.
Still, the findings demonstrate that private equity acquisitions of physician medical groups are accelerating across multiple specialties, Dr. Zhu said in an interview.
“From our data, acquired medical groups seem to have relatively large footprints with multiple office sites and multiple physicians, which mirrors a typical investment strategy for these firms,” she said.
Dr. Zhu said that more research is needed about how these purchases affect practice patterns, delivery of care, and clinician behavior. Private equity firms expect greater than 20% annual returns, and such financial incentives may conflict with the need for longer-term investments in practice stability, physician recruitment, quality, and safety, according to the study.
“In theory, there may be greater efficiencies introduced from private equity investment – for example, through administrative and billing efficiencies, reorganizing practice structures, or strengthening technology supports,” Dr. Zhu said. “But because of private equity firms’ emphasis on return on investment, there may be unintended consequences of these purchases on practice stability and patient care. We don’t yet know what these effects will be, and we need robust, longitudinal data to investigate this question.”
Dr. Zhu and colleagues reported that they had no disclosures.
SOURCE: Zhu JM et al. JAMA. 2020 Feb 18;323(17):663-5.
Lead author Jane M. Zhu, MD, of Oregon Health & Science University, Portland, and colleagues examined physician group practice acquisitions by private equity firms using the Irving Levin Associates Health Care M&A data set, which includes manually collected and verified transactional information on health care mergers and acquisitions. Investigators linked acquisitions to the SK&A data set, a commercial data set of verified physicians and practice-level characteristics of U.S. office-based practices.
Of about 18,000 unique group medical practices, private equity firms acquired 355 physician practice acquisitions from 2013 to 2016, a trend that rose from 59 practices in 2013 to 136 practices in 2016, Dr. Zhu and colleagues reported on Feb. 18 , 2020, in a research letter published in JAMA.
Acquired practices had a mean of four sites, 16 physicians in each practice, and 6 physicians affiliated with each site, the data found. Overall, 81% of these medical practices reported accepting new patients, 83% accepted Medicare, and 60% accepted Medicaid. The majority of acquired practices were in the South (44%).
Anesthesiology (19%) and multispecialty (19%) were the most commonly represented medical groups in the acquisitions, followed by emergency medicine (12%), family practice (11%), and dermatology (10%). In addition, from 2015 to 2016, the number of acquired cardiology, ophthalmology, radiology, and ob.gyn. practices increased. Within acquired practices, anesthesiologists represented the majority of all physicians, followed by emergency medicine specialists, family physicians, and dermatologists.
Dr. Zhu and colleagues cited a key limitation: Because the data are based on transactions that have been publicly announced, the acquisition of smaller practices might have been underestimated.
Still, the findings demonstrate that private equity acquisitions of physician medical groups are accelerating across multiple specialties, Dr. Zhu said in an interview.
“From our data, acquired medical groups seem to have relatively large footprints with multiple office sites and multiple physicians, which mirrors a typical investment strategy for these firms,” she said.
Dr. Zhu said that more research is needed about how these purchases affect practice patterns, delivery of care, and clinician behavior. Private equity firms expect greater than 20% annual returns, and such financial incentives may conflict with the need for longer-term investments in practice stability, physician recruitment, quality, and safety, according to the study.
“In theory, there may be greater efficiencies introduced from private equity investment – for example, through administrative and billing efficiencies, reorganizing practice structures, or strengthening technology supports,” Dr. Zhu said. “But because of private equity firms’ emphasis on return on investment, there may be unintended consequences of these purchases on practice stability and patient care. We don’t yet know what these effects will be, and we need robust, longitudinal data to investigate this question.”
Dr. Zhu and colleagues reported that they had no disclosures.
SOURCE: Zhu JM et al. JAMA. 2020 Feb 18;323(17):663-5.
Lead author Jane M. Zhu, MD, of Oregon Health & Science University, Portland, and colleagues examined physician group practice acquisitions by private equity firms using the Irving Levin Associates Health Care M&A data set, which includes manually collected and verified transactional information on health care mergers and acquisitions. Investigators linked acquisitions to the SK&A data set, a commercial data set of verified physicians and practice-level characteristics of U.S. office-based practices.
Of about 18,000 unique group medical practices, private equity firms acquired 355 physician practice acquisitions from 2013 to 2016, a trend that rose from 59 practices in 2013 to 136 practices in 2016, Dr. Zhu and colleagues reported on Feb. 18 , 2020, in a research letter published in JAMA.
Acquired practices had a mean of four sites, 16 physicians in each practice, and 6 physicians affiliated with each site, the data found. Overall, 81% of these medical practices reported accepting new patients, 83% accepted Medicare, and 60% accepted Medicaid. The majority of acquired practices were in the South (44%).
Anesthesiology (19%) and multispecialty (19%) were the most commonly represented medical groups in the acquisitions, followed by emergency medicine (12%), family practice (11%), and dermatology (10%). In addition, from 2015 to 2016, the number of acquired cardiology, ophthalmology, radiology, and ob.gyn. practices increased. Within acquired practices, anesthesiologists represented the majority of all physicians, followed by emergency medicine specialists, family physicians, and dermatologists.
Dr. Zhu and colleagues cited a key limitation: Because the data are based on transactions that have been publicly announced, the acquisition of smaller practices might have been underestimated.
Still, the findings demonstrate that private equity acquisitions of physician medical groups are accelerating across multiple specialties, Dr. Zhu said in an interview.
“From our data, acquired medical groups seem to have relatively large footprints with multiple office sites and multiple physicians, which mirrors a typical investment strategy for these firms,” she said.
Dr. Zhu said that more research is needed about how these purchases affect practice patterns, delivery of care, and clinician behavior. Private equity firms expect greater than 20% annual returns, and such financial incentives may conflict with the need for longer-term investments in practice stability, physician recruitment, quality, and safety, according to the study.
“In theory, there may be greater efficiencies introduced from private equity investment – for example, through administrative and billing efficiencies, reorganizing practice structures, or strengthening technology supports,” Dr. Zhu said. “But because of private equity firms’ emphasis on return on investment, there may be unintended consequences of these purchases on practice stability and patient care. We don’t yet know what these effects will be, and we need robust, longitudinal data to investigate this question.”
Dr. Zhu and colleagues reported that they had no disclosures.
SOURCE: Zhu JM et al. JAMA. 2020 Feb 18;323(17):663-5.
FROM JAMA
Gene therapy effective in hemophilia B patients with neutralizing antibodies
The gene therapy etranacogene dezaparvovec (AMT-061) continues to demonstrate safety and efficacy in patients with hemophilia B, according to a 1-year update of a phase 2b trial.
All three patients in this trial experienced sustained increases in factor IX (FIX) activity and were able to stop prophylaxis without suffering any bleeds. Adverse events related to treatment were mild and transient.
These favorable results are particularly noteworthy because all three patients had anti-AAV5 neutralizing antibodies at baseline, according to Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. He noted that studies of etranacogene dezaparvovec and its predecessor, AMT-060, are the only studies that have not excluded hemophilia patients based on preexisting immunity.
Dr. Pipe presented the latest phase 2b results with etranacogene dezaparvovec at the annual congress of the European Association for Haemophilia and Allied Disorders.
Etranacogene dezaparvovec uses an AAV5 serotype with a transgene expression cassette that codes for the hyperactive Padua FIX variant, Dr. Pipe explained. Etranacogene dezaparvovec has a structure that is nearly identical to that of AMT-060, except for two nucleotide substitutions in the coding sequence for FIX.
AMT-060 enabled stable expression of FIX that has persisted for up to 4 years without any late-emergent safety signals (Blood 2019. 134 Supplement 1: 2059). Dr. Pipe said the “enhanced version” of AMT-060, etranacogene dezaparvovec, has produced even higher levels of FIX activity in the phase 2b study (NCT03489291).
The ongoing study enrolled three men with moderate to severe FIX deficiency at baseline. The patients were 43, 50, and 47 years of age, respectively. Two patients are HIV positive, and all had hepatitis C that resolved.
All three patients were receiving FIX prophylaxis and on-demand treatment at baseline. In the year prior to screening, patients had one, three, and five bleeds, respectively. All three patients had anti-AAV5 neutralizing antibodies.
Efficacy
Patients received a single dose of etranacogene dezaparvovec at 2 x 1013 genome copies/kg. All three patients achieved the primary endpoint, which was FIX activity of at least 5% at 6 weeks.
At 52 weeks, the mean FIX activity was 41%. Patients 1 and 3 have maintained FIX activity of 40% or greater, which is in the nonhemophilic range. Patient 2 has maintained FIX activity in the mild range. At 52 weeks, FIX activity levels were 50.2%, 40.8%, and 31.3%, respectively.
All patients remain free of prophylaxis and bleeds. Patient 3 received a single FIX infusion as a precaution in the perioperative setting. There was no evidence of a bleed in this patient.
Safety
Etranacogene dezaparvovec was generally well tolerated, Dr. Pipe said. One patient had two adverse events that were possibly related to etranacogene dezaparvovec. Both events – transient, self-limiting headache and slightly elevated C-reactive protein – resolved without intervention.
There was one serious adverse event, but it was considered unrelated to treatment. Patient 3 required hip surgery for preexisting avascular necrosis.
Dr. Pipe said there was no evidence of transaminitis. There were modest, transient elevations in liver enzymes, but this was not enough to trigger protocol-specified immunosuppression.
Specifically, one patient had ALT elevations at weeks 22 and 44, and one patient had AST elevations at weeks 2, 4, and 31. All of these resolved quickly without treatment or an impact on FIX activity, Dr. Pipe noted.
Next steps
This study is ongoing, and patients will be followed for 5 years. Dr. Pipe said the main focus of follow-up will be to determine if patients maintain durable expression of FIX.
A phase 3 trial of etranacogene dezaparvovec is ongoing as well. The trial, HOPE-B (NCT03569891), is fully enrolled, and dosing is planned for 55 patients.
“We’re looking forward to data analysis later this year,” Dr. Pipe said. “This will be the only phase 3 study, and really the only platform so far, that is not planning to exclude patients based on preexisting immunity.”
If all goes well in the phase 3 study, etranacogene dezaparvovec could be approved by the Food and Drug Administration very soon, Dr. Pipe added.
UniQure, the company developing etranacogene dezaparvovec, is planning to submit the biologics license application to the FDA next year. Etranacogene dezaparvovec was granted breakthrough designation from the FDA and is therefore eligible for priority review, so the gene therapy could be approved as early as 2021.
The phase 2b trial of etranacogene dezaparvovec is sponsored by uniQure. Dr. Pipe disclosed relationships with uniQure and other companies.
SOURCE: Pipe SW et al. EAHAD 2020, Abstract OR10.
The gene therapy etranacogene dezaparvovec (AMT-061) continues to demonstrate safety and efficacy in patients with hemophilia B, according to a 1-year update of a phase 2b trial.
All three patients in this trial experienced sustained increases in factor IX (FIX) activity and were able to stop prophylaxis without suffering any bleeds. Adverse events related to treatment were mild and transient.
These favorable results are particularly noteworthy because all three patients had anti-AAV5 neutralizing antibodies at baseline, according to Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. He noted that studies of etranacogene dezaparvovec and its predecessor, AMT-060, are the only studies that have not excluded hemophilia patients based on preexisting immunity.
Dr. Pipe presented the latest phase 2b results with etranacogene dezaparvovec at the annual congress of the European Association for Haemophilia and Allied Disorders.
Etranacogene dezaparvovec uses an AAV5 serotype with a transgene expression cassette that codes for the hyperactive Padua FIX variant, Dr. Pipe explained. Etranacogene dezaparvovec has a structure that is nearly identical to that of AMT-060, except for two nucleotide substitutions in the coding sequence for FIX.
AMT-060 enabled stable expression of FIX that has persisted for up to 4 years without any late-emergent safety signals (Blood 2019. 134 Supplement 1: 2059). Dr. Pipe said the “enhanced version” of AMT-060, etranacogene dezaparvovec, has produced even higher levels of FIX activity in the phase 2b study (NCT03489291).
The ongoing study enrolled three men with moderate to severe FIX deficiency at baseline. The patients were 43, 50, and 47 years of age, respectively. Two patients are HIV positive, and all had hepatitis C that resolved.
All three patients were receiving FIX prophylaxis and on-demand treatment at baseline. In the year prior to screening, patients had one, three, and five bleeds, respectively. All three patients had anti-AAV5 neutralizing antibodies.
Efficacy
Patients received a single dose of etranacogene dezaparvovec at 2 x 1013 genome copies/kg. All three patients achieved the primary endpoint, which was FIX activity of at least 5% at 6 weeks.
At 52 weeks, the mean FIX activity was 41%. Patients 1 and 3 have maintained FIX activity of 40% or greater, which is in the nonhemophilic range. Patient 2 has maintained FIX activity in the mild range. At 52 weeks, FIX activity levels were 50.2%, 40.8%, and 31.3%, respectively.
All patients remain free of prophylaxis and bleeds. Patient 3 received a single FIX infusion as a precaution in the perioperative setting. There was no evidence of a bleed in this patient.
Safety
Etranacogene dezaparvovec was generally well tolerated, Dr. Pipe said. One patient had two adverse events that were possibly related to etranacogene dezaparvovec. Both events – transient, self-limiting headache and slightly elevated C-reactive protein – resolved without intervention.
There was one serious adverse event, but it was considered unrelated to treatment. Patient 3 required hip surgery for preexisting avascular necrosis.
Dr. Pipe said there was no evidence of transaminitis. There were modest, transient elevations in liver enzymes, but this was not enough to trigger protocol-specified immunosuppression.
Specifically, one patient had ALT elevations at weeks 22 and 44, and one patient had AST elevations at weeks 2, 4, and 31. All of these resolved quickly without treatment or an impact on FIX activity, Dr. Pipe noted.
Next steps
This study is ongoing, and patients will be followed for 5 years. Dr. Pipe said the main focus of follow-up will be to determine if patients maintain durable expression of FIX.
A phase 3 trial of etranacogene dezaparvovec is ongoing as well. The trial, HOPE-B (NCT03569891), is fully enrolled, and dosing is planned for 55 patients.
“We’re looking forward to data analysis later this year,” Dr. Pipe said. “This will be the only phase 3 study, and really the only platform so far, that is not planning to exclude patients based on preexisting immunity.”
If all goes well in the phase 3 study, etranacogene dezaparvovec could be approved by the Food and Drug Administration very soon, Dr. Pipe added.
UniQure, the company developing etranacogene dezaparvovec, is planning to submit the biologics license application to the FDA next year. Etranacogene dezaparvovec was granted breakthrough designation from the FDA and is therefore eligible for priority review, so the gene therapy could be approved as early as 2021.
The phase 2b trial of etranacogene dezaparvovec is sponsored by uniQure. Dr. Pipe disclosed relationships with uniQure and other companies.
SOURCE: Pipe SW et al. EAHAD 2020, Abstract OR10.
The gene therapy etranacogene dezaparvovec (AMT-061) continues to demonstrate safety and efficacy in patients with hemophilia B, according to a 1-year update of a phase 2b trial.
All three patients in this trial experienced sustained increases in factor IX (FIX) activity and were able to stop prophylaxis without suffering any bleeds. Adverse events related to treatment were mild and transient.
These favorable results are particularly noteworthy because all three patients had anti-AAV5 neutralizing antibodies at baseline, according to Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. He noted that studies of etranacogene dezaparvovec and its predecessor, AMT-060, are the only studies that have not excluded hemophilia patients based on preexisting immunity.
Dr. Pipe presented the latest phase 2b results with etranacogene dezaparvovec at the annual congress of the European Association for Haemophilia and Allied Disorders.
Etranacogene dezaparvovec uses an AAV5 serotype with a transgene expression cassette that codes for the hyperactive Padua FIX variant, Dr. Pipe explained. Etranacogene dezaparvovec has a structure that is nearly identical to that of AMT-060, except for two nucleotide substitutions in the coding sequence for FIX.
AMT-060 enabled stable expression of FIX that has persisted for up to 4 years without any late-emergent safety signals (Blood 2019. 134 Supplement 1: 2059). Dr. Pipe said the “enhanced version” of AMT-060, etranacogene dezaparvovec, has produced even higher levels of FIX activity in the phase 2b study (NCT03489291).
The ongoing study enrolled three men with moderate to severe FIX deficiency at baseline. The patients were 43, 50, and 47 years of age, respectively. Two patients are HIV positive, and all had hepatitis C that resolved.
All three patients were receiving FIX prophylaxis and on-demand treatment at baseline. In the year prior to screening, patients had one, three, and five bleeds, respectively. All three patients had anti-AAV5 neutralizing antibodies.
Efficacy
Patients received a single dose of etranacogene dezaparvovec at 2 x 1013 genome copies/kg. All three patients achieved the primary endpoint, which was FIX activity of at least 5% at 6 weeks.
At 52 weeks, the mean FIX activity was 41%. Patients 1 and 3 have maintained FIX activity of 40% or greater, which is in the nonhemophilic range. Patient 2 has maintained FIX activity in the mild range. At 52 weeks, FIX activity levels were 50.2%, 40.8%, and 31.3%, respectively.
All patients remain free of prophylaxis and bleeds. Patient 3 received a single FIX infusion as a precaution in the perioperative setting. There was no evidence of a bleed in this patient.
Safety
Etranacogene dezaparvovec was generally well tolerated, Dr. Pipe said. One patient had two adverse events that were possibly related to etranacogene dezaparvovec. Both events – transient, self-limiting headache and slightly elevated C-reactive protein – resolved without intervention.
There was one serious adverse event, but it was considered unrelated to treatment. Patient 3 required hip surgery for preexisting avascular necrosis.
Dr. Pipe said there was no evidence of transaminitis. There were modest, transient elevations in liver enzymes, but this was not enough to trigger protocol-specified immunosuppression.
Specifically, one patient had ALT elevations at weeks 22 and 44, and one patient had AST elevations at weeks 2, 4, and 31. All of these resolved quickly without treatment or an impact on FIX activity, Dr. Pipe noted.
Next steps
This study is ongoing, and patients will be followed for 5 years. Dr. Pipe said the main focus of follow-up will be to determine if patients maintain durable expression of FIX.
A phase 3 trial of etranacogene dezaparvovec is ongoing as well. The trial, HOPE-B (NCT03569891), is fully enrolled, and dosing is planned for 55 patients.
“We’re looking forward to data analysis later this year,” Dr. Pipe said. “This will be the only phase 3 study, and really the only platform so far, that is not planning to exclude patients based on preexisting immunity.”
If all goes well in the phase 3 study, etranacogene dezaparvovec could be approved by the Food and Drug Administration very soon, Dr. Pipe added.
UniQure, the company developing etranacogene dezaparvovec, is planning to submit the biologics license application to the FDA next year. Etranacogene dezaparvovec was granted breakthrough designation from the FDA and is therefore eligible for priority review, so the gene therapy could be approved as early as 2021.
The phase 2b trial of etranacogene dezaparvovec is sponsored by uniQure. Dr. Pipe disclosed relationships with uniQure and other companies.
SOURCE: Pipe SW et al. EAHAD 2020, Abstract OR10.
REPORTING FROM EAHAD 2020
Make the Diagnosis - March 2020
The patient’s biopsy showed sparse and grouped and slightly enlarged atypical stained mononuclear cells in mostly perifollicular areas with focal epidermotropism. CD30 staining was positive. She responded to potent topical steroids.
The etiology of LyP is unknown. It is unclear whether the proliferation of T-cells is a benign and chronic disorder, or an indolent T-cell malignancy.
In addition, 10% of LyP cases are associated with anaplastic large-cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin lymphoma. Borderline cases are those that overlap LyP and lymphoma.
Patients typically present with crops of asymptomatic erythematous to brown papules that may become pustular, vesicular, or necrotic. Lesions tend to resolve within 2-8 weeks with or without scarring. The trunk and extremities are commonly affected. The condition tends to be chronic over months to years. The waxing and waning course is characteristic of LyP. Constitutional symptoms are generally absent in cases not associated with systemic disease.
Histopathologic examination reveals a dense wedge-shaped dermal infiltrate of atypical lymphocytes along with numerous eosinophils and neutrophils. Epidermotropism may be present and lymphocytes stain positive for CD30+. Vessels in the dermis may exhibit fibrin deposition and red blood cell extravasation. Histologically, LyP can be classified as Type A to E. These subtypes are determined by the size and type of atypical cells, location and amount of infiltrate, and staining of CD30 and CD8.
The differential diagnosis of LyP includes pityriasis lichenoides, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, folliculitis, arthropod assault, Langerhans cell histiocytosis, and leukemia cutis. Treatment is symptomatic. Mild forms of LyP can many times be managed with superpotent topical corticosteroids. Bexarotene gel has been used for early lesions. For more widespread or persistent disease, intralesional corticosteroids, phototherapy (UVB or PUVA), tetracycline antibiotics, and methotrexate have been reported to be effective. Refractory cases may respond to interferon alpha or oral bexarotene. Routine evaluations are recommended as patients may be at increased risk for the development of lymphoma.
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
The patient’s biopsy showed sparse and grouped and slightly enlarged atypical stained mononuclear cells in mostly perifollicular areas with focal epidermotropism. CD30 staining was positive. She responded to potent topical steroids.
The etiology of LyP is unknown. It is unclear whether the proliferation of T-cells is a benign and chronic disorder, or an indolent T-cell malignancy.
In addition, 10% of LyP cases are associated with anaplastic large-cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin lymphoma. Borderline cases are those that overlap LyP and lymphoma.
Patients typically present with crops of asymptomatic erythematous to brown papules that may become pustular, vesicular, or necrotic. Lesions tend to resolve within 2-8 weeks with or without scarring. The trunk and extremities are commonly affected. The condition tends to be chronic over months to years. The waxing and waning course is characteristic of LyP. Constitutional symptoms are generally absent in cases not associated with systemic disease.
Histopathologic examination reveals a dense wedge-shaped dermal infiltrate of atypical lymphocytes along with numerous eosinophils and neutrophils. Epidermotropism may be present and lymphocytes stain positive for CD30+. Vessels in the dermis may exhibit fibrin deposition and red blood cell extravasation. Histologically, LyP can be classified as Type A to E. These subtypes are determined by the size and type of atypical cells, location and amount of infiltrate, and staining of CD30 and CD8.
The differential diagnosis of LyP includes pityriasis lichenoides, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, folliculitis, arthropod assault, Langerhans cell histiocytosis, and leukemia cutis. Treatment is symptomatic. Mild forms of LyP can many times be managed with superpotent topical corticosteroids. Bexarotene gel has been used for early lesions. For more widespread or persistent disease, intralesional corticosteroids, phototherapy (UVB or PUVA), tetracycline antibiotics, and methotrexate have been reported to be effective. Refractory cases may respond to interferon alpha or oral bexarotene. Routine evaluations are recommended as patients may be at increased risk for the development of lymphoma.
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
The patient’s biopsy showed sparse and grouped and slightly enlarged atypical stained mononuclear cells in mostly perifollicular areas with focal epidermotropism. CD30 staining was positive. She responded to potent topical steroids.
The etiology of LyP is unknown. It is unclear whether the proliferation of T-cells is a benign and chronic disorder, or an indolent T-cell malignancy.
In addition, 10% of LyP cases are associated with anaplastic large-cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin lymphoma. Borderline cases are those that overlap LyP and lymphoma.
Patients typically present with crops of asymptomatic erythematous to brown papules that may become pustular, vesicular, or necrotic. Lesions tend to resolve within 2-8 weeks with or without scarring. The trunk and extremities are commonly affected. The condition tends to be chronic over months to years. The waxing and waning course is characteristic of LyP. Constitutional symptoms are generally absent in cases not associated with systemic disease.
Histopathologic examination reveals a dense wedge-shaped dermal infiltrate of atypical lymphocytes along with numerous eosinophils and neutrophils. Epidermotropism may be present and lymphocytes stain positive for CD30+. Vessels in the dermis may exhibit fibrin deposition and red blood cell extravasation. Histologically, LyP can be classified as Type A to E. These subtypes are determined by the size and type of atypical cells, location and amount of infiltrate, and staining of CD30 and CD8.
The differential diagnosis of LyP includes pityriasis lichenoides, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, folliculitis, arthropod assault, Langerhans cell histiocytosis, and leukemia cutis. Treatment is symptomatic. Mild forms of LyP can many times be managed with superpotent topical corticosteroids. Bexarotene gel has been used for early lesions. For more widespread or persistent disease, intralesional corticosteroids, phototherapy (UVB or PUVA), tetracycline antibiotics, and methotrexate have been reported to be effective. Refractory cases may respond to interferon alpha or oral bexarotene. Routine evaluations are recommended as patients may be at increased risk for the development of lymphoma.
This case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
Trump seeks to cut NIH, CDC budgets, some Medicare spending
The Trump administration on Feb. 10 argued for cutting spending for a federal agency at the forefront of the efforts to combat the coronavirus, while also seeking to slow spending in certain parts of the Medicare and Medicaid programs.
President Donald Trump presented his fiscal 2021 request to Congress for refilling the coffers of federal agencies. In any administration, an annual budget serves only as a political blueprint, as the White House document itself makes no changes in federal spending.
In Mr. Trump’s case, several of his requests for agencies within the Department of Health & Human Services run counter to recent budget trends. Republicans and Democrats in Congress have worked together in recent years to increase budgets for major federal health agencies.
But Mr. Trump asked Congress to cut annual budget authority for the National Institute of Allergy and Infectious Diseases by $430 million to $5.446 billion for fiscal 2021. In contrast, Congress has raised the annual budget for NIAID, a key agency in combating the coronavirus, from $5.545 billion in fiscal 2019 to $5.876 billion in fiscal 2020, which began in October, according to an HHS summary of Mr. Trump’s request.
For the Centers for Disease Control and Prevention, which is central to the battle against the coronavirus, Mr. Trump proposed a drop in discretionary funding to $5.627 billion. In contrast, Congress raised the CDC budget from $6.544 billion in fiscal 2019 to $6.917 in fiscal 2020.
Mr. Trump also wants to cut $559 million from the budget of the National Cancer Institute, dropping it to $5.881 billion in fiscal 2021. In contrast, Congress raised NCI’s budget from $6.121 billion in fiscal 2019 to $6.440 billion in fiscal 2020.
Mr. Trump requested a $2.6 billion reduction in the National Institutes of Health’s total discretionary budget, seeking to drop it to $37.70 billion. In contrast, Congress raised NIH’s budget from $37.887 in fiscal 2019 to $40.304 billion in fiscal 2020.
Mr. Trump’s budget proposal also includes an estimate of $152 billion in savings over a decade for Medicaid through the implementation of what the administration calls “community engagement” requirements.
The Trump administration has been at odds with Democrats for years about whether work requirements should be attached to Medicaid. “Well-designed community engagement incentives have great potential to improve health and well-being while empowering beneficiaries to rise out of poverty,” HHS said in a budget document.
Yet researchers last year reported that Arkansas’ attempt to attach work requirements to Medicaid caused almost 17,000 adults to lose this health care coverage within the first 6 months, and there was no significant difference in employment.
The researchers say this loss of coverage was partly a result of bureaucratic obstacles and confusion about the new rules. In June 2018, Arkansas became the first state to implement work requirements for Medicaid, Benjamin D. Sommers, MD, PhD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues wrote in the New England Journal of Medicine (2019 Sep 12;381[11]:1073-82).
Budget ‘would thwart’ progress
A few medical groups on Monday quickly criticized Mr. Trump’s proposals.
“In a time where our nation continues to face significant public health challenges — including 2019 novel coronavirus, climate change, gun violence, and costly chronic diseases such as heart disease and cancer – the administration should be investing more resources in better health, not cutting federal health budgets,” said Georges C. Benjamin, MD, executive director of the American Public Health Association, in a statement.
David J. Skorton, MD, chief executive and president of the Association of American Medical Colleges (AAMC) also urged increased investment in fighting disease.
“We must continue the bipartisan budget trajectory set forth by Congress over the last several years, not reverse course,” Dr. Skorton said in a statement.
Mr. Trump’s proposed cuts in medical research “would thwart scientific progress on strategies to prevent, diagnose, treat, and cure medical conditions that affect countless patients nationwide,” he said.
In total, the new 2021 appropriations for HHS would fall by $9.46 billion to $85.667 billion under Mr. Trump’s proposal. Appropriations, also called discretionary budget authority, represents the operating budgets for federal agencies. These are decided through annual spending bills.
Congress has separate sets of laws for handling payments the federal government makes through Medicare and Medicaid. These are known as mandatory spending.
‘Untenable cuts’
AAMC’s Dr. Skorton also objected to what he termed Mr. Trump’s bid “to reduce and consolidate Medicare, Medicaid, and children’s hospital graduate medical education into a single grant program.”
This would force teaching hospitals to absorb $52 billion in “untenable cuts,” he said.
“The proposal ignores the intent of the Medicare GME program, which is to ensure an adequate physician workforce to care for Medicare beneficiaries and support the critical patient care missions of America’s teaching hospitals,” Dr. Skorton said.
The budget also seeks cuts to Medicaid, which come in addition to the administration’s “recent proposals to scale back Medicaid coverage,” Dr. Skorton said.
“More than 26% of all Medicaid hospitalizations occur at AAMC-member teaching hospitals, even though these institutions represent only 5% of all hospitals,” Dr. Skorton said. “Each of the administration’s proposals on their own would be devastating for patients – and combined, they would be disastrous.”
Rick Pollack, the chief executive and president of the American Hospital Association, described Mr. Trump’s fiscal 2021 proposal as another bid to undermine medical care in the United States.
“Every year, we adapt to a constantly changing environment, but every year, the administration aims to gut our nation’s health care infrastructure,” Mr. Pollack said in a statement.
In it, he noted that about one in five people in America depend on Medicaid, with children accounting for a large proportion of those covered by the state-federal program.
“The budget’s proposal on Medicaid financing and service delivery would cut hundreds of billions of dollars from the Medicaid program annually,” Mr. Pollack said.
He also objected to “hundreds of billions of proposed reductions to Medicare” endorsed by Mr. Trump.
Medical malpractice overhaul
The Trump administration also offered many suggestions for changing federal laws to reduce health care spending. Among these was a proposed overhaul of the approach to medical malpractice cases.
The president’s budget proposal estimates $40 billion in savings over a decade from steps to limit medical liability, according to a report from the Office of Management and Budget (OMB).
“The current medical liability system does not work for patients or providers, nor does it promote high-quality, evidence-based care,” OMB said. “Providers practice with a threat of potentially frivolous lawsuits, and injured patients often do not receive just compensation for their injuries.”
Mr. Trump’s fiscal 2021 budget calls for a cap on noneconomic damage awards of $250,000, which would increase with inflation over time, and a 3-year statute of limitations. Under this plan, courts could also modify attorney’s fee arrangements. HHS could provide guidance to states on how to create expert panels and administrative health care tribunals to review medical liability.
These steps would lead to lower health care spending, with clinicians dropping “defensive medicine practices,” OMB said. That would benefit the Medicare and Medicaid programs as well as lowering costs of health insurance in general.
Mr. Trump’s fiscal 2021 budget also includes a series of proposals for Medicare that it estimates would, in aggregate, save $755.5 billion over a decade.
Site-neutral policy
A large chunk of the estimated Medicare savings in Mr. Trump’s fiscal 2021 health budget would come from lowering payments to hospitals for services provided in their outpatient and physician offices.
In the fiscal 2021 proposal, HHS noted that “Medicare generally pays on-campus hospital outpatient departments substantially more than physician offices for the same services.”
Mr. Trump’s budget proposal seeks a more expansive shift to what’s called a “site-neutral” payment for services delivered in hospital outpatient programs or physician offices. This would bring these payments more in line with those made to independent physician practices.
“This proposal would eliminate the often significant disparity between what Medicare pays in these different settings for the same services,” HHS said in the budget summary.
HHS estimated this change in policy would generate $117.2 billion in savings over a decade. Combined with saving from medical malpractice reforms, the Trump administration estimates these two moves combined could save about $164 billion over a decade.
The site-neutral policy has been a legal battleground, with hospital and physician groups winning a round last year.
Another Medicare proposal included in Mr. Trump’s fiscal 2021 budget homes in on this issue for cases where a hospital owns a physician office. Medicare now pays most off-campus hospital outpatient departments higher rates than the program’s physician fee schedule dictates for the same services.
Switching to a site-neutral policy for these hospital-owned physician offices would result in $47.2 billion in savings over a decade, HHS said in the budget document.
This article first appeared on Medscape.com.
The Trump administration on Feb. 10 argued for cutting spending for a federal agency at the forefront of the efforts to combat the coronavirus, while also seeking to slow spending in certain parts of the Medicare and Medicaid programs.
President Donald Trump presented his fiscal 2021 request to Congress for refilling the coffers of federal agencies. In any administration, an annual budget serves only as a political blueprint, as the White House document itself makes no changes in federal spending.
In Mr. Trump’s case, several of his requests for agencies within the Department of Health & Human Services run counter to recent budget trends. Republicans and Democrats in Congress have worked together in recent years to increase budgets for major federal health agencies.
But Mr. Trump asked Congress to cut annual budget authority for the National Institute of Allergy and Infectious Diseases by $430 million to $5.446 billion for fiscal 2021. In contrast, Congress has raised the annual budget for NIAID, a key agency in combating the coronavirus, from $5.545 billion in fiscal 2019 to $5.876 billion in fiscal 2020, which began in October, according to an HHS summary of Mr. Trump’s request.
For the Centers for Disease Control and Prevention, which is central to the battle against the coronavirus, Mr. Trump proposed a drop in discretionary funding to $5.627 billion. In contrast, Congress raised the CDC budget from $6.544 billion in fiscal 2019 to $6.917 in fiscal 2020.
Mr. Trump also wants to cut $559 million from the budget of the National Cancer Institute, dropping it to $5.881 billion in fiscal 2021. In contrast, Congress raised NCI’s budget from $6.121 billion in fiscal 2019 to $6.440 billion in fiscal 2020.
Mr. Trump requested a $2.6 billion reduction in the National Institutes of Health’s total discretionary budget, seeking to drop it to $37.70 billion. In contrast, Congress raised NIH’s budget from $37.887 in fiscal 2019 to $40.304 billion in fiscal 2020.
Mr. Trump’s budget proposal also includes an estimate of $152 billion in savings over a decade for Medicaid through the implementation of what the administration calls “community engagement” requirements.
The Trump administration has been at odds with Democrats for years about whether work requirements should be attached to Medicaid. “Well-designed community engagement incentives have great potential to improve health and well-being while empowering beneficiaries to rise out of poverty,” HHS said in a budget document.
Yet researchers last year reported that Arkansas’ attempt to attach work requirements to Medicaid caused almost 17,000 adults to lose this health care coverage within the first 6 months, and there was no significant difference in employment.
The researchers say this loss of coverage was partly a result of bureaucratic obstacles and confusion about the new rules. In June 2018, Arkansas became the first state to implement work requirements for Medicaid, Benjamin D. Sommers, MD, PhD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues wrote in the New England Journal of Medicine (2019 Sep 12;381[11]:1073-82).
Budget ‘would thwart’ progress
A few medical groups on Monday quickly criticized Mr. Trump’s proposals.
“In a time where our nation continues to face significant public health challenges — including 2019 novel coronavirus, climate change, gun violence, and costly chronic diseases such as heart disease and cancer – the administration should be investing more resources in better health, not cutting federal health budgets,” said Georges C. Benjamin, MD, executive director of the American Public Health Association, in a statement.
David J. Skorton, MD, chief executive and president of the Association of American Medical Colleges (AAMC) also urged increased investment in fighting disease.
“We must continue the bipartisan budget trajectory set forth by Congress over the last several years, not reverse course,” Dr. Skorton said in a statement.
Mr. Trump’s proposed cuts in medical research “would thwart scientific progress on strategies to prevent, diagnose, treat, and cure medical conditions that affect countless patients nationwide,” he said.
In total, the new 2021 appropriations for HHS would fall by $9.46 billion to $85.667 billion under Mr. Trump’s proposal. Appropriations, also called discretionary budget authority, represents the operating budgets for federal agencies. These are decided through annual spending bills.
Congress has separate sets of laws for handling payments the federal government makes through Medicare and Medicaid. These are known as mandatory spending.
‘Untenable cuts’
AAMC’s Dr. Skorton also objected to what he termed Mr. Trump’s bid “to reduce and consolidate Medicare, Medicaid, and children’s hospital graduate medical education into a single grant program.”
This would force teaching hospitals to absorb $52 billion in “untenable cuts,” he said.
“The proposal ignores the intent of the Medicare GME program, which is to ensure an adequate physician workforce to care for Medicare beneficiaries and support the critical patient care missions of America’s teaching hospitals,” Dr. Skorton said.
The budget also seeks cuts to Medicaid, which come in addition to the administration’s “recent proposals to scale back Medicaid coverage,” Dr. Skorton said.
“More than 26% of all Medicaid hospitalizations occur at AAMC-member teaching hospitals, even though these institutions represent only 5% of all hospitals,” Dr. Skorton said. “Each of the administration’s proposals on their own would be devastating for patients – and combined, they would be disastrous.”
Rick Pollack, the chief executive and president of the American Hospital Association, described Mr. Trump’s fiscal 2021 proposal as another bid to undermine medical care in the United States.
“Every year, we adapt to a constantly changing environment, but every year, the administration aims to gut our nation’s health care infrastructure,” Mr. Pollack said in a statement.
In it, he noted that about one in five people in America depend on Medicaid, with children accounting for a large proportion of those covered by the state-federal program.
“The budget’s proposal on Medicaid financing and service delivery would cut hundreds of billions of dollars from the Medicaid program annually,” Mr. Pollack said.
He also objected to “hundreds of billions of proposed reductions to Medicare” endorsed by Mr. Trump.
Medical malpractice overhaul
The Trump administration also offered many suggestions for changing federal laws to reduce health care spending. Among these was a proposed overhaul of the approach to medical malpractice cases.
The president’s budget proposal estimates $40 billion in savings over a decade from steps to limit medical liability, according to a report from the Office of Management and Budget (OMB).
“The current medical liability system does not work for patients or providers, nor does it promote high-quality, evidence-based care,” OMB said. “Providers practice with a threat of potentially frivolous lawsuits, and injured patients often do not receive just compensation for their injuries.”
Mr. Trump’s fiscal 2021 budget calls for a cap on noneconomic damage awards of $250,000, which would increase with inflation over time, and a 3-year statute of limitations. Under this plan, courts could also modify attorney’s fee arrangements. HHS could provide guidance to states on how to create expert panels and administrative health care tribunals to review medical liability.
These steps would lead to lower health care spending, with clinicians dropping “defensive medicine practices,” OMB said. That would benefit the Medicare and Medicaid programs as well as lowering costs of health insurance in general.
Mr. Trump’s fiscal 2021 budget also includes a series of proposals for Medicare that it estimates would, in aggregate, save $755.5 billion over a decade.
Site-neutral policy
A large chunk of the estimated Medicare savings in Mr. Trump’s fiscal 2021 health budget would come from lowering payments to hospitals for services provided in their outpatient and physician offices.
In the fiscal 2021 proposal, HHS noted that “Medicare generally pays on-campus hospital outpatient departments substantially more than physician offices for the same services.”
Mr. Trump’s budget proposal seeks a more expansive shift to what’s called a “site-neutral” payment for services delivered in hospital outpatient programs or physician offices. This would bring these payments more in line with those made to independent physician practices.
“This proposal would eliminate the often significant disparity between what Medicare pays in these different settings for the same services,” HHS said in the budget summary.
HHS estimated this change in policy would generate $117.2 billion in savings over a decade. Combined with saving from medical malpractice reforms, the Trump administration estimates these two moves combined could save about $164 billion over a decade.
The site-neutral policy has been a legal battleground, with hospital and physician groups winning a round last year.
Another Medicare proposal included in Mr. Trump’s fiscal 2021 budget homes in on this issue for cases where a hospital owns a physician office. Medicare now pays most off-campus hospital outpatient departments higher rates than the program’s physician fee schedule dictates for the same services.
Switching to a site-neutral policy for these hospital-owned physician offices would result in $47.2 billion in savings over a decade, HHS said in the budget document.
This article first appeared on Medscape.com.
The Trump administration on Feb. 10 argued for cutting spending for a federal agency at the forefront of the efforts to combat the coronavirus, while also seeking to slow spending in certain parts of the Medicare and Medicaid programs.
President Donald Trump presented his fiscal 2021 request to Congress for refilling the coffers of federal agencies. In any administration, an annual budget serves only as a political blueprint, as the White House document itself makes no changes in federal spending.
In Mr. Trump’s case, several of his requests for agencies within the Department of Health & Human Services run counter to recent budget trends. Republicans and Democrats in Congress have worked together in recent years to increase budgets for major federal health agencies.
But Mr. Trump asked Congress to cut annual budget authority for the National Institute of Allergy and Infectious Diseases by $430 million to $5.446 billion for fiscal 2021. In contrast, Congress has raised the annual budget for NIAID, a key agency in combating the coronavirus, from $5.545 billion in fiscal 2019 to $5.876 billion in fiscal 2020, which began in October, according to an HHS summary of Mr. Trump’s request.
For the Centers for Disease Control and Prevention, which is central to the battle against the coronavirus, Mr. Trump proposed a drop in discretionary funding to $5.627 billion. In contrast, Congress raised the CDC budget from $6.544 billion in fiscal 2019 to $6.917 in fiscal 2020.
Mr. Trump also wants to cut $559 million from the budget of the National Cancer Institute, dropping it to $5.881 billion in fiscal 2021. In contrast, Congress raised NCI’s budget from $6.121 billion in fiscal 2019 to $6.440 billion in fiscal 2020.
Mr. Trump requested a $2.6 billion reduction in the National Institutes of Health’s total discretionary budget, seeking to drop it to $37.70 billion. In contrast, Congress raised NIH’s budget from $37.887 in fiscal 2019 to $40.304 billion in fiscal 2020.
Mr. Trump’s budget proposal also includes an estimate of $152 billion in savings over a decade for Medicaid through the implementation of what the administration calls “community engagement” requirements.
The Trump administration has been at odds with Democrats for years about whether work requirements should be attached to Medicaid. “Well-designed community engagement incentives have great potential to improve health and well-being while empowering beneficiaries to rise out of poverty,” HHS said in a budget document.
Yet researchers last year reported that Arkansas’ attempt to attach work requirements to Medicaid caused almost 17,000 adults to lose this health care coverage within the first 6 months, and there was no significant difference in employment.
The researchers say this loss of coverage was partly a result of bureaucratic obstacles and confusion about the new rules. In June 2018, Arkansas became the first state to implement work requirements for Medicaid, Benjamin D. Sommers, MD, PhD, of the Harvard T.H. Chan School of Public Health, Boston, and colleagues wrote in the New England Journal of Medicine (2019 Sep 12;381[11]:1073-82).
Budget ‘would thwart’ progress
A few medical groups on Monday quickly criticized Mr. Trump’s proposals.
“In a time where our nation continues to face significant public health challenges — including 2019 novel coronavirus, climate change, gun violence, and costly chronic diseases such as heart disease and cancer – the administration should be investing more resources in better health, not cutting federal health budgets,” said Georges C. Benjamin, MD, executive director of the American Public Health Association, in a statement.
David J. Skorton, MD, chief executive and president of the Association of American Medical Colleges (AAMC) also urged increased investment in fighting disease.
“We must continue the bipartisan budget trajectory set forth by Congress over the last several years, not reverse course,” Dr. Skorton said in a statement.
Mr. Trump’s proposed cuts in medical research “would thwart scientific progress on strategies to prevent, diagnose, treat, and cure medical conditions that affect countless patients nationwide,” he said.
In total, the new 2021 appropriations for HHS would fall by $9.46 billion to $85.667 billion under Mr. Trump’s proposal. Appropriations, also called discretionary budget authority, represents the operating budgets for federal agencies. These are decided through annual spending bills.
Congress has separate sets of laws for handling payments the federal government makes through Medicare and Medicaid. These are known as mandatory spending.
‘Untenable cuts’
AAMC’s Dr. Skorton also objected to what he termed Mr. Trump’s bid “to reduce and consolidate Medicare, Medicaid, and children’s hospital graduate medical education into a single grant program.”
This would force teaching hospitals to absorb $52 billion in “untenable cuts,” he said.
“The proposal ignores the intent of the Medicare GME program, which is to ensure an adequate physician workforce to care for Medicare beneficiaries and support the critical patient care missions of America’s teaching hospitals,” Dr. Skorton said.
The budget also seeks cuts to Medicaid, which come in addition to the administration’s “recent proposals to scale back Medicaid coverage,” Dr. Skorton said.
“More than 26% of all Medicaid hospitalizations occur at AAMC-member teaching hospitals, even though these institutions represent only 5% of all hospitals,” Dr. Skorton said. “Each of the administration’s proposals on their own would be devastating for patients – and combined, they would be disastrous.”
Rick Pollack, the chief executive and president of the American Hospital Association, described Mr. Trump’s fiscal 2021 proposal as another bid to undermine medical care in the United States.
“Every year, we adapt to a constantly changing environment, but every year, the administration aims to gut our nation’s health care infrastructure,” Mr. Pollack said in a statement.
In it, he noted that about one in five people in America depend on Medicaid, with children accounting for a large proportion of those covered by the state-federal program.
“The budget’s proposal on Medicaid financing and service delivery would cut hundreds of billions of dollars from the Medicaid program annually,” Mr. Pollack said.
He also objected to “hundreds of billions of proposed reductions to Medicare” endorsed by Mr. Trump.
Medical malpractice overhaul
The Trump administration also offered many suggestions for changing federal laws to reduce health care spending. Among these was a proposed overhaul of the approach to medical malpractice cases.
The president’s budget proposal estimates $40 billion in savings over a decade from steps to limit medical liability, according to a report from the Office of Management and Budget (OMB).
“The current medical liability system does not work for patients or providers, nor does it promote high-quality, evidence-based care,” OMB said. “Providers practice with a threat of potentially frivolous lawsuits, and injured patients often do not receive just compensation for their injuries.”
Mr. Trump’s fiscal 2021 budget calls for a cap on noneconomic damage awards of $250,000, which would increase with inflation over time, and a 3-year statute of limitations. Under this plan, courts could also modify attorney’s fee arrangements. HHS could provide guidance to states on how to create expert panels and administrative health care tribunals to review medical liability.
These steps would lead to lower health care spending, with clinicians dropping “defensive medicine practices,” OMB said. That would benefit the Medicare and Medicaid programs as well as lowering costs of health insurance in general.
Mr. Trump’s fiscal 2021 budget also includes a series of proposals for Medicare that it estimates would, in aggregate, save $755.5 billion over a decade.
Site-neutral policy
A large chunk of the estimated Medicare savings in Mr. Trump’s fiscal 2021 health budget would come from lowering payments to hospitals for services provided in their outpatient and physician offices.
In the fiscal 2021 proposal, HHS noted that “Medicare generally pays on-campus hospital outpatient departments substantially more than physician offices for the same services.”
Mr. Trump’s budget proposal seeks a more expansive shift to what’s called a “site-neutral” payment for services delivered in hospital outpatient programs or physician offices. This would bring these payments more in line with those made to independent physician practices.
“This proposal would eliminate the often significant disparity between what Medicare pays in these different settings for the same services,” HHS said in the budget summary.
HHS estimated this change in policy would generate $117.2 billion in savings over a decade. Combined with saving from medical malpractice reforms, the Trump administration estimates these two moves combined could save about $164 billion over a decade.
The site-neutral policy has been a legal battleground, with hospital and physician groups winning a round last year.
Another Medicare proposal included in Mr. Trump’s fiscal 2021 budget homes in on this issue for cases where a hospital owns a physician office. Medicare now pays most off-campus hospital outpatient departments higher rates than the program’s physician fee schedule dictates for the same services.
Switching to a site-neutral policy for these hospital-owned physician offices would result in $47.2 billion in savings over a decade, HHS said in the budget document.
This article first appeared on Medscape.com.
Glaring gap in CV event reporting in pivotal cancer trials
Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.
Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).
Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).
“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.
The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.
“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
Lower Rate of Reported Events
The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.
Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.
To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.
Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).
There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
No malicious intent
“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”
“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”
Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.
“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”
Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.
The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.
“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.
“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
One size does not fit all
Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.
“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”
His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.
The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.
Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.
“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”
Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.
In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.
“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”
In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.
“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.
The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.
This article first appeared on Medscape.com.
Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.
Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).
Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).
“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.
The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.
“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
Lower Rate of Reported Events
The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.
Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.
To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.
Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).
There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
No malicious intent
“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”
“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”
Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.
“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”
Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.
The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.
“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.
“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
One size does not fit all
Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.
“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”
His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.
The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.
Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.
“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”
Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.
In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.
“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”
In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.
“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.
The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.
This article first appeared on Medscape.com.
Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.
Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).
Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).
“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.
The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.
“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
Lower Rate of Reported Events
The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.
Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.
To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.
Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).
There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
No malicious intent
“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”
“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”
Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.
“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”
Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.
The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.
“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.
“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
One size does not fit all
Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.
“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”
His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.
The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.
Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.
“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”
Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.
In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.
“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”
In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.
“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.
The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.
This article first appeared on Medscape.com.
Phase 2 data: Inotuzumab, approved in adults with B-ALL, shows promise in kids, too
ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.
Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.
Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.
Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.
“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.
Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.
Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.
“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”
All patients received one cycle of InO at a dose of 1.8mg/m2, with .8mg/m2 given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.
Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m2 on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.
After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.
Seven patients received three or more cycles.
“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”
Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.
“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.
Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.
Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.
“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.
Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.
“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”
The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.
Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.
Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”
COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.
SOURCE: O’Brien M et al. ASH 2019, Abstract 741.
ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.
Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.
Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.
Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.
“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.
Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.
Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.
“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”
All patients received one cycle of InO at a dose of 1.8mg/m2, with .8mg/m2 given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.
Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m2 on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.
After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.
Seven patients received three or more cycles.
“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”
Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.
“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.
Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.
Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.
“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.
Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.
“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”
The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.
Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.
Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”
COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.
SOURCE: O’Brien M et al. ASH 2019, Abstract 741.
ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.
Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.
Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.
Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.
“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.
Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.
Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.
“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”
All patients received one cycle of InO at a dose of 1.8mg/m2, with .8mg/m2 given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.
Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m2 on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.
After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.
Seven patients received three or more cycles.
“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”
Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.
“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.
Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.
Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.
“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.
Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.
“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”
The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.
Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.
Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”
COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.
SOURCE: O’Brien M et al. ASH 2019, Abstract 741.
REPORTING FROM ASH 2019
FDA: Cell phones still look safe
according to a review by the Food and Drug Administration.
The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.
The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.
The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.
The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.
Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”
The full review is available on the FDA website.
according to a review by the Food and Drug Administration.
The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.
The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.
The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.
The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.
Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”
The full review is available on the FDA website.
according to a review by the Food and Drug Administration.
The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.
The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.
The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.
The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.
Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”
The full review is available on the FDA website.
Older NHL survivors show worse cognitive decline
Older long-term survivors of non-Hodgkin lymphoma (NHL) may have worse cognitive outcomes compared with the noncancer aging population, according to a cross-sectional study.
The findings suggest additional research is needed to better understand cognitive decline in older survivors of NHL.
“The aim of the present study was to examine the difference in cognitive status between a group of long-term older survivors of NHL compared with a group of noncancer controls of the same age,” wrote Domenico La Carpia, MD, of Fondazione ANT Italia Onlus, Florence, Italy, and colleagues.
The researchers conducted a multicenter cross-sectional cohort study involving 63 long-term survivors of NHL and 61 age-matched controls. Their report was published in the Journal of Geriatric Oncology.
Eligible survivors and controls were aged 65 years and older. Among both groups, the mean age of study participants was 74 years, and most survivors were women (58.7%).
While cognitive decline was assessed via standardized neuropsychological testing, the team also evaluated polypharmacy, functional status, and level of multimorbidity in the cohort.
Other clinical data, including the time from complete remission, type of treatment received, and histopathological type of tumor, were collected from patient charts and included in the analysis.
After analysis, the researchers found that NHL survivors had a higher mean number of chronic conditions (3.4 vs. 2.3; P = .003), were receiving more medications (3.4 vs. 2.3; P = .03), and had worse functional status compared with controls.
In addition, survivors had impaired executive functioning compared with control subjects (Trail Making Test B-A, 47.9 vs. 32.1; P = .04), but scores on the Mini Mental State Examination (MMSE) did not differ between the groups.
“A small, statistically significant difference was also observed in verbal memory scores between the two groups,” they reported.
The researchers acknowledged that a key limitation was the cross-sectional nature of the study; hence, causality cannot be inferred from the data.
“Comprehensive geriatric assessment for older cancer survivors is advisable to identify those individuals who are at highest risk of developing disability and to implement tailored early interventions,” they concluded.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: La Carpia D et al. J Geriatr Oncol. 2020 Jan 31. doi: 10.1016/j.jgo.2020.01.007.
Older long-term survivors of non-Hodgkin lymphoma (NHL) may have worse cognitive outcomes compared with the noncancer aging population, according to a cross-sectional study.
The findings suggest additional research is needed to better understand cognitive decline in older survivors of NHL.
“The aim of the present study was to examine the difference in cognitive status between a group of long-term older survivors of NHL compared with a group of noncancer controls of the same age,” wrote Domenico La Carpia, MD, of Fondazione ANT Italia Onlus, Florence, Italy, and colleagues.
The researchers conducted a multicenter cross-sectional cohort study involving 63 long-term survivors of NHL and 61 age-matched controls. Their report was published in the Journal of Geriatric Oncology.
Eligible survivors and controls were aged 65 years and older. Among both groups, the mean age of study participants was 74 years, and most survivors were women (58.7%).
While cognitive decline was assessed via standardized neuropsychological testing, the team also evaluated polypharmacy, functional status, and level of multimorbidity in the cohort.
Other clinical data, including the time from complete remission, type of treatment received, and histopathological type of tumor, were collected from patient charts and included in the analysis.
After analysis, the researchers found that NHL survivors had a higher mean number of chronic conditions (3.4 vs. 2.3; P = .003), were receiving more medications (3.4 vs. 2.3; P = .03), and had worse functional status compared with controls.
In addition, survivors had impaired executive functioning compared with control subjects (Trail Making Test B-A, 47.9 vs. 32.1; P = .04), but scores on the Mini Mental State Examination (MMSE) did not differ between the groups.
“A small, statistically significant difference was also observed in verbal memory scores between the two groups,” they reported.
The researchers acknowledged that a key limitation was the cross-sectional nature of the study; hence, causality cannot be inferred from the data.
“Comprehensive geriatric assessment for older cancer survivors is advisable to identify those individuals who are at highest risk of developing disability and to implement tailored early interventions,” they concluded.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: La Carpia D et al. J Geriatr Oncol. 2020 Jan 31. doi: 10.1016/j.jgo.2020.01.007.
Older long-term survivors of non-Hodgkin lymphoma (NHL) may have worse cognitive outcomes compared with the noncancer aging population, according to a cross-sectional study.
The findings suggest additional research is needed to better understand cognitive decline in older survivors of NHL.
“The aim of the present study was to examine the difference in cognitive status between a group of long-term older survivors of NHL compared with a group of noncancer controls of the same age,” wrote Domenico La Carpia, MD, of Fondazione ANT Italia Onlus, Florence, Italy, and colleagues.
The researchers conducted a multicenter cross-sectional cohort study involving 63 long-term survivors of NHL and 61 age-matched controls. Their report was published in the Journal of Geriatric Oncology.
Eligible survivors and controls were aged 65 years and older. Among both groups, the mean age of study participants was 74 years, and most survivors were women (58.7%).
While cognitive decline was assessed via standardized neuropsychological testing, the team also evaluated polypharmacy, functional status, and level of multimorbidity in the cohort.
Other clinical data, including the time from complete remission, type of treatment received, and histopathological type of tumor, were collected from patient charts and included in the analysis.
After analysis, the researchers found that NHL survivors had a higher mean number of chronic conditions (3.4 vs. 2.3; P = .003), were receiving more medications (3.4 vs. 2.3; P = .03), and had worse functional status compared with controls.
In addition, survivors had impaired executive functioning compared with control subjects (Trail Making Test B-A, 47.9 vs. 32.1; P = .04), but scores on the Mini Mental State Examination (MMSE) did not differ between the groups.
“A small, statistically significant difference was also observed in verbal memory scores between the two groups,” they reported.
The researchers acknowledged that a key limitation was the cross-sectional nature of the study; hence, causality cannot be inferred from the data.
“Comprehensive geriatric assessment for older cancer survivors is advisable to identify those individuals who are at highest risk of developing disability and to implement tailored early interventions,” they concluded.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: La Carpia D et al. J Geriatr Oncol. 2020 Jan 31. doi: 10.1016/j.jgo.2020.01.007.
FROM THE JOURNAL OF GERIATRIC ONCOLOGY
Genetic testing helps avoid false hemoglobinopathy diagnoses in newborns
Confirmatory genetic testing may be useful in the diagnosis of hemoglobinopathies for newborns with an abnormal hemoglobin (Hb) pattern, according to a recent study.
The findings suggest further research is needed to evaluate whether genetic testing programs for newborns could have diagnostic value in the clinical setting.
“We studied a consecutive cohort of newborns with an ‘FSA’ pattern (a suspected diagnosis of HbSbeta+) on the initial newborn screening test,” explained Lisa M. Shook of the University of Cincinnati and colleagues. The results were published in the International Journal of Neonatal Screening.
The retrospective study included a total of 1,151 newborns with an abnormal Hb pattern, 31 of which had an FSA pattern. The newborns were screened for hemoglobinopathies from 2015 to 2018. The findings of the initial newborn screening test (a suspected diagnosis of HbSbeta+) were compared with the diagnosis established using both protein-based and genetic confirmatory testing. Protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when beta-thalassemia mutations are involved, according to the authors.
“During this study period, genetic testing was not universally applied in advance; it was used based on clinical suspicion,” the researchers wrote.
Among newborns with an FSA pattern, the mean gestational age was 38.7 weeks. In total, 17 newborns received genetic testing, and 30 had protein-based confirmatory testing.
“In this consecutive cohort of 31 newborns with a suspected diagnosis of HbSbeta+ based on initial newborn screening (an FSA pattern), none actually had HbSbeta+. All had the sickle cell trait (HbAS), instead; that is, we found that an initial FSA pattern was much more likely to indicate a final diagnosis of HbAS than HbSbeta+,” the authors wrote.
This meant that two-thirds of these newborns had a correct diagnosis of HbAS established at 2-4 weeks of age by protein-based confirmatory testing (and confirmed by genetic testing in a subset), but that the remaining one-third still had an incorrect, suspected diagnosis of HbSbeta+. This could lead to unnecessary treatment and testing of infants and incorrect, disease-focused counseling of parents and family members, according to the authors.
Two key limitations of the study were the small sample size and retrospective design.
“Based on this experience in which genetic testing was not universally applied, we now perform simultaneous protein-based and genetic testing as our standard clinical practice,” they concluded.
The study was funded by the National Institutes of Health and the Ohio Department of Health. The authors reported having no conflicts of interest.
SOURCE: Shook LM et al. Int J Neonatal Screen. 2020 Jan 31. doi: 10.3390/ijns6010007
Confirmatory genetic testing may be useful in the diagnosis of hemoglobinopathies for newborns with an abnormal hemoglobin (Hb) pattern, according to a recent study.
The findings suggest further research is needed to evaluate whether genetic testing programs for newborns could have diagnostic value in the clinical setting.
“We studied a consecutive cohort of newborns with an ‘FSA’ pattern (a suspected diagnosis of HbSbeta+) on the initial newborn screening test,” explained Lisa M. Shook of the University of Cincinnati and colleagues. The results were published in the International Journal of Neonatal Screening.
The retrospective study included a total of 1,151 newborns with an abnormal Hb pattern, 31 of which had an FSA pattern. The newborns were screened for hemoglobinopathies from 2015 to 2018. The findings of the initial newborn screening test (a suspected diagnosis of HbSbeta+) were compared with the diagnosis established using both protein-based and genetic confirmatory testing. Protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when beta-thalassemia mutations are involved, according to the authors.
“During this study period, genetic testing was not universally applied in advance; it was used based on clinical suspicion,” the researchers wrote.
Among newborns with an FSA pattern, the mean gestational age was 38.7 weeks. In total, 17 newborns received genetic testing, and 30 had protein-based confirmatory testing.
“In this consecutive cohort of 31 newborns with a suspected diagnosis of HbSbeta+ based on initial newborn screening (an FSA pattern), none actually had HbSbeta+. All had the sickle cell trait (HbAS), instead; that is, we found that an initial FSA pattern was much more likely to indicate a final diagnosis of HbAS than HbSbeta+,” the authors wrote.
This meant that two-thirds of these newborns had a correct diagnosis of HbAS established at 2-4 weeks of age by protein-based confirmatory testing (and confirmed by genetic testing in a subset), but that the remaining one-third still had an incorrect, suspected diagnosis of HbSbeta+. This could lead to unnecessary treatment and testing of infants and incorrect, disease-focused counseling of parents and family members, according to the authors.
Two key limitations of the study were the small sample size and retrospective design.
“Based on this experience in which genetic testing was not universally applied, we now perform simultaneous protein-based and genetic testing as our standard clinical practice,” they concluded.
The study was funded by the National Institutes of Health and the Ohio Department of Health. The authors reported having no conflicts of interest.
SOURCE: Shook LM et al. Int J Neonatal Screen. 2020 Jan 31. doi: 10.3390/ijns6010007
Confirmatory genetic testing may be useful in the diagnosis of hemoglobinopathies for newborns with an abnormal hemoglobin (Hb) pattern, according to a recent study.
The findings suggest further research is needed to evaluate whether genetic testing programs for newborns could have diagnostic value in the clinical setting.
“We studied a consecutive cohort of newborns with an ‘FSA’ pattern (a suspected diagnosis of HbSbeta+) on the initial newborn screening test,” explained Lisa M. Shook of the University of Cincinnati and colleagues. The results were published in the International Journal of Neonatal Screening.
The retrospective study included a total of 1,151 newborns with an abnormal Hb pattern, 31 of which had an FSA pattern. The newborns were screened for hemoglobinopathies from 2015 to 2018. The findings of the initial newborn screening test (a suspected diagnosis of HbSbeta+) were compared with the diagnosis established using both protein-based and genetic confirmatory testing. Protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when beta-thalassemia mutations are involved, according to the authors.
“During this study period, genetic testing was not universally applied in advance; it was used based on clinical suspicion,” the researchers wrote.
Among newborns with an FSA pattern, the mean gestational age was 38.7 weeks. In total, 17 newborns received genetic testing, and 30 had protein-based confirmatory testing.
“In this consecutive cohort of 31 newborns with a suspected diagnosis of HbSbeta+ based on initial newborn screening (an FSA pattern), none actually had HbSbeta+. All had the sickle cell trait (HbAS), instead; that is, we found that an initial FSA pattern was much more likely to indicate a final diagnosis of HbAS than HbSbeta+,” the authors wrote.
This meant that two-thirds of these newborns had a correct diagnosis of HbAS established at 2-4 weeks of age by protein-based confirmatory testing (and confirmed by genetic testing in a subset), but that the remaining one-third still had an incorrect, suspected diagnosis of HbSbeta+. This could lead to unnecessary treatment and testing of infants and incorrect, disease-focused counseling of parents and family members, according to the authors.
Two key limitations of the study were the small sample size and retrospective design.
“Based on this experience in which genetic testing was not universally applied, we now perform simultaneous protein-based and genetic testing as our standard clinical practice,” they concluded.
The study was funded by the National Institutes of Health and the Ohio Department of Health. The authors reported having no conflicts of interest.
SOURCE: Shook LM et al. Int J Neonatal Screen. 2020 Jan 31. doi: 10.3390/ijns6010007
FROM THE INTERNATIONAL JOURNAL OF NEONATAL SCREENING