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'New benchmark' set in phase-3 blood cancer study
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
High rates of med student burnout during COVID
NEW ORLEANS –
Researchers surveyed 613 medical students representing all years of a medical program during the last week of the Spring semester of 2021.
Based on the Maslach Burnout Inventory-Student Survey (MBI-SS), more than half (54%) of the students had symptoms of burnout.
Eighty percent of students scored high on emotional exhaustion, 57% scored high on cynicism, and 36% scored low on academic effectiveness.
Compared with male medical students, female medical students were more apt to exhibit signs of burnout (60% vs. 44%), emotional exhaustion (80% vs. 73%), and cynicism (62% vs. 49%).
After adjusting for associated factors, female medical students were significantly more likely to suffer from burnout than male students (odds ratio, 1.90; 95% confidence interval, 1.34-2.70; P < .001).
Smoking was also linked to higher likelihood of burnout among medical students (OR, 2.12; 95% CI, 1.18-3.81; P < .05). The death of a family member from COVID-19 also put medical students at heightened risk for burnout (OR, 1.60; 95% CI, 1.08-2.36; P < .05).
The survey results were presented at the American Psychiatric Association (APA) Annual Meeting.
The findings point to the need to study burnout prevalence in universities and develop strategies to promote the mental health of future physicians, presenter Sofia Jezzini-Martínez, fourth-year medical student, Autonomous University of Nuevo Leon, Monterrey, Mexico, wrote in her conference abstract.
In related research presented at the APA meeting, researchers surveyed second-, third-, and fourth-year medical students from California during the pandemic.
Roughly 80% exhibited symptoms of anxiety and 68% exhibited depressive symptoms, of whom about 18% also reported having thoughts of suicide.
Yet only about half of the medical students exhibiting anxiety or depressive symptoms sought help from a mental health professional, and 20% reported using substances to cope with stress.
“Given that the pandemic is ongoing, we hope to draw attention to mental health needs of medical students and influence medical schools to direct appropriate and timely resources to this group,” presenter Sarthak Angal, MD, psychiatry resident, Kaiser Permanente San Jose Medical Center, California, wrote in his conference abstract.
Managing expectations
Weighing in on medical student burnout, Ihuoma Njoku, MD, department of psychiatry and neurobehavioral sciences, University of Virginia, Charlottesville, noted that, “particularly for women in multiple fields, including medicine, there’s a lot of burden placed on them.”
“Women are pulled in a lot of different directions and have increased demands, which may help explain their higher rate of burnout,” Dr. Njoku commented.
She noted that these surveys were conducted during the COVID-19 pandemic, “a period when students’ education experience was a lot different than what they expected and maybe what they wanted.”
Dr. Njoku noted that the challenges of the pandemic are particularly hard on fourth-year medical students.
“A big part of fourth year is applying to residency, and many were doing virtual interviews for residency. That makes it hard to really get an appreciation of the place you will spend the next three to eight years of your life,” she told this news organization.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
Researchers surveyed 613 medical students representing all years of a medical program during the last week of the Spring semester of 2021.
Based on the Maslach Burnout Inventory-Student Survey (MBI-SS), more than half (54%) of the students had symptoms of burnout.
Eighty percent of students scored high on emotional exhaustion, 57% scored high on cynicism, and 36% scored low on academic effectiveness.
Compared with male medical students, female medical students were more apt to exhibit signs of burnout (60% vs. 44%), emotional exhaustion (80% vs. 73%), and cynicism (62% vs. 49%).
After adjusting for associated factors, female medical students were significantly more likely to suffer from burnout than male students (odds ratio, 1.90; 95% confidence interval, 1.34-2.70; P < .001).
Smoking was also linked to higher likelihood of burnout among medical students (OR, 2.12; 95% CI, 1.18-3.81; P < .05). The death of a family member from COVID-19 also put medical students at heightened risk for burnout (OR, 1.60; 95% CI, 1.08-2.36; P < .05).
The survey results were presented at the American Psychiatric Association (APA) Annual Meeting.
The findings point to the need to study burnout prevalence in universities and develop strategies to promote the mental health of future physicians, presenter Sofia Jezzini-Martínez, fourth-year medical student, Autonomous University of Nuevo Leon, Monterrey, Mexico, wrote in her conference abstract.
In related research presented at the APA meeting, researchers surveyed second-, third-, and fourth-year medical students from California during the pandemic.
Roughly 80% exhibited symptoms of anxiety and 68% exhibited depressive symptoms, of whom about 18% also reported having thoughts of suicide.
Yet only about half of the medical students exhibiting anxiety or depressive symptoms sought help from a mental health professional, and 20% reported using substances to cope with stress.
“Given that the pandemic is ongoing, we hope to draw attention to mental health needs of medical students and influence medical schools to direct appropriate and timely resources to this group,” presenter Sarthak Angal, MD, psychiatry resident, Kaiser Permanente San Jose Medical Center, California, wrote in his conference abstract.
Managing expectations
Weighing in on medical student burnout, Ihuoma Njoku, MD, department of psychiatry and neurobehavioral sciences, University of Virginia, Charlottesville, noted that, “particularly for women in multiple fields, including medicine, there’s a lot of burden placed on them.”
“Women are pulled in a lot of different directions and have increased demands, which may help explain their higher rate of burnout,” Dr. Njoku commented.
She noted that these surveys were conducted during the COVID-19 pandemic, “a period when students’ education experience was a lot different than what they expected and maybe what they wanted.”
Dr. Njoku noted that the challenges of the pandemic are particularly hard on fourth-year medical students.
“A big part of fourth year is applying to residency, and many were doing virtual interviews for residency. That makes it hard to really get an appreciation of the place you will spend the next three to eight years of your life,” she told this news organization.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
Researchers surveyed 613 medical students representing all years of a medical program during the last week of the Spring semester of 2021.
Based on the Maslach Burnout Inventory-Student Survey (MBI-SS), more than half (54%) of the students had symptoms of burnout.
Eighty percent of students scored high on emotional exhaustion, 57% scored high on cynicism, and 36% scored low on academic effectiveness.
Compared with male medical students, female medical students were more apt to exhibit signs of burnout (60% vs. 44%), emotional exhaustion (80% vs. 73%), and cynicism (62% vs. 49%).
After adjusting for associated factors, female medical students were significantly more likely to suffer from burnout than male students (odds ratio, 1.90; 95% confidence interval, 1.34-2.70; P < .001).
Smoking was also linked to higher likelihood of burnout among medical students (OR, 2.12; 95% CI, 1.18-3.81; P < .05). The death of a family member from COVID-19 also put medical students at heightened risk for burnout (OR, 1.60; 95% CI, 1.08-2.36; P < .05).
The survey results were presented at the American Psychiatric Association (APA) Annual Meeting.
The findings point to the need to study burnout prevalence in universities and develop strategies to promote the mental health of future physicians, presenter Sofia Jezzini-Martínez, fourth-year medical student, Autonomous University of Nuevo Leon, Monterrey, Mexico, wrote in her conference abstract.
In related research presented at the APA meeting, researchers surveyed second-, third-, and fourth-year medical students from California during the pandemic.
Roughly 80% exhibited symptoms of anxiety and 68% exhibited depressive symptoms, of whom about 18% also reported having thoughts of suicide.
Yet only about half of the medical students exhibiting anxiety or depressive symptoms sought help from a mental health professional, and 20% reported using substances to cope with stress.
“Given that the pandemic is ongoing, we hope to draw attention to mental health needs of medical students and influence medical schools to direct appropriate and timely resources to this group,” presenter Sarthak Angal, MD, psychiatry resident, Kaiser Permanente San Jose Medical Center, California, wrote in his conference abstract.
Managing expectations
Weighing in on medical student burnout, Ihuoma Njoku, MD, department of psychiatry and neurobehavioral sciences, University of Virginia, Charlottesville, noted that, “particularly for women in multiple fields, including medicine, there’s a lot of burden placed on them.”
“Women are pulled in a lot of different directions and have increased demands, which may help explain their higher rate of burnout,” Dr. Njoku commented.
She noted that these surveys were conducted during the COVID-19 pandemic, “a period when students’ education experience was a lot different than what they expected and maybe what they wanted.”
Dr. Njoku noted that the challenges of the pandemic are particularly hard on fourth-year medical students.
“A big part of fourth year is applying to residency, and many were doing virtual interviews for residency. That makes it hard to really get an appreciation of the place you will spend the next three to eight years of your life,” she told this news organization.
A version of this article first appeared on Medscape.com.
FROM APA 2022
Today’s medical oxymoron: Healthy overconfidence
Doctor, doctor, gimme the news. I got a bad case of knowing better than you
Stop us if you’ve heard this before. One of your parents (let’s be honest, probably your ornery father) refuses to go to the doctor. You tell him it’s for the best, but in his words, “Doctors don’t know nothin’. I’m fine.” How many TV shows with grumpy fathers feature this exact plot in an episode as the frustrated child attempts increasingly convoluted traps to encourage the stubborn parent to get himself to the doctor?
As is so often the case, wacky sitcoms reflect reality, according to a new study from the Journal of the Economics of Aging. In a massive survey of 80,000 Europeans aged 50 years and older, the researchers found that individuals who were overconfident and rated their health as better than it actually was visited their doctor 17% less often than did those who correctly judge their own health. Fewer medical visits leaves them more vulnerable to chronic disease, since they’re not getting the preventive care they need to catch illnesses early.
Perhaps unsurprisingly, the inverse is also true: People who underestimate their health status visit the doctor 21% more often. On the one hand, regular visits to the doctor are a good thing, as is awareness of how healthy one really is. On the other hand, though, extra visits cost money and time, especially relevant in an aging society with high public health costs.
Nobody likes visiting the doctor, but it is kind of important, especially as we age and our bodies start to let us down. Confidence is fine, but don’t be overly confident. And if you do go, don’t be like a certain former president of the United States. Don’t pay a sycophant to look in your general direction and then declare that you are in very good (great!) condition on Twitter. That’s not how medicine is meant to work.
Your liver stays toddler age
Rapid cell regeneration might seem like something straight out of a sci-fi novel, but it happens to your liver all the time. So much so that the human liver is never a day over 3 years old.
How’s that possible? The liver deals with a lot of toxic substances in its job as the Brita filter of the human body, so it has a unique capacity among organs to regenerate itself after damage.
Dr. Olaf Bergmann and his team at Technical University Dresden’s (Germany) Center for Regenerative Therapies used retrospective radiocarbon birth dating to determine the age of the livers of a group of people who died at the ages of 20-84 years. The results were the same regardless of age.
This information could be a complete game changer for understanding cell regeneration. It’s important in determining cancer cell formation in the liver but also if new heart muscle cells can be generated in people with cardiovascular disease, which the researchers are looking into.
So sure, your liver may be totally capable of filtering those drinks at happy hour, but as old as it is, a juice box might be more appropriate.
To bee, or not to bee? That is the vacation
Sleeping is pretty important for humans, no doubt about that, so anything that improves sleep is worth considering, right? But how far would you go for a good night’s sleep? Would you be willing to travel to Italy to experience the ultimate white-noise generator?
For more on this exciting, yet also sleep-inducing, news story, let’s go to the village of Grottole in southern Italy, where we meet bee keeper and Airbnb host Rocco Filomeno. ”This is the first place in the world where you can sleep immersed in the distinctive sound and aroma of the bees, experiencing ‘bee-therapy’ in the most authentic and natural way,” he said in a written statement for Airbnb.
Mr. Filomeno worked with local NGO Wonder Grottole and a self-build specialist to take the next step in tiny-house evolution. The resulting structure cost just $17,000 – crowdfunded, of course, and built by 25 local bee-lievers (aka volunteers) – and consists of a single room surrounded by nine apiaries, which contain a combined total of 1 million working bees. It is now available to book on Airbnb, and guests “will receive their first lesson on bees and how to live with them,” Airbnb said.
The immersion in bee sound/scent is fully realized through the building’s most prominent interior feature, a screened box in the ceiling with a working hive that allows guests to see the bees and fall asleep to the “gently humming sound,” Airbnb explained. The sound from the hive is said to have a soothing effect that “acts as salve to day-to-day stressors,” according to the BBC.
This is just the start of a trend and we want in on it. Should our tiny house feature the sights/smells/sounds of angry rattlesnakes or a swarm of locusts?
Joysticks can make the world a better place
Someday, it might be possible for surgeons to treat a stroke or aneurysm during the “golden hour,” even if they’re not in the same hospital as the patient. MIT engineers have created a robotic system that can be controlled remotely with a modified joystick, so the patient can go to a closer, smaller hospital and be treated by a surgeon at a larger facility through live imaging.
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Endovascular surgery seems difficult enough with the patient and doctor in the same hospital, “but having a robot twist with the same level of sophistication [as a surgeon] is challenging,” Yoonho Kim, lead author of a study in Science Robotics, said in a written statement. “Our system is based on a fundamentally different mechanism.”
It involves “a medical-grade robotic arm with a magnet attached to its wrist. With a joystick and live imaging, an operator can adjust the magnet’s orientation and manipulate the arm to guide a soft and thin magnetic wire through arteries and vessels,” MIT explained in the statement.
The system was tested using life-like models, and it took each surgeon about an hour of training to learn how to use the new joystick and other equipment. Another perk: No exposure to radiation from x-ray imaging.
If someone you know is obsessed with video games, stop thinking “slacker” and start thinking “neurosurgeon.”
Doctor, doctor, gimme the news. I got a bad case of knowing better than you
Stop us if you’ve heard this before. One of your parents (let’s be honest, probably your ornery father) refuses to go to the doctor. You tell him it’s for the best, but in his words, “Doctors don’t know nothin’. I’m fine.” How many TV shows with grumpy fathers feature this exact plot in an episode as the frustrated child attempts increasingly convoluted traps to encourage the stubborn parent to get himself to the doctor?
As is so often the case, wacky sitcoms reflect reality, according to a new study from the Journal of the Economics of Aging. In a massive survey of 80,000 Europeans aged 50 years and older, the researchers found that individuals who were overconfident and rated their health as better than it actually was visited their doctor 17% less often than did those who correctly judge their own health. Fewer medical visits leaves them more vulnerable to chronic disease, since they’re not getting the preventive care they need to catch illnesses early.
Perhaps unsurprisingly, the inverse is also true: People who underestimate their health status visit the doctor 21% more often. On the one hand, regular visits to the doctor are a good thing, as is awareness of how healthy one really is. On the other hand, though, extra visits cost money and time, especially relevant in an aging society with high public health costs.
Nobody likes visiting the doctor, but it is kind of important, especially as we age and our bodies start to let us down. Confidence is fine, but don’t be overly confident. And if you do go, don’t be like a certain former president of the United States. Don’t pay a sycophant to look in your general direction and then declare that you are in very good (great!) condition on Twitter. That’s not how medicine is meant to work.
Your liver stays toddler age
Rapid cell regeneration might seem like something straight out of a sci-fi novel, but it happens to your liver all the time. So much so that the human liver is never a day over 3 years old.
How’s that possible? The liver deals with a lot of toxic substances in its job as the Brita filter of the human body, so it has a unique capacity among organs to regenerate itself after damage.
Dr. Olaf Bergmann and his team at Technical University Dresden’s (Germany) Center for Regenerative Therapies used retrospective radiocarbon birth dating to determine the age of the livers of a group of people who died at the ages of 20-84 years. The results were the same regardless of age.
This information could be a complete game changer for understanding cell regeneration. It’s important in determining cancer cell formation in the liver but also if new heart muscle cells can be generated in people with cardiovascular disease, which the researchers are looking into.
So sure, your liver may be totally capable of filtering those drinks at happy hour, but as old as it is, a juice box might be more appropriate.
To bee, or not to bee? That is the vacation
Sleeping is pretty important for humans, no doubt about that, so anything that improves sleep is worth considering, right? But how far would you go for a good night’s sleep? Would you be willing to travel to Italy to experience the ultimate white-noise generator?
For more on this exciting, yet also sleep-inducing, news story, let’s go to the village of Grottole in southern Italy, where we meet bee keeper and Airbnb host Rocco Filomeno. ”This is the first place in the world where you can sleep immersed in the distinctive sound and aroma of the bees, experiencing ‘bee-therapy’ in the most authentic and natural way,” he said in a written statement for Airbnb.
Mr. Filomeno worked with local NGO Wonder Grottole and a self-build specialist to take the next step in tiny-house evolution. The resulting structure cost just $17,000 – crowdfunded, of course, and built by 25 local bee-lievers (aka volunteers) – and consists of a single room surrounded by nine apiaries, which contain a combined total of 1 million working bees. It is now available to book on Airbnb, and guests “will receive their first lesson on bees and how to live with them,” Airbnb said.
The immersion in bee sound/scent is fully realized through the building’s most prominent interior feature, a screened box in the ceiling with a working hive that allows guests to see the bees and fall asleep to the “gently humming sound,” Airbnb explained. The sound from the hive is said to have a soothing effect that “acts as salve to day-to-day stressors,” according to the BBC.
This is just the start of a trend and we want in on it. Should our tiny house feature the sights/smells/sounds of angry rattlesnakes or a swarm of locusts?
Joysticks can make the world a better place
Someday, it might be possible for surgeons to treat a stroke or aneurysm during the “golden hour,” even if they’re not in the same hospital as the patient. MIT engineers have created a robotic system that can be controlled remotely with a modified joystick, so the patient can go to a closer, smaller hospital and be treated by a surgeon at a larger facility through live imaging.
Endovascular surgery seems difficult enough with the patient and doctor in the same hospital, “but having a robot twist with the same level of sophistication [as a surgeon] is challenging,” Yoonho Kim, lead author of a study in Science Robotics, said in a written statement. “Our system is based on a fundamentally different mechanism.”
It involves “a medical-grade robotic arm with a magnet attached to its wrist. With a joystick and live imaging, an operator can adjust the magnet’s orientation and manipulate the arm to guide a soft and thin magnetic wire through arteries and vessels,” MIT explained in the statement.
The system was tested using life-like models, and it took each surgeon about an hour of training to learn how to use the new joystick and other equipment. Another perk: No exposure to radiation from x-ray imaging.
If someone you know is obsessed with video games, stop thinking “slacker” and start thinking “neurosurgeon.”
Doctor, doctor, gimme the news. I got a bad case of knowing better than you
Stop us if you’ve heard this before. One of your parents (let’s be honest, probably your ornery father) refuses to go to the doctor. You tell him it’s for the best, but in his words, “Doctors don’t know nothin’. I’m fine.” How many TV shows with grumpy fathers feature this exact plot in an episode as the frustrated child attempts increasingly convoluted traps to encourage the stubborn parent to get himself to the doctor?
As is so often the case, wacky sitcoms reflect reality, according to a new study from the Journal of the Economics of Aging. In a massive survey of 80,000 Europeans aged 50 years and older, the researchers found that individuals who were overconfident and rated their health as better than it actually was visited their doctor 17% less often than did those who correctly judge their own health. Fewer medical visits leaves them more vulnerable to chronic disease, since they’re not getting the preventive care they need to catch illnesses early.
Perhaps unsurprisingly, the inverse is also true: People who underestimate their health status visit the doctor 21% more often. On the one hand, regular visits to the doctor are a good thing, as is awareness of how healthy one really is. On the other hand, though, extra visits cost money and time, especially relevant in an aging society with high public health costs.
Nobody likes visiting the doctor, but it is kind of important, especially as we age and our bodies start to let us down. Confidence is fine, but don’t be overly confident. And if you do go, don’t be like a certain former president of the United States. Don’t pay a sycophant to look in your general direction and then declare that you are in very good (great!) condition on Twitter. That’s not how medicine is meant to work.
Your liver stays toddler age
Rapid cell regeneration might seem like something straight out of a sci-fi novel, but it happens to your liver all the time. So much so that the human liver is never a day over 3 years old.
How’s that possible? The liver deals with a lot of toxic substances in its job as the Brita filter of the human body, so it has a unique capacity among organs to regenerate itself after damage.
Dr. Olaf Bergmann and his team at Technical University Dresden’s (Germany) Center for Regenerative Therapies used retrospective radiocarbon birth dating to determine the age of the livers of a group of people who died at the ages of 20-84 years. The results were the same regardless of age.
This information could be a complete game changer for understanding cell regeneration. It’s important in determining cancer cell formation in the liver but also if new heart muscle cells can be generated in people with cardiovascular disease, which the researchers are looking into.
So sure, your liver may be totally capable of filtering those drinks at happy hour, but as old as it is, a juice box might be more appropriate.
To bee, or not to bee? That is the vacation
Sleeping is pretty important for humans, no doubt about that, so anything that improves sleep is worth considering, right? But how far would you go for a good night’s sleep? Would you be willing to travel to Italy to experience the ultimate white-noise generator?
For more on this exciting, yet also sleep-inducing, news story, let’s go to the village of Grottole in southern Italy, where we meet bee keeper and Airbnb host Rocco Filomeno. ”This is the first place in the world where you can sleep immersed in the distinctive sound and aroma of the bees, experiencing ‘bee-therapy’ in the most authentic and natural way,” he said in a written statement for Airbnb.
Mr. Filomeno worked with local NGO Wonder Grottole and a self-build specialist to take the next step in tiny-house evolution. The resulting structure cost just $17,000 – crowdfunded, of course, and built by 25 local bee-lievers (aka volunteers) – and consists of a single room surrounded by nine apiaries, which contain a combined total of 1 million working bees. It is now available to book on Airbnb, and guests “will receive their first lesson on bees and how to live with them,” Airbnb said.
The immersion in bee sound/scent is fully realized through the building’s most prominent interior feature, a screened box in the ceiling with a working hive that allows guests to see the bees and fall asleep to the “gently humming sound,” Airbnb explained. The sound from the hive is said to have a soothing effect that “acts as salve to day-to-day stressors,” according to the BBC.
This is just the start of a trend and we want in on it. Should our tiny house feature the sights/smells/sounds of angry rattlesnakes or a swarm of locusts?
Joysticks can make the world a better place
Someday, it might be possible for surgeons to treat a stroke or aneurysm during the “golden hour,” even if they’re not in the same hospital as the patient. MIT engineers have created a robotic system that can be controlled remotely with a modified joystick, so the patient can go to a closer, smaller hospital and be treated by a surgeon at a larger facility through live imaging.
Endovascular surgery seems difficult enough with the patient and doctor in the same hospital, “but having a robot twist with the same level of sophistication [as a surgeon] is challenging,” Yoonho Kim, lead author of a study in Science Robotics, said in a written statement. “Our system is based on a fundamentally different mechanism.”
It involves “a medical-grade robotic arm with a magnet attached to its wrist. With a joystick and live imaging, an operator can adjust the magnet’s orientation and manipulate the arm to guide a soft and thin magnetic wire through arteries and vessels,” MIT explained in the statement.
The system was tested using life-like models, and it took each surgeon about an hour of training to learn how to use the new joystick and other equipment. Another perk: No exposure to radiation from x-ray imaging.
If someone you know is obsessed with video games, stop thinking “slacker” and start thinking “neurosurgeon.”
FDA withdraws lymphoma drug approval after investigation
Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.
Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.
Five months later, the results are in.
“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.
In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.
The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”
In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.
The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.
A version of this article first appeared on Medscape.com.
Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.
Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.
Five months later, the results are in.
“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.
In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.
The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”
In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.
The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.
A version of this article first appeared on Medscape.com.
Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.
Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.
Five months later, the results are in.
“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.
In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.
The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”
In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.
The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.
A version of this article first appeared on Medscape.com.
Studies address ibrutinib bleeding risk in patients with CLL receiving Mohs surgery
Patients receiving , new research shows.
“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.
“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).
With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.
While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.
In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.
However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.
The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.
The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).
Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.
In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.
“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.
In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).
Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).
There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).
In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”
Holding treatment
To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”
“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.
Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.
The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.
The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.
“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.
“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.
She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.
“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”
Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients receiving , new research shows.
“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.
“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).
With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.
While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.
In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.
However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.
The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.
The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).
Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.
In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.
“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.
In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).
Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).
There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).
In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”
Holding treatment
To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”
“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.
Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.
The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.
The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.
“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.
“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.
She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.
“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”
Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients receiving , new research shows.
“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.
“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).
With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.
While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.
In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.
However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.
The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.
The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).
Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.
In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.
“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.
In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).
Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).
There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).
In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”
Holding treatment
To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”
“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.
Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.
The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.
The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.
“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.
“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.
She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.
“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”
Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE ACMS ANNUAL MEETING
Are docs getting fed up with hearing about burnout?
There is a feeling of exhaustion, being unable to shake a lingering cold, suffering from frequent headaches and gastrointestinal disturbances, sleeplessness and shortness of breath ...
That was how burnout was described by clinical psychologist Herbert Freudenberger, PhD, who first used the phrase in a paper back in 1974, after observing the emotional depletion and accompanying psychosomatic symptoms among volunteer staff of a free clinic in New York City. He called it “burnout,” a term borrowed from the slang of substance abusers.
It has now been established beyond a shadow of a doubt that burnout is a serious issue facing physicians across specialties, albeit some more intensely than others. But with the constant barrage of stories published on an almost daily basis, along with studies and surveys, it begs the question:
Some have suggested that the focus should be more on tackling burnout and instituting viable solutions rather than rehashing the problem.
There haven’t been studies or surveys on this question, but several experts have offered their opinion.
Jonathan Fisher, MD, a cardiologist and organizational well-being and resiliency leader at Novant Health, Charlotte, N.C., cautioned that he hesitates to speak about what physicians in general believe. “We are a diverse group of nearly 1 million in the United States alone,” he said.
But he noted that there is a specific phenomenon among burned-out health care providers who are “burned out on burnout.”
“Essentially, the underlying thought is ‘talk is cheap and we want action,’” said Dr. Fisher, who is chair and co-founder of the Ending Physician Burnout Global Summit that was held in 2021. “This reaction is often a reflection of disheartened physicians’ sense of hopelessness and cynicism that systemic change to improve working conditions will happen in our lifetime.”
Dr. Fisher explained that “typically, anyone suffering – physicians or nonphysicians – cares more about ending the suffering as soon as possible than learning its causes, but to alleviate suffering at its core – including the emotional suffering of burnout – we must understand the many causes.”
“To address both the organizational and individual drivers of burnout requires a keen awareness of the thoughts, fears, and dreams of physicians, health care executives, and all other stakeholders in health care,” he added.
Burnout, of course, is a very real problem. The 2022 Medscape Physician Burnout & Depression Report found that nearly half of all respondents (47%) said they are burned out, which was higher than the prior year. Perhaps not surprisingly, burnout among emergency physicians took the biggest leap, jumping from 43% in 2021 to 60% this year. More than half of critical care physicians (56%) also reported that they were burned out.
The World Health Organization’s International Classification of Diseases (ICD-11) – the official compendium of diseases – has categorized burnout as a “syndrome” that results from “chronic workplace stress that has not been successfully managed.” It is considered to be an occupational phenomenon and is not classified as a medical condition.
But whether or not physicians are burned out on hearing about burnout remains unclear. “I am not sure if physicians are tired of hearing about ‘burnout,’ but I do think that they want to hear about solutions that go beyond just telling them to take better care of themselves,” said Anne Thorndike, MD, MPH, an internal medicine physician at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, Boston. “There are major systematic factors that contribute to physicians burning out.”
Why talk about negative outcomes?
Jonathan Ripp, MD, MPH, however, is familiar with this sentiment. “‘Why do we keep identifying a problem without solutions’ is certainly a sentiment that is being expressed,” he said. “It’s a negative outcome, so why do we keep talking about negative outcomes?”
Dr. Ripp, who is a professor of medicine, medical education, and geriatrics and palliative medicine; the senior associate dean for well-being and resilience; and chief wellness officer at Icahn School of Medicine at Mount Sinai, New York, is also a well-known expert and researcher in burnout and physician well-being.
He noted that burnout was one of the first “tools” used as a metric to measure well-being, but it is a negative measurement. “It’s been around a long time, so it has a lot of evidence,” said Dr. Ripp. “But that said, there are other ways of measuring well-being without a negative association, and ways of measuring meaning in work – fulfillment and satisfaction, and so on. It should be balanced.”
But for the average physician not familiar with the long legacy of research, they may be frustrated by this situation. “Then they ask, ‘Why are you just showing me more of this instead of doing something about it?’ but we are actually doing something about it,” said Dr. Ripp.
There are many efforts underway, he explained, but it’s a challenging and complex issue. “There are numerous drivers impacting the well-being of any given segment within the health care workforce,” he said. “It will also vary by discipline and location, and there are also a host of individual factors that may have very little to do with the work environment. There are some very well-established efforts for an organizational approach, but it remains to be seen which is the most effective.”
But in broad strokes, he continued, it’s about tackling the system and not about making an individual more resilient. “Individuals that do engage in activities that improve resilience do better, but that’s not what this is about – it’s not going to solve the problem,” said Dr. Ripp. “Those of us like myself, who are working in this space, are trying to promote a culture of well-being – at the system level.”
The question is how to enable the workforce to do their best work in an efficient way so that the balance of their activities are not the meaningless aspects. “And instead, shoot that balance to the meaningful aspects of work,” he added. “There are enormous challenges, but even though we are working on solutions, I can see how the individual may not see that – they may say, ‘Stop telling me to be resilient, stop telling me there’s a problem,’ but we’re working on it.”
Moving medicine forward
James Jerzak, MD, a family physician in Green Bay, Wisc., and physician lead at Bellin Health, noted that “it seems to me that doctors aren’t burned out talking about burnout, but they are burned out hearing that the solution to burnout is simply for them to become more resilient,” he said. “In actuality, the path to dealing with this huge problem is to make meaningful systemic changes in how medicine is practiced.”
He reiterated that medical care has become increasingly complex, with the aging of the population; the increasing incidence of chronic diseases, such as diabetes; the challenges with the increasing cost of care, higher copays, and lack of health insurance for a large portion of the country; and general incivility toward health care workers that was exacerbated by the pandemic.
“This has all led to significantly increased stress levels for medical workers,” he said. “Couple all of that with the increased work involved in meeting the demands of the electronic health record, and it is clear that the current situation is unsustainable.”
In his own health care system, moving medicine forward has meant advancing team-based care, which translates to expanding teams to include adequate support for physicians. This strategy addressed problems in health care delivery, part of which is burnout.
“In many systems practicing advanced team-based care, the ancillary staff – medical assistants, LPNs, and RNs – play an enhanced role in the patient visit and perform functions such as quality care gap closure, medication review and refill pending, pending orders, and helping with documentation,” he said. “Although the current health care workforce shortages has created challenges, there are a lot of innovative approaches being tried [that are] aimed at providing solutions.”
The second key factor is for systems is to develop robust support for their providers with a broad range of team members, such as case managers, clinical pharmacists, diabetic educators, care coordinators, and others. “The day has passed where individual physicians can effectivity manage all of the complexities of care, especially since there are so many nonclinical factors affecting care,” said Dr. Jerzak.
“The recent focus on the social determinants of health and health equity underlies the fact that it truly takes a team of health care professionals working together to provide optimal care for patients,” he said.
Dr. Thorndike, who mentors premedical and medical trainees, has pointed out that burnout begins way before an individual enters the workplace as a doctor. Burnout begins in the earliest stages of medical practice, with the application process to medical school. The admissions process extends over a 12-month period, causing a great deal of “toxic stress.”
One study found that, compared with non-premedical students, premedical students had greater depression severity and emotional exhaustion.
“The current system of medical school admissions ignores the toll that the lengthy and emotionally exhausting process takes on aspiring physicians,” she said. “This is just one example of many in training and health care that requires physicians to set aside their own lives to achieve their goals and to provide the best possible care to others.”
A version of this article first appeared on Medscape.com.
There is a feeling of exhaustion, being unable to shake a lingering cold, suffering from frequent headaches and gastrointestinal disturbances, sleeplessness and shortness of breath ...
That was how burnout was described by clinical psychologist Herbert Freudenberger, PhD, who first used the phrase in a paper back in 1974, after observing the emotional depletion and accompanying psychosomatic symptoms among volunteer staff of a free clinic in New York City. He called it “burnout,” a term borrowed from the slang of substance abusers.
It has now been established beyond a shadow of a doubt that burnout is a serious issue facing physicians across specialties, albeit some more intensely than others. But with the constant barrage of stories published on an almost daily basis, along with studies and surveys, it begs the question:
Some have suggested that the focus should be more on tackling burnout and instituting viable solutions rather than rehashing the problem.
There haven’t been studies or surveys on this question, but several experts have offered their opinion.
Jonathan Fisher, MD, a cardiologist and organizational well-being and resiliency leader at Novant Health, Charlotte, N.C., cautioned that he hesitates to speak about what physicians in general believe. “We are a diverse group of nearly 1 million in the United States alone,” he said.
But he noted that there is a specific phenomenon among burned-out health care providers who are “burned out on burnout.”
“Essentially, the underlying thought is ‘talk is cheap and we want action,’” said Dr. Fisher, who is chair and co-founder of the Ending Physician Burnout Global Summit that was held in 2021. “This reaction is often a reflection of disheartened physicians’ sense of hopelessness and cynicism that systemic change to improve working conditions will happen in our lifetime.”
Dr. Fisher explained that “typically, anyone suffering – physicians or nonphysicians – cares more about ending the suffering as soon as possible than learning its causes, but to alleviate suffering at its core – including the emotional suffering of burnout – we must understand the many causes.”
“To address both the organizational and individual drivers of burnout requires a keen awareness of the thoughts, fears, and dreams of physicians, health care executives, and all other stakeholders in health care,” he added.
Burnout, of course, is a very real problem. The 2022 Medscape Physician Burnout & Depression Report found that nearly half of all respondents (47%) said they are burned out, which was higher than the prior year. Perhaps not surprisingly, burnout among emergency physicians took the biggest leap, jumping from 43% in 2021 to 60% this year. More than half of critical care physicians (56%) also reported that they were burned out.
The World Health Organization’s International Classification of Diseases (ICD-11) – the official compendium of diseases – has categorized burnout as a “syndrome” that results from “chronic workplace stress that has not been successfully managed.” It is considered to be an occupational phenomenon and is not classified as a medical condition.
But whether or not physicians are burned out on hearing about burnout remains unclear. “I am not sure if physicians are tired of hearing about ‘burnout,’ but I do think that they want to hear about solutions that go beyond just telling them to take better care of themselves,” said Anne Thorndike, MD, MPH, an internal medicine physician at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, Boston. “There are major systematic factors that contribute to physicians burning out.”
Why talk about negative outcomes?
Jonathan Ripp, MD, MPH, however, is familiar with this sentiment. “‘Why do we keep identifying a problem without solutions’ is certainly a sentiment that is being expressed,” he said. “It’s a negative outcome, so why do we keep talking about negative outcomes?”
Dr. Ripp, who is a professor of medicine, medical education, and geriatrics and palliative medicine; the senior associate dean for well-being and resilience; and chief wellness officer at Icahn School of Medicine at Mount Sinai, New York, is also a well-known expert and researcher in burnout and physician well-being.
He noted that burnout was one of the first “tools” used as a metric to measure well-being, but it is a negative measurement. “It’s been around a long time, so it has a lot of evidence,” said Dr. Ripp. “But that said, there are other ways of measuring well-being without a negative association, and ways of measuring meaning in work – fulfillment and satisfaction, and so on. It should be balanced.”
But for the average physician not familiar with the long legacy of research, they may be frustrated by this situation. “Then they ask, ‘Why are you just showing me more of this instead of doing something about it?’ but we are actually doing something about it,” said Dr. Ripp.
There are many efforts underway, he explained, but it’s a challenging and complex issue. “There are numerous drivers impacting the well-being of any given segment within the health care workforce,” he said. “It will also vary by discipline and location, and there are also a host of individual factors that may have very little to do with the work environment. There are some very well-established efforts for an organizational approach, but it remains to be seen which is the most effective.”
But in broad strokes, he continued, it’s about tackling the system and not about making an individual more resilient. “Individuals that do engage in activities that improve resilience do better, but that’s not what this is about – it’s not going to solve the problem,” said Dr. Ripp. “Those of us like myself, who are working in this space, are trying to promote a culture of well-being – at the system level.”
The question is how to enable the workforce to do their best work in an efficient way so that the balance of their activities are not the meaningless aspects. “And instead, shoot that balance to the meaningful aspects of work,” he added. “There are enormous challenges, but even though we are working on solutions, I can see how the individual may not see that – they may say, ‘Stop telling me to be resilient, stop telling me there’s a problem,’ but we’re working on it.”
Moving medicine forward
James Jerzak, MD, a family physician in Green Bay, Wisc., and physician lead at Bellin Health, noted that “it seems to me that doctors aren’t burned out talking about burnout, but they are burned out hearing that the solution to burnout is simply for them to become more resilient,” he said. “In actuality, the path to dealing with this huge problem is to make meaningful systemic changes in how medicine is practiced.”
He reiterated that medical care has become increasingly complex, with the aging of the population; the increasing incidence of chronic diseases, such as diabetes; the challenges with the increasing cost of care, higher copays, and lack of health insurance for a large portion of the country; and general incivility toward health care workers that was exacerbated by the pandemic.
“This has all led to significantly increased stress levels for medical workers,” he said. “Couple all of that with the increased work involved in meeting the demands of the electronic health record, and it is clear that the current situation is unsustainable.”
In his own health care system, moving medicine forward has meant advancing team-based care, which translates to expanding teams to include adequate support for physicians. This strategy addressed problems in health care delivery, part of which is burnout.
“In many systems practicing advanced team-based care, the ancillary staff – medical assistants, LPNs, and RNs – play an enhanced role in the patient visit and perform functions such as quality care gap closure, medication review and refill pending, pending orders, and helping with documentation,” he said. “Although the current health care workforce shortages has created challenges, there are a lot of innovative approaches being tried [that are] aimed at providing solutions.”
The second key factor is for systems is to develop robust support for their providers with a broad range of team members, such as case managers, clinical pharmacists, diabetic educators, care coordinators, and others. “The day has passed where individual physicians can effectivity manage all of the complexities of care, especially since there are so many nonclinical factors affecting care,” said Dr. Jerzak.
“The recent focus on the social determinants of health and health equity underlies the fact that it truly takes a team of health care professionals working together to provide optimal care for patients,” he said.
Dr. Thorndike, who mentors premedical and medical trainees, has pointed out that burnout begins way before an individual enters the workplace as a doctor. Burnout begins in the earliest stages of medical practice, with the application process to medical school. The admissions process extends over a 12-month period, causing a great deal of “toxic stress.”
One study found that, compared with non-premedical students, premedical students had greater depression severity and emotional exhaustion.
“The current system of medical school admissions ignores the toll that the lengthy and emotionally exhausting process takes on aspiring physicians,” she said. “This is just one example of many in training and health care that requires physicians to set aside their own lives to achieve their goals and to provide the best possible care to others.”
A version of this article first appeared on Medscape.com.
There is a feeling of exhaustion, being unable to shake a lingering cold, suffering from frequent headaches and gastrointestinal disturbances, sleeplessness and shortness of breath ...
That was how burnout was described by clinical psychologist Herbert Freudenberger, PhD, who first used the phrase in a paper back in 1974, after observing the emotional depletion and accompanying psychosomatic symptoms among volunteer staff of a free clinic in New York City. He called it “burnout,” a term borrowed from the slang of substance abusers.
It has now been established beyond a shadow of a doubt that burnout is a serious issue facing physicians across specialties, albeit some more intensely than others. But with the constant barrage of stories published on an almost daily basis, along with studies and surveys, it begs the question:
Some have suggested that the focus should be more on tackling burnout and instituting viable solutions rather than rehashing the problem.
There haven’t been studies or surveys on this question, but several experts have offered their opinion.
Jonathan Fisher, MD, a cardiologist and organizational well-being and resiliency leader at Novant Health, Charlotte, N.C., cautioned that he hesitates to speak about what physicians in general believe. “We are a diverse group of nearly 1 million in the United States alone,” he said.
But he noted that there is a specific phenomenon among burned-out health care providers who are “burned out on burnout.”
“Essentially, the underlying thought is ‘talk is cheap and we want action,’” said Dr. Fisher, who is chair and co-founder of the Ending Physician Burnout Global Summit that was held in 2021. “This reaction is often a reflection of disheartened physicians’ sense of hopelessness and cynicism that systemic change to improve working conditions will happen in our lifetime.”
Dr. Fisher explained that “typically, anyone suffering – physicians or nonphysicians – cares more about ending the suffering as soon as possible than learning its causes, but to alleviate suffering at its core – including the emotional suffering of burnout – we must understand the many causes.”
“To address both the organizational and individual drivers of burnout requires a keen awareness of the thoughts, fears, and dreams of physicians, health care executives, and all other stakeholders in health care,” he added.
Burnout, of course, is a very real problem. The 2022 Medscape Physician Burnout & Depression Report found that nearly half of all respondents (47%) said they are burned out, which was higher than the prior year. Perhaps not surprisingly, burnout among emergency physicians took the biggest leap, jumping from 43% in 2021 to 60% this year. More than half of critical care physicians (56%) also reported that they were burned out.
The World Health Organization’s International Classification of Diseases (ICD-11) – the official compendium of diseases – has categorized burnout as a “syndrome” that results from “chronic workplace stress that has not been successfully managed.” It is considered to be an occupational phenomenon and is not classified as a medical condition.
But whether or not physicians are burned out on hearing about burnout remains unclear. “I am not sure if physicians are tired of hearing about ‘burnout,’ but I do think that they want to hear about solutions that go beyond just telling them to take better care of themselves,” said Anne Thorndike, MD, MPH, an internal medicine physician at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, Boston. “There are major systematic factors that contribute to physicians burning out.”
Why talk about negative outcomes?
Jonathan Ripp, MD, MPH, however, is familiar with this sentiment. “‘Why do we keep identifying a problem without solutions’ is certainly a sentiment that is being expressed,” he said. “It’s a negative outcome, so why do we keep talking about negative outcomes?”
Dr. Ripp, who is a professor of medicine, medical education, and geriatrics and palliative medicine; the senior associate dean for well-being and resilience; and chief wellness officer at Icahn School of Medicine at Mount Sinai, New York, is also a well-known expert and researcher in burnout and physician well-being.
He noted that burnout was one of the first “tools” used as a metric to measure well-being, but it is a negative measurement. “It’s been around a long time, so it has a lot of evidence,” said Dr. Ripp. “But that said, there are other ways of measuring well-being without a negative association, and ways of measuring meaning in work – fulfillment and satisfaction, and so on. It should be balanced.”
But for the average physician not familiar with the long legacy of research, they may be frustrated by this situation. “Then they ask, ‘Why are you just showing me more of this instead of doing something about it?’ but we are actually doing something about it,” said Dr. Ripp.
There are many efforts underway, he explained, but it’s a challenging and complex issue. “There are numerous drivers impacting the well-being of any given segment within the health care workforce,” he said. “It will also vary by discipline and location, and there are also a host of individual factors that may have very little to do with the work environment. There are some very well-established efforts for an organizational approach, but it remains to be seen which is the most effective.”
But in broad strokes, he continued, it’s about tackling the system and not about making an individual more resilient. “Individuals that do engage in activities that improve resilience do better, but that’s not what this is about – it’s not going to solve the problem,” said Dr. Ripp. “Those of us like myself, who are working in this space, are trying to promote a culture of well-being – at the system level.”
The question is how to enable the workforce to do their best work in an efficient way so that the balance of their activities are not the meaningless aspects. “And instead, shoot that balance to the meaningful aspects of work,” he added. “There are enormous challenges, but even though we are working on solutions, I can see how the individual may not see that – they may say, ‘Stop telling me to be resilient, stop telling me there’s a problem,’ but we’re working on it.”
Moving medicine forward
James Jerzak, MD, a family physician in Green Bay, Wisc., and physician lead at Bellin Health, noted that “it seems to me that doctors aren’t burned out talking about burnout, but they are burned out hearing that the solution to burnout is simply for them to become more resilient,” he said. “In actuality, the path to dealing with this huge problem is to make meaningful systemic changes in how medicine is practiced.”
He reiterated that medical care has become increasingly complex, with the aging of the population; the increasing incidence of chronic diseases, such as diabetes; the challenges with the increasing cost of care, higher copays, and lack of health insurance for a large portion of the country; and general incivility toward health care workers that was exacerbated by the pandemic.
“This has all led to significantly increased stress levels for medical workers,” he said. “Couple all of that with the increased work involved in meeting the demands of the electronic health record, and it is clear that the current situation is unsustainable.”
In his own health care system, moving medicine forward has meant advancing team-based care, which translates to expanding teams to include adequate support for physicians. This strategy addressed problems in health care delivery, part of which is burnout.
“In many systems practicing advanced team-based care, the ancillary staff – medical assistants, LPNs, and RNs – play an enhanced role in the patient visit and perform functions such as quality care gap closure, medication review and refill pending, pending orders, and helping with documentation,” he said. “Although the current health care workforce shortages has created challenges, there are a lot of innovative approaches being tried [that are] aimed at providing solutions.”
The second key factor is for systems is to develop robust support for their providers with a broad range of team members, such as case managers, clinical pharmacists, diabetic educators, care coordinators, and others. “The day has passed where individual physicians can effectivity manage all of the complexities of care, especially since there are so many nonclinical factors affecting care,” said Dr. Jerzak.
“The recent focus on the social determinants of health and health equity underlies the fact that it truly takes a team of health care professionals working together to provide optimal care for patients,” he said.
Dr. Thorndike, who mentors premedical and medical trainees, has pointed out that burnout begins way before an individual enters the workplace as a doctor. Burnout begins in the earliest stages of medical practice, with the application process to medical school. The admissions process extends over a 12-month period, causing a great deal of “toxic stress.”
One study found that, compared with non-premedical students, premedical students had greater depression severity and emotional exhaustion.
“The current system of medical school admissions ignores the toll that the lengthy and emotionally exhausting process takes on aspiring physicians,” she said. “This is just one example of many in training and health care that requires physicians to set aside their own lives to achieve their goals and to provide the best possible care to others.”
A version of this article first appeared on Medscape.com.
Legislative efforts continue to revamp laws governing PAs
INDIANAPOLIS – That’s according to Phil Bongiorno, BA, senior vice president of advocacy and government relations at the American Academy of Physician Associates (AAPA), who spoke at the group’s annual meeting.
OTP refers to the AAPA’s goal of improving patient access to care and lessening administrative obligations by eliminating the legal requirement that there be a specific relationship between a PA, physician, or any other health care provider. This would allow a PA to practice to the full extent of their education, training, and experience, Mr. Bongiorno said.
The second tenet of OTP is to persuade states to create a separate majority PA board to regulate PAs. An alternative to this would be for states to add PAs and physicians who work with PAs to their medical or healing arts boards, he said.
Third, in an OTP environment, each state would authorize PAs to be eligible for direct payment by all public and private insurers. “We have seen that development at the federal level, as far as Medicare is concerned,” Mr. Bongiorno said. “Now, we’re focusing on making that happen in the individual states as well.”
According to Mr. Bongiorno, this year’s state advocacy priorities are to pursue new legislation in additional states, even as efforts continue to persuade state legislatures to act on carryover bills from the previous legislative session.
Mr. Bongiorno briefly summarized what he called “OTP successes” from 2021:
- Federal government: Authorized direct payment to PAs under Medicare
- Arkansas, Delaware, Illinois, Pennsylvania: Added one or more PAs to their medical boards
- Florida, Utah: Approved direct payment to PAs
- Tennessee, Wisconsin: Created a separate PA review board
- Utah, Wisconsin: Removed the relationship/agreement requirement (Wisconsin now requires 10,000 hours of practice to remove the relationship requirement)
North Central region
In Colorado, House Bill 1095 (HB1095) would have removed requirements for a legal relationship between a PA and a physician. Initially that would have happened after 3,000 hours of practice, although changing that to 5,000 hours has been a compromise measure. PAs changing specialties must collaborate for 2,000 hours, now negotiated to 3,000 hours.
HB1095 ultimately was not successful last year or this year, said Erika Miller, director of state advocacy and outreach for the AAPA. “But we do see it as a success, because in the 2022 session, we managed to get it passed in committee by a 10-to-1 vote,” she said. “It then moved to the full house and was not successful there.”
Ms. Miller said that South Dakota Senate Bill 134 would have removed the requirement for a legal PA/physician relationship after 1,040 hours, which is the requirement for nurse practitioners. “South Dakota had introduced similar legislation the year before, but also like Colorado, they went from not getting out of committee last year to making it to the senate floor this time,” she said.
In Wisconsin, the new PA-affiliated credentialing board began on April 1. It gives PAs the authority to license, discipline, and write regulations, Ms. Miller said.
South Central region
Arizona Senate Bill 1367 included direct pay, removed the relationship tether with a physician, and made each PA fully responsible for the care they provide. “The bill passed out of committee successfully but did not make it to a vote due to unexpected struggles between the Arizona medical society and PA chapter,” said Shannon Morey, senior director of state advocacy and outreach at the AAPA. “They are ready to go again next year.”
In Louisiana, Senate Bill 158 is a “strong” bill that addressed all the desired aspects of OTP, Ms. Morey said; “The legislation stands subject to call on the Senate floor, but it has been killed by the sponsor.”
Northeast region
Massachusetts Senate Bill 740 (S740) would remove the legal tether between PA and physician, said Carson Walker, senior director of state advocacy and outreach at the AAPA. “The committee decided to extend its time in committee until June,” he said. “By next month, we expect that the committee will schedule a hearing that includes S740, and we fully plan on submitting testimony.”
In New York, Senate Bill 9233 (S9233) would remove physician supervision after 3,600 hours of practice.
“Just about 10 days ago, sponsors were able to have S9233 introduced, which is the most succinct and, I think, the most effective OTP bill I have ever seen,” Mr. Walker said.
“S9233 says that after 3,600 hours a PA can practice without the supervision of a physician, and that’s all. There’s not a lot of time left in this session, but we are hopeful that it lays the groundwork for success next year.”
New Hampshire Senate Bill 228 has passed the legislature and is awaiting the governor’s signature. It will allow direct payment, make PAs responsible for the care they provide, and shift the physician-PA relationship from supervision to collaboration, Mr. Walker said.
Southeast region
Stephanie Radix, senior director of state advocacy and outreach at the AAPA, discussed North Carolina’s Senate Bill 345, which passed the Senate unanimously in 2021 and has been carried over to this year’s session. The bill defines team-based settings, eliminates the relationship tether, and establishes a supervised career entry interval of 4,000 clinical hours in the state.
The legislature is slated to adjourn June 30, Ms. Radix said: “We are very hopeful that we will get it across the finish line.”
In an interview, Mr. Bongiorno said that the AAPA’s overall advocacy progress is as expected.
“Optimal team practice is about allowing each practice to make that determination on how the team should work as a true collaboration,” he said. “The bottom line is that OTP would allow us to reach more patients, serve the community, and ensure that people are able to get healthcare, especially in underserved areas.”
A version of this article first appeared on Medscape.com.
INDIANAPOLIS – That’s according to Phil Bongiorno, BA, senior vice president of advocacy and government relations at the American Academy of Physician Associates (AAPA), who spoke at the group’s annual meeting.
OTP refers to the AAPA’s goal of improving patient access to care and lessening administrative obligations by eliminating the legal requirement that there be a specific relationship between a PA, physician, or any other health care provider. This would allow a PA to practice to the full extent of their education, training, and experience, Mr. Bongiorno said.
The second tenet of OTP is to persuade states to create a separate majority PA board to regulate PAs. An alternative to this would be for states to add PAs and physicians who work with PAs to their medical or healing arts boards, he said.
Third, in an OTP environment, each state would authorize PAs to be eligible for direct payment by all public and private insurers. “We have seen that development at the federal level, as far as Medicare is concerned,” Mr. Bongiorno said. “Now, we’re focusing on making that happen in the individual states as well.”
According to Mr. Bongiorno, this year’s state advocacy priorities are to pursue new legislation in additional states, even as efforts continue to persuade state legislatures to act on carryover bills from the previous legislative session.
Mr. Bongiorno briefly summarized what he called “OTP successes” from 2021:
- Federal government: Authorized direct payment to PAs under Medicare
- Arkansas, Delaware, Illinois, Pennsylvania: Added one or more PAs to their medical boards
- Florida, Utah: Approved direct payment to PAs
- Tennessee, Wisconsin: Created a separate PA review board
- Utah, Wisconsin: Removed the relationship/agreement requirement (Wisconsin now requires 10,000 hours of practice to remove the relationship requirement)
North Central region
In Colorado, House Bill 1095 (HB1095) would have removed requirements for a legal relationship between a PA and a physician. Initially that would have happened after 3,000 hours of practice, although changing that to 5,000 hours has been a compromise measure. PAs changing specialties must collaborate for 2,000 hours, now negotiated to 3,000 hours.
HB1095 ultimately was not successful last year or this year, said Erika Miller, director of state advocacy and outreach for the AAPA. “But we do see it as a success, because in the 2022 session, we managed to get it passed in committee by a 10-to-1 vote,” she said. “It then moved to the full house and was not successful there.”
Ms. Miller said that South Dakota Senate Bill 134 would have removed the requirement for a legal PA/physician relationship after 1,040 hours, which is the requirement for nurse practitioners. “South Dakota had introduced similar legislation the year before, but also like Colorado, they went from not getting out of committee last year to making it to the senate floor this time,” she said.
In Wisconsin, the new PA-affiliated credentialing board began on April 1. It gives PAs the authority to license, discipline, and write regulations, Ms. Miller said.
South Central region
Arizona Senate Bill 1367 included direct pay, removed the relationship tether with a physician, and made each PA fully responsible for the care they provide. “The bill passed out of committee successfully but did not make it to a vote due to unexpected struggles between the Arizona medical society and PA chapter,” said Shannon Morey, senior director of state advocacy and outreach at the AAPA. “They are ready to go again next year.”
In Louisiana, Senate Bill 158 is a “strong” bill that addressed all the desired aspects of OTP, Ms. Morey said; “The legislation stands subject to call on the Senate floor, but it has been killed by the sponsor.”
Northeast region
Massachusetts Senate Bill 740 (S740) would remove the legal tether between PA and physician, said Carson Walker, senior director of state advocacy and outreach at the AAPA. “The committee decided to extend its time in committee until June,” he said. “By next month, we expect that the committee will schedule a hearing that includes S740, and we fully plan on submitting testimony.”
In New York, Senate Bill 9233 (S9233) would remove physician supervision after 3,600 hours of practice.
“Just about 10 days ago, sponsors were able to have S9233 introduced, which is the most succinct and, I think, the most effective OTP bill I have ever seen,” Mr. Walker said.
“S9233 says that after 3,600 hours a PA can practice without the supervision of a physician, and that’s all. There’s not a lot of time left in this session, but we are hopeful that it lays the groundwork for success next year.”
New Hampshire Senate Bill 228 has passed the legislature and is awaiting the governor’s signature. It will allow direct payment, make PAs responsible for the care they provide, and shift the physician-PA relationship from supervision to collaboration, Mr. Walker said.
Southeast region
Stephanie Radix, senior director of state advocacy and outreach at the AAPA, discussed North Carolina’s Senate Bill 345, which passed the Senate unanimously in 2021 and has been carried over to this year’s session. The bill defines team-based settings, eliminates the relationship tether, and establishes a supervised career entry interval of 4,000 clinical hours in the state.
The legislature is slated to adjourn June 30, Ms. Radix said: “We are very hopeful that we will get it across the finish line.”
In an interview, Mr. Bongiorno said that the AAPA’s overall advocacy progress is as expected.
“Optimal team practice is about allowing each practice to make that determination on how the team should work as a true collaboration,” he said. “The bottom line is that OTP would allow us to reach more patients, serve the community, and ensure that people are able to get healthcare, especially in underserved areas.”
A version of this article first appeared on Medscape.com.
INDIANAPOLIS – That’s according to Phil Bongiorno, BA, senior vice president of advocacy and government relations at the American Academy of Physician Associates (AAPA), who spoke at the group’s annual meeting.
OTP refers to the AAPA’s goal of improving patient access to care and lessening administrative obligations by eliminating the legal requirement that there be a specific relationship between a PA, physician, or any other health care provider. This would allow a PA to practice to the full extent of their education, training, and experience, Mr. Bongiorno said.
The second tenet of OTP is to persuade states to create a separate majority PA board to regulate PAs. An alternative to this would be for states to add PAs and physicians who work with PAs to their medical or healing arts boards, he said.
Third, in an OTP environment, each state would authorize PAs to be eligible for direct payment by all public and private insurers. “We have seen that development at the federal level, as far as Medicare is concerned,” Mr. Bongiorno said. “Now, we’re focusing on making that happen in the individual states as well.”
According to Mr. Bongiorno, this year’s state advocacy priorities are to pursue new legislation in additional states, even as efforts continue to persuade state legislatures to act on carryover bills from the previous legislative session.
Mr. Bongiorno briefly summarized what he called “OTP successes” from 2021:
- Federal government: Authorized direct payment to PAs under Medicare
- Arkansas, Delaware, Illinois, Pennsylvania: Added one or more PAs to their medical boards
- Florida, Utah: Approved direct payment to PAs
- Tennessee, Wisconsin: Created a separate PA review board
- Utah, Wisconsin: Removed the relationship/agreement requirement (Wisconsin now requires 10,000 hours of practice to remove the relationship requirement)
North Central region
In Colorado, House Bill 1095 (HB1095) would have removed requirements for a legal relationship between a PA and a physician. Initially that would have happened after 3,000 hours of practice, although changing that to 5,000 hours has been a compromise measure. PAs changing specialties must collaborate for 2,000 hours, now negotiated to 3,000 hours.
HB1095 ultimately was not successful last year or this year, said Erika Miller, director of state advocacy and outreach for the AAPA. “But we do see it as a success, because in the 2022 session, we managed to get it passed in committee by a 10-to-1 vote,” she said. “It then moved to the full house and was not successful there.”
Ms. Miller said that South Dakota Senate Bill 134 would have removed the requirement for a legal PA/physician relationship after 1,040 hours, which is the requirement for nurse practitioners. “South Dakota had introduced similar legislation the year before, but also like Colorado, they went from not getting out of committee last year to making it to the senate floor this time,” she said.
In Wisconsin, the new PA-affiliated credentialing board began on April 1. It gives PAs the authority to license, discipline, and write regulations, Ms. Miller said.
South Central region
Arizona Senate Bill 1367 included direct pay, removed the relationship tether with a physician, and made each PA fully responsible for the care they provide. “The bill passed out of committee successfully but did not make it to a vote due to unexpected struggles between the Arizona medical society and PA chapter,” said Shannon Morey, senior director of state advocacy and outreach at the AAPA. “They are ready to go again next year.”
In Louisiana, Senate Bill 158 is a “strong” bill that addressed all the desired aspects of OTP, Ms. Morey said; “The legislation stands subject to call on the Senate floor, but it has been killed by the sponsor.”
Northeast region
Massachusetts Senate Bill 740 (S740) would remove the legal tether between PA and physician, said Carson Walker, senior director of state advocacy and outreach at the AAPA. “The committee decided to extend its time in committee until June,” he said. “By next month, we expect that the committee will schedule a hearing that includes S740, and we fully plan on submitting testimony.”
In New York, Senate Bill 9233 (S9233) would remove physician supervision after 3,600 hours of practice.
“Just about 10 days ago, sponsors were able to have S9233 introduced, which is the most succinct and, I think, the most effective OTP bill I have ever seen,” Mr. Walker said.
“S9233 says that after 3,600 hours a PA can practice without the supervision of a physician, and that’s all. There’s not a lot of time left in this session, but we are hopeful that it lays the groundwork for success next year.”
New Hampshire Senate Bill 228 has passed the legislature and is awaiting the governor’s signature. It will allow direct payment, make PAs responsible for the care they provide, and shift the physician-PA relationship from supervision to collaboration, Mr. Walker said.
Southeast region
Stephanie Radix, senior director of state advocacy and outreach at the AAPA, discussed North Carolina’s Senate Bill 345, which passed the Senate unanimously in 2021 and has been carried over to this year’s session. The bill defines team-based settings, eliminates the relationship tether, and establishes a supervised career entry interval of 4,000 clinical hours in the state.
The legislature is slated to adjourn June 30, Ms. Radix said: “We are very hopeful that we will get it across the finish line.”
In an interview, Mr. Bongiorno said that the AAPA’s overall advocacy progress is as expected.
“Optimal team practice is about allowing each practice to make that determination on how the team should work as a true collaboration,” he said. “The bottom line is that OTP would allow us to reach more patients, serve the community, and ensure that people are able to get healthcare, especially in underserved areas.”
A version of this article first appeared on Medscape.com.
AT AAPA 2022
Crohn’s disease research goes to the dogs
Why it might be better to be a dog person
Here’s that old debate again: Dogs or cats? You probably have your own opinion, but research presented at this year’s Digestive Disease Week may have tipped the scale by showing that children who lived with dogs may be less likely to have Crohn’s disease as adults.
The research was done by having approximately 4,300 people closely related to patients with Crohn’s disease fill out an environmental questionnaire. Using these data, the research team looked into environmental factors such as size of the families, where the home was, how many bathrooms the homes had, and quality of drinking water.
The researchers found that those who had or were exposed to dogs between the ages of 5 and 15 years were more likely to have healthy gut permeability and balanced microbes, which increased their protection against Crohn’s disease.
“Our study seems to add to others that have explored the ‘hygiene hypothesis’ which suggests that the lack of exposure to microbes early in life may lead to lack of immune regulation toward environmental microbes,” senior author Williams Turpin, PhD, said in the written statement.
The researchers aren’t sure why they didn’t get the same findings with cats, but Dr. Turpin theorized that dog owners tend to be outside more with their dogs or live in places with more green space, which are good protectors against Crohn’s disease.
It’s all good for dog owners, but do their pets’ parasites make you more attractive? Just more fuel for the ongoing debate.
Come for the history, stay for the fossilized parasites
Another week, another analysis of old British poop. LOTME really is your one-stop shop for all the important, hard-hitting news about historic parasites. You’re welcome, Internet.
The news this week is from Stonehenge, which is apparently kind of a big deal. Rocks in a circle, celestial calendar, cultural significance, whatever. We’re not here to talk about rocks. We’re here to talk about, uh, rocks. Smaller rocks. Specifically, coprolites, which are essentially poop turned into a rock. (Though now we’re imagining Stonehenge made out of fossilized poop rocks. Would it still be a big tourist destination? We can see both sides of the argument on that one.)
Archaeologists from the University of Cambridge have conducted an analysis of coprolites from Durrington Walls, a Neolithic settlement just a few kilometers from Stonehenge. The town dates to the same time that Stonehenge was constructed, and it’s believed that the residents were responsible for building the landmark. These coprolites, depending on what’s inside, can tell us a lot about how the builders of Stonehenge lived and, more specifically, how they ate.
In this case, the coprolites of one human and three dogs contained capillariid worm eggs. These worms come from cows, and when a human is typically infected, the eggs embed in the liver and do not pass through the body. Finding them in excrement indicates that the people were eating raw cow organs and feeding leftovers to their dogs. This is interesting, because a preponderance of pottery and cooking implements also found at the site indicates that the residents of Durrington Walls were spit-roasting or boiling their beef and pork. So the meat was cooked, but not the organs. That is an interesting dietary decision, ancient British people. Then again, modern British cuisine exists. At least now we know where they got it from.
This new research raises one other very important question: When are we going to get a full-on guided tour of all the important coprolite sites in Britain? They’ve clearly got plenty of them, and the tourist demand for ancient parasites must be sky-high. Come on, capitalism, follow through on this. We’d go.
Everyone lies: Food intake edition
Do you have any patients on special diets? Do you ask them if they are following those diets? Don’t bother, because they’re lying. Everyone lies about the food they eat. Everyone. Obese people lie, and nonobese people lie.
Investigators at the University of Essex in England asked 221 adults to keep food diaries, and then they checked on energy consumption by analyzing radioactive water levels in the participants’ urine over a 10-day period.
Underreporting of food consumption was rampant, even among those who were not obese. The obese subjects did underreport by a greater extent (1,200 calories per day) than did those who were not obese, who were off by only 800 calories, but the obese participants burned about 400 calories more each day than did the nonobese, so the difference was a wash.
Everyone ended up underreporting their calorie consumption by an average of about 900 calories, and the investigators were good enough to provide some food equivalents, tops on the list being three MacDonald’s cheeseburgers.
“Public health recommendations have historically relied heavily on self-reported energy intake values,” senior author Gavin Sandercock, PhD, said in a EurekAlert statement, and “recognising that the measures of energy intake are incorrect might result in the setting of more realistic targets.”
Maybe you can be more realistic with your patients, too. Go ahead and ask Mr. Smith about the burger sticking out of his coat pocket, because there are probably two more you can’t see. We’ve each got 900 calories hiding on us somewhere. Ours is usually pizza.
The art of the gallbladder
Ever thought you would see a portrait of a gallbladder hanging up in a gallery? Not just an artist’s rendition, but an actual photo from an actual patient? Well, you can at the Soloway Gallery in Brooklyn, N.Y., at least until June 12.
The artist? K.C. Joseph, MD, a general surgeon from St. Marie, Pa., who died in 2015. His daughter Melissa is the curator of the show and told ARTnews about the interesting connection her father had with art and surgery.
In 2010, Dr. Joseph gave his daughter a box of photos and said “Make me a famous artist,” she recalled. At first, “I was like, ‘These are weird,’ and then I put them under my bed for 10 years.”
Apparently he had been making art with his patients’ organs for about 15 years and had a system in which he put each one together. Before a surgery Dr. Joseph would make a note card with the patient’s name handwritten in calligraphy with a couple of pages taken out of the magazine from the waiting room as the backdrop. Afterward, when the patient was in recovery, the removed organ would be placed among the pages and the name card. A photo was taken with the same endoscope that was used for the procedure.
After the show’s debut, people reached out expressing their love for their photos. “I wish, before he died, I had asked him more questions about it,” Ms. Joseph told ARTnews. “I’m regretting it so much now, kicking myself.”
Who gets to take home an artsy photo of their gallbladder after getting it removed? Not us, that’s who. Each collage is a one-of-a-kind piece. They definitely should be framed and shown in an art gallery. Oh, right. Never mind.
Why it might be better to be a dog person
Here’s that old debate again: Dogs or cats? You probably have your own opinion, but research presented at this year’s Digestive Disease Week may have tipped the scale by showing that children who lived with dogs may be less likely to have Crohn’s disease as adults.
The research was done by having approximately 4,300 people closely related to patients with Crohn’s disease fill out an environmental questionnaire. Using these data, the research team looked into environmental factors such as size of the families, where the home was, how many bathrooms the homes had, and quality of drinking water.
The researchers found that those who had or were exposed to dogs between the ages of 5 and 15 years were more likely to have healthy gut permeability and balanced microbes, which increased their protection against Crohn’s disease.
“Our study seems to add to others that have explored the ‘hygiene hypothesis’ which suggests that the lack of exposure to microbes early in life may lead to lack of immune regulation toward environmental microbes,” senior author Williams Turpin, PhD, said in the written statement.
The researchers aren’t sure why they didn’t get the same findings with cats, but Dr. Turpin theorized that dog owners tend to be outside more with their dogs or live in places with more green space, which are good protectors against Crohn’s disease.
It’s all good for dog owners, but do their pets’ parasites make you more attractive? Just more fuel for the ongoing debate.
Come for the history, stay for the fossilized parasites
Another week, another analysis of old British poop. LOTME really is your one-stop shop for all the important, hard-hitting news about historic parasites. You’re welcome, Internet.
The news this week is from Stonehenge, which is apparently kind of a big deal. Rocks in a circle, celestial calendar, cultural significance, whatever. We’re not here to talk about rocks. We’re here to talk about, uh, rocks. Smaller rocks. Specifically, coprolites, which are essentially poop turned into a rock. (Though now we’re imagining Stonehenge made out of fossilized poop rocks. Would it still be a big tourist destination? We can see both sides of the argument on that one.)
Archaeologists from the University of Cambridge have conducted an analysis of coprolites from Durrington Walls, a Neolithic settlement just a few kilometers from Stonehenge. The town dates to the same time that Stonehenge was constructed, and it’s believed that the residents were responsible for building the landmark. These coprolites, depending on what’s inside, can tell us a lot about how the builders of Stonehenge lived and, more specifically, how they ate.
In this case, the coprolites of one human and three dogs contained capillariid worm eggs. These worms come from cows, and when a human is typically infected, the eggs embed in the liver and do not pass through the body. Finding them in excrement indicates that the people were eating raw cow organs and feeding leftovers to their dogs. This is interesting, because a preponderance of pottery and cooking implements also found at the site indicates that the residents of Durrington Walls were spit-roasting or boiling their beef and pork. So the meat was cooked, but not the organs. That is an interesting dietary decision, ancient British people. Then again, modern British cuisine exists. At least now we know where they got it from.
This new research raises one other very important question: When are we going to get a full-on guided tour of all the important coprolite sites in Britain? They’ve clearly got plenty of them, and the tourist demand for ancient parasites must be sky-high. Come on, capitalism, follow through on this. We’d go.
Everyone lies: Food intake edition
Do you have any patients on special diets? Do you ask them if they are following those diets? Don’t bother, because they’re lying. Everyone lies about the food they eat. Everyone. Obese people lie, and nonobese people lie.
Investigators at the University of Essex in England asked 221 adults to keep food diaries, and then they checked on energy consumption by analyzing radioactive water levels in the participants’ urine over a 10-day period.
Underreporting of food consumption was rampant, even among those who were not obese. The obese subjects did underreport by a greater extent (1,200 calories per day) than did those who were not obese, who were off by only 800 calories, but the obese participants burned about 400 calories more each day than did the nonobese, so the difference was a wash.
Everyone ended up underreporting their calorie consumption by an average of about 900 calories, and the investigators were good enough to provide some food equivalents, tops on the list being three MacDonald’s cheeseburgers.
“Public health recommendations have historically relied heavily on self-reported energy intake values,” senior author Gavin Sandercock, PhD, said in a EurekAlert statement, and “recognising that the measures of energy intake are incorrect might result in the setting of more realistic targets.”
Maybe you can be more realistic with your patients, too. Go ahead and ask Mr. Smith about the burger sticking out of his coat pocket, because there are probably two more you can’t see. We’ve each got 900 calories hiding on us somewhere. Ours is usually pizza.
The art of the gallbladder
Ever thought you would see a portrait of a gallbladder hanging up in a gallery? Not just an artist’s rendition, but an actual photo from an actual patient? Well, you can at the Soloway Gallery in Brooklyn, N.Y., at least until June 12.
The artist? K.C. Joseph, MD, a general surgeon from St. Marie, Pa., who died in 2015. His daughter Melissa is the curator of the show and told ARTnews about the interesting connection her father had with art and surgery.
In 2010, Dr. Joseph gave his daughter a box of photos and said “Make me a famous artist,” she recalled. At first, “I was like, ‘These are weird,’ and then I put them under my bed for 10 years.”
Apparently he had been making art with his patients’ organs for about 15 years and had a system in which he put each one together. Before a surgery Dr. Joseph would make a note card with the patient’s name handwritten in calligraphy with a couple of pages taken out of the magazine from the waiting room as the backdrop. Afterward, when the patient was in recovery, the removed organ would be placed among the pages and the name card. A photo was taken with the same endoscope that was used for the procedure.
After the show’s debut, people reached out expressing their love for their photos. “I wish, before he died, I had asked him more questions about it,” Ms. Joseph told ARTnews. “I’m regretting it so much now, kicking myself.”
Who gets to take home an artsy photo of their gallbladder after getting it removed? Not us, that’s who. Each collage is a one-of-a-kind piece. They definitely should be framed and shown in an art gallery. Oh, right. Never mind.
Why it might be better to be a dog person
Here’s that old debate again: Dogs or cats? You probably have your own opinion, but research presented at this year’s Digestive Disease Week may have tipped the scale by showing that children who lived with dogs may be less likely to have Crohn’s disease as adults.
The research was done by having approximately 4,300 people closely related to patients with Crohn’s disease fill out an environmental questionnaire. Using these data, the research team looked into environmental factors such as size of the families, where the home was, how many bathrooms the homes had, and quality of drinking water.
The researchers found that those who had or were exposed to dogs between the ages of 5 and 15 years were more likely to have healthy gut permeability and balanced microbes, which increased their protection against Crohn’s disease.
“Our study seems to add to others that have explored the ‘hygiene hypothesis’ which suggests that the lack of exposure to microbes early in life may lead to lack of immune regulation toward environmental microbes,” senior author Williams Turpin, PhD, said in the written statement.
The researchers aren’t sure why they didn’t get the same findings with cats, but Dr. Turpin theorized that dog owners tend to be outside more with their dogs or live in places with more green space, which are good protectors against Crohn’s disease.
It’s all good for dog owners, but do their pets’ parasites make you more attractive? Just more fuel for the ongoing debate.
Come for the history, stay for the fossilized parasites
Another week, another analysis of old British poop. LOTME really is your one-stop shop for all the important, hard-hitting news about historic parasites. You’re welcome, Internet.
The news this week is from Stonehenge, which is apparently kind of a big deal. Rocks in a circle, celestial calendar, cultural significance, whatever. We’re not here to talk about rocks. We’re here to talk about, uh, rocks. Smaller rocks. Specifically, coprolites, which are essentially poop turned into a rock. (Though now we’re imagining Stonehenge made out of fossilized poop rocks. Would it still be a big tourist destination? We can see both sides of the argument on that one.)
Archaeologists from the University of Cambridge have conducted an analysis of coprolites from Durrington Walls, a Neolithic settlement just a few kilometers from Stonehenge. The town dates to the same time that Stonehenge was constructed, and it’s believed that the residents were responsible for building the landmark. These coprolites, depending on what’s inside, can tell us a lot about how the builders of Stonehenge lived and, more specifically, how they ate.
In this case, the coprolites of one human and three dogs contained capillariid worm eggs. These worms come from cows, and when a human is typically infected, the eggs embed in the liver and do not pass through the body. Finding them in excrement indicates that the people were eating raw cow organs and feeding leftovers to their dogs. This is interesting, because a preponderance of pottery and cooking implements also found at the site indicates that the residents of Durrington Walls were spit-roasting or boiling their beef and pork. So the meat was cooked, but not the organs. That is an interesting dietary decision, ancient British people. Then again, modern British cuisine exists. At least now we know where they got it from.
This new research raises one other very important question: When are we going to get a full-on guided tour of all the important coprolite sites in Britain? They’ve clearly got plenty of them, and the tourist demand for ancient parasites must be sky-high. Come on, capitalism, follow through on this. We’d go.
Everyone lies: Food intake edition
Do you have any patients on special diets? Do you ask them if they are following those diets? Don’t bother, because they’re lying. Everyone lies about the food they eat. Everyone. Obese people lie, and nonobese people lie.
Investigators at the University of Essex in England asked 221 adults to keep food diaries, and then they checked on energy consumption by analyzing radioactive water levels in the participants’ urine over a 10-day period.
Underreporting of food consumption was rampant, even among those who were not obese. The obese subjects did underreport by a greater extent (1,200 calories per day) than did those who were not obese, who were off by only 800 calories, but the obese participants burned about 400 calories more each day than did the nonobese, so the difference was a wash.
Everyone ended up underreporting their calorie consumption by an average of about 900 calories, and the investigators were good enough to provide some food equivalents, tops on the list being three MacDonald’s cheeseburgers.
“Public health recommendations have historically relied heavily on self-reported energy intake values,” senior author Gavin Sandercock, PhD, said in a EurekAlert statement, and “recognising that the measures of energy intake are incorrect might result in the setting of more realistic targets.”
Maybe you can be more realistic with your patients, too. Go ahead and ask Mr. Smith about the burger sticking out of his coat pocket, because there are probably two more you can’t see. We’ve each got 900 calories hiding on us somewhere. Ours is usually pizza.
The art of the gallbladder
Ever thought you would see a portrait of a gallbladder hanging up in a gallery? Not just an artist’s rendition, but an actual photo from an actual patient? Well, you can at the Soloway Gallery in Brooklyn, N.Y., at least until June 12.
The artist? K.C. Joseph, MD, a general surgeon from St. Marie, Pa., who died in 2015. His daughter Melissa is the curator of the show and told ARTnews about the interesting connection her father had with art and surgery.
In 2010, Dr. Joseph gave his daughter a box of photos and said “Make me a famous artist,” she recalled. At first, “I was like, ‘These are weird,’ and then I put them under my bed for 10 years.”
Apparently he had been making art with his patients’ organs for about 15 years and had a system in which he put each one together. Before a surgery Dr. Joseph would make a note card with the patient’s name handwritten in calligraphy with a couple of pages taken out of the magazine from the waiting room as the backdrop. Afterward, when the patient was in recovery, the removed organ would be placed among the pages and the name card. A photo was taken with the same endoscope that was used for the procedure.
After the show’s debut, people reached out expressing their love for their photos. “I wish, before he died, I had asked him more questions about it,” Ms. Joseph told ARTnews. “I’m regretting it so much now, kicking myself.”
Who gets to take home an artsy photo of their gallbladder after getting it removed? Not us, that’s who. Each collage is a one-of-a-kind piece. They definitely should be framed and shown in an art gallery. Oh, right. Never mind.
Specialists hail new era in hemophilia treatment
“It’s an amazing time to be a hemophilia provider,” Alice D. Ma, MD, University of North Carolina at Chapel Hill hematologist and bleeding disorder specialist, said in an interview. “There are real options, and it’s very exciting.”
But the drugs come with quirks that hematologists must understand, hemophilia specialists cautioned, and stubborn insurers pose significant obstacles to appropriate care. Also, new generations of medications in development offer both hope and more questions.
By far, the biggest game changer in hemophilia A is a monoclonal antibody called emicizumab (Hemlibra), first approved by the Food and Drug Administration for hemophilia A patients with factor VIII inhibitors and then in 2018 for those without factor VIII inhibitors.
“It’s just been getting a bigger and bigger slice of market share as patients and parents really buy in to how great that product is,” Dr. Ma said. “I do not have any hemophilia A patients with factor VIII inhibitors who aren’t on it. That’s just kind of a no-brainer, no ifs, ands, or buts.”
About 50%-60% of her noninhibitor patients with hemophilia A take the drug, she said.
According to its manufacturer, Genentech, the drug “acts like a bridge, bringing factor IXa and factor X together to allow the blood coagulation process to continue without needing to replace factor VIII.”
Since emicizumab is not a blood factor, Dr. Ma said, it doesn’t cross-react with antibodies or inhibitors. “The other thing that is pretty amazing is that it’s given subcutaneously as opposed to intravenously. It’s given under the skin, kind of like an insulin shot, rather than into a vein.”
Prophylaxis treatments did exist for patients with hemophilia A prior to emicizumab, University of North Carolina at Chapel Hill hematologist and blood disorder specialist Nigel S. Key, MB, ChB, said in an interview. But the treatments didn’t stop all bleeding. “We never really kept them under control,” he said, adding that patients needed to get infusions several times a week. “It was cumbersome and took a lot of compliance, a lot of effort to do it.
Thanks to emicizumab, adult patients don’t have to put on tourniquets and stick butterfly needles into their own veins anymore, and parents no longer need to regularly give factor infusions to their children every 2-3 days, Dr. Ma said. Instead, doses may be required just once a week.
Not every patient is eager to embrace emicizumab
Emicizumab isn’t necessarily an easy sell. Home-care company pharmacies don’t get reimbursed as much for providing emicizumab, compared with factor infusions, Dr. Ma said, and some of these companies are urging parents to not accept the drug for their kids.
Prior experience can also make people wary. According to Dr. Ma, one of her patients – a 62-year-old man – was reluctant to take factor because he’d gotten infected with HIV from an infusion. “For guys of that certain age, factor was death. It was poison, so you tried really hard not to take it.”
The patient now regrets not taking emicizumab earlier. He told Dr. Ma that his joints “do feel better than when I took factor regularly,” and “he really thinks that it has made his hemophilia recede into the background of his life, which is pretty, pretty nice.”
In fact, Dr. Ma said, he dropped a 7-pound rock on his foot but did not need to take factor or be hospitalized because of bleeding. Instead, he simply “watched a bruise form and then get better.”
As for challenges beyond convincing patients to take emicizumab, Dr. Ma said that insurers can may still refuse to pay for it in noninhibitor patients. “Some of them say you have to fail a regular clotting factor to be able to take Hemlibra,” she said, noting that she finds this viewpoint intolerable.
Hemlibra is remarkably expensive, but treatment of bleeds is also pricey. A 2021 study found that median 6-month hemostatic treatment costs in hemophilia A patients fell from more than $176,000 to barely $128,000 after they started taking the drug.
There’s another hitch. Some hematologists don’t realize that the drug can throw off certain coagulation readings. Dr. Ma recalled that a patient with hemophilia A went to a different healthcare facility for a gall bladder operation, and hematology fellows there failed to adjust his factor VIII level – an extraordinarily high 400%, suggesting high coagulation – to reflect his use of emicizumab.
“My patient bled severely and could have lost his life,” Dr. Ma said.
Despite gains, hemophilia B remains hard to treat
The much rarer hemophilia B (the type that affected members of European royal families who descended from Queen Victoria) has proved more difficult to treat than hemophilia A. An estimated 1 in 5,600 males in the United States are born with hemophilia A, compared with 1 in 19,300 males born with hemophilia B. The conditions rarely affect females.
Recombinant factor IX products that replace a missing protein have been improved and can now be given every 7 or 14 days, instead of twice a week, Dr. Key said. As for the future, so-called rebalancing therapies are in phase 3 trials and look promising: “Instead of trying to beef up the proclotting proteins, you’re trying to knock down the anticlotting proteins. ‘Rebalancing’ is a good way to think of it.”
These treatments are also agnostic – like Hemlibra – to the presence of inhibitors, he said.
These drugs could be available within a few years, Dr. Key said. “The major concern is always going to be a risk of thrombosis or clotting. Some of that has only become apparent through clinical trials and require a return to the drawing board to redesign the dosing to hit the safe, sweet spot that prevents bleeds but doesn’t cause clots.”
Dr. Ma agreed that clots are a significant risk from rebalancing agents. “I don’t know that I would put a factor IX patient without an inhibitor on a rebalancing therapy, because we already have pretty darn good therapies for them,” she said. However, factor IX patients with inhibitors do need better treatments, “and we’re all looking forward to the next approved drugs there.”
Hoopla for gene therapy, with questions, as well
The prospect of gene therapy for hemophilia, meanwhile, continues to draw attention as phase 3 trials continue. Potentially, gene therapy could be given just once to patients with hemophilia A or hemophilia B and provide bleeding control indefinitely, Dr. Ma said.
However, Dr. Key wondered whether gene therapy may be useful in hemophilia A, since emicizumab has worked so well. “I just don’t see the tsunami of patients who are wanting to undergo gene therapy in the first few years. I think there’ll be relatively slow uptake due to a lot of factors, including reimbursement.”
Hematologist Amar H. Kelkar, MD, of Dana-Farber Cancer Institute in Boston, is also skeptical that a groundswell of patients will embrace gene therapy, even if one-time treatment lasts for years. Current treatments are working well for many patients, Dr. Kelkar said in an interview, “and comfort with novel therapies may be slow within the community, especially if the treatment effect is expected to be transient. This is the same community that was hit hard by contaminated blood products during the HIV crisis, so it may be hard to convince a large number of patients to adopt a new type of therapy. There’s also the issue of the projected high upfront cost of gene therapies. Of course, I’d love to be wrong, especially if cost issues for the patients can be mitigated.”
Moving forward, both Dr. Ma and Dr. Key urged hematologists to send their hemophilia patients to Hemophilia Treatment Centers so they can get specialized care. There are about 140 of these federally funded centers around the country, according to the National Hemophilia Foundation. Many are located in children’s hospitals.
Hemophilia treatment now requires a subspecialty degree of knowledge that’s difficult for a hematologist in general practice to master, Dr. Ma said. “If you have a patient with hemophilia, and you’re in private practice for general hematology/oncology, please send them to a Hemophilia Treatment Center for something like a once-a-year check-in to make sure that the patient is getting comprehensive care.”
Dr. Ma discloses relationships with Takeda (research funding and consultation). Dr. Key discloses relationships with BioMarin and Takeda (advisory board), Novo Nordisk (grants review committee), and Uniqure (steering committee). Dr. Kelkar has no disclosures.
“It’s an amazing time to be a hemophilia provider,” Alice D. Ma, MD, University of North Carolina at Chapel Hill hematologist and bleeding disorder specialist, said in an interview. “There are real options, and it’s very exciting.”
But the drugs come with quirks that hematologists must understand, hemophilia specialists cautioned, and stubborn insurers pose significant obstacles to appropriate care. Also, new generations of medications in development offer both hope and more questions.
By far, the biggest game changer in hemophilia A is a monoclonal antibody called emicizumab (Hemlibra), first approved by the Food and Drug Administration for hemophilia A patients with factor VIII inhibitors and then in 2018 for those without factor VIII inhibitors.
“It’s just been getting a bigger and bigger slice of market share as patients and parents really buy in to how great that product is,” Dr. Ma said. “I do not have any hemophilia A patients with factor VIII inhibitors who aren’t on it. That’s just kind of a no-brainer, no ifs, ands, or buts.”
About 50%-60% of her noninhibitor patients with hemophilia A take the drug, she said.
According to its manufacturer, Genentech, the drug “acts like a bridge, bringing factor IXa and factor X together to allow the blood coagulation process to continue without needing to replace factor VIII.”
Since emicizumab is not a blood factor, Dr. Ma said, it doesn’t cross-react with antibodies or inhibitors. “The other thing that is pretty amazing is that it’s given subcutaneously as opposed to intravenously. It’s given under the skin, kind of like an insulin shot, rather than into a vein.”
Prophylaxis treatments did exist for patients with hemophilia A prior to emicizumab, University of North Carolina at Chapel Hill hematologist and blood disorder specialist Nigel S. Key, MB, ChB, said in an interview. But the treatments didn’t stop all bleeding. “We never really kept them under control,” he said, adding that patients needed to get infusions several times a week. “It was cumbersome and took a lot of compliance, a lot of effort to do it.
Thanks to emicizumab, adult patients don’t have to put on tourniquets and stick butterfly needles into their own veins anymore, and parents no longer need to regularly give factor infusions to their children every 2-3 days, Dr. Ma said. Instead, doses may be required just once a week.
Not every patient is eager to embrace emicizumab
Emicizumab isn’t necessarily an easy sell. Home-care company pharmacies don’t get reimbursed as much for providing emicizumab, compared with factor infusions, Dr. Ma said, and some of these companies are urging parents to not accept the drug for their kids.
Prior experience can also make people wary. According to Dr. Ma, one of her patients – a 62-year-old man – was reluctant to take factor because he’d gotten infected with HIV from an infusion. “For guys of that certain age, factor was death. It was poison, so you tried really hard not to take it.”
The patient now regrets not taking emicizumab earlier. He told Dr. Ma that his joints “do feel better than when I took factor regularly,” and “he really thinks that it has made his hemophilia recede into the background of his life, which is pretty, pretty nice.”
In fact, Dr. Ma said, he dropped a 7-pound rock on his foot but did not need to take factor or be hospitalized because of bleeding. Instead, he simply “watched a bruise form and then get better.”
As for challenges beyond convincing patients to take emicizumab, Dr. Ma said that insurers can may still refuse to pay for it in noninhibitor patients. “Some of them say you have to fail a regular clotting factor to be able to take Hemlibra,” she said, noting that she finds this viewpoint intolerable.
Hemlibra is remarkably expensive, but treatment of bleeds is also pricey. A 2021 study found that median 6-month hemostatic treatment costs in hemophilia A patients fell from more than $176,000 to barely $128,000 after they started taking the drug.
There’s another hitch. Some hematologists don’t realize that the drug can throw off certain coagulation readings. Dr. Ma recalled that a patient with hemophilia A went to a different healthcare facility for a gall bladder operation, and hematology fellows there failed to adjust his factor VIII level – an extraordinarily high 400%, suggesting high coagulation – to reflect his use of emicizumab.
“My patient bled severely and could have lost his life,” Dr. Ma said.
Despite gains, hemophilia B remains hard to treat
The much rarer hemophilia B (the type that affected members of European royal families who descended from Queen Victoria) has proved more difficult to treat than hemophilia A. An estimated 1 in 5,600 males in the United States are born with hemophilia A, compared with 1 in 19,300 males born with hemophilia B. The conditions rarely affect females.
Recombinant factor IX products that replace a missing protein have been improved and can now be given every 7 or 14 days, instead of twice a week, Dr. Key said. As for the future, so-called rebalancing therapies are in phase 3 trials and look promising: “Instead of trying to beef up the proclotting proteins, you’re trying to knock down the anticlotting proteins. ‘Rebalancing’ is a good way to think of it.”
These treatments are also agnostic – like Hemlibra – to the presence of inhibitors, he said.
These drugs could be available within a few years, Dr. Key said. “The major concern is always going to be a risk of thrombosis or clotting. Some of that has only become apparent through clinical trials and require a return to the drawing board to redesign the dosing to hit the safe, sweet spot that prevents bleeds but doesn’t cause clots.”
Dr. Ma agreed that clots are a significant risk from rebalancing agents. “I don’t know that I would put a factor IX patient without an inhibitor on a rebalancing therapy, because we already have pretty darn good therapies for them,” she said. However, factor IX patients with inhibitors do need better treatments, “and we’re all looking forward to the next approved drugs there.”
Hoopla for gene therapy, with questions, as well
The prospect of gene therapy for hemophilia, meanwhile, continues to draw attention as phase 3 trials continue. Potentially, gene therapy could be given just once to patients with hemophilia A or hemophilia B and provide bleeding control indefinitely, Dr. Ma said.
However, Dr. Key wondered whether gene therapy may be useful in hemophilia A, since emicizumab has worked so well. “I just don’t see the tsunami of patients who are wanting to undergo gene therapy in the first few years. I think there’ll be relatively slow uptake due to a lot of factors, including reimbursement.”
Hematologist Amar H. Kelkar, MD, of Dana-Farber Cancer Institute in Boston, is also skeptical that a groundswell of patients will embrace gene therapy, even if one-time treatment lasts for years. Current treatments are working well for many patients, Dr. Kelkar said in an interview, “and comfort with novel therapies may be slow within the community, especially if the treatment effect is expected to be transient. This is the same community that was hit hard by contaminated blood products during the HIV crisis, so it may be hard to convince a large number of patients to adopt a new type of therapy. There’s also the issue of the projected high upfront cost of gene therapies. Of course, I’d love to be wrong, especially if cost issues for the patients can be mitigated.”
Moving forward, both Dr. Ma and Dr. Key urged hematologists to send their hemophilia patients to Hemophilia Treatment Centers so they can get specialized care. There are about 140 of these federally funded centers around the country, according to the National Hemophilia Foundation. Many are located in children’s hospitals.
Hemophilia treatment now requires a subspecialty degree of knowledge that’s difficult for a hematologist in general practice to master, Dr. Ma said. “If you have a patient with hemophilia, and you’re in private practice for general hematology/oncology, please send them to a Hemophilia Treatment Center for something like a once-a-year check-in to make sure that the patient is getting comprehensive care.”
Dr. Ma discloses relationships with Takeda (research funding and consultation). Dr. Key discloses relationships with BioMarin and Takeda (advisory board), Novo Nordisk (grants review committee), and Uniqure (steering committee). Dr. Kelkar has no disclosures.
“It’s an amazing time to be a hemophilia provider,” Alice D. Ma, MD, University of North Carolina at Chapel Hill hematologist and bleeding disorder specialist, said in an interview. “There are real options, and it’s very exciting.”
But the drugs come with quirks that hematologists must understand, hemophilia specialists cautioned, and stubborn insurers pose significant obstacles to appropriate care. Also, new generations of medications in development offer both hope and more questions.
By far, the biggest game changer in hemophilia A is a monoclonal antibody called emicizumab (Hemlibra), first approved by the Food and Drug Administration for hemophilia A patients with factor VIII inhibitors and then in 2018 for those without factor VIII inhibitors.
“It’s just been getting a bigger and bigger slice of market share as patients and parents really buy in to how great that product is,” Dr. Ma said. “I do not have any hemophilia A patients with factor VIII inhibitors who aren’t on it. That’s just kind of a no-brainer, no ifs, ands, or buts.”
About 50%-60% of her noninhibitor patients with hemophilia A take the drug, she said.
According to its manufacturer, Genentech, the drug “acts like a bridge, bringing factor IXa and factor X together to allow the blood coagulation process to continue without needing to replace factor VIII.”
Since emicizumab is not a blood factor, Dr. Ma said, it doesn’t cross-react with antibodies or inhibitors. “The other thing that is pretty amazing is that it’s given subcutaneously as opposed to intravenously. It’s given under the skin, kind of like an insulin shot, rather than into a vein.”
Prophylaxis treatments did exist for patients with hemophilia A prior to emicizumab, University of North Carolina at Chapel Hill hematologist and blood disorder specialist Nigel S. Key, MB, ChB, said in an interview. But the treatments didn’t stop all bleeding. “We never really kept them under control,” he said, adding that patients needed to get infusions several times a week. “It was cumbersome and took a lot of compliance, a lot of effort to do it.
Thanks to emicizumab, adult patients don’t have to put on tourniquets and stick butterfly needles into their own veins anymore, and parents no longer need to regularly give factor infusions to their children every 2-3 days, Dr. Ma said. Instead, doses may be required just once a week.
Not every patient is eager to embrace emicizumab
Emicizumab isn’t necessarily an easy sell. Home-care company pharmacies don’t get reimbursed as much for providing emicizumab, compared with factor infusions, Dr. Ma said, and some of these companies are urging parents to not accept the drug for their kids.
Prior experience can also make people wary. According to Dr. Ma, one of her patients – a 62-year-old man – was reluctant to take factor because he’d gotten infected with HIV from an infusion. “For guys of that certain age, factor was death. It was poison, so you tried really hard not to take it.”
The patient now regrets not taking emicizumab earlier. He told Dr. Ma that his joints “do feel better than when I took factor regularly,” and “he really thinks that it has made his hemophilia recede into the background of his life, which is pretty, pretty nice.”
In fact, Dr. Ma said, he dropped a 7-pound rock on his foot but did not need to take factor or be hospitalized because of bleeding. Instead, he simply “watched a bruise form and then get better.”
As for challenges beyond convincing patients to take emicizumab, Dr. Ma said that insurers can may still refuse to pay for it in noninhibitor patients. “Some of them say you have to fail a regular clotting factor to be able to take Hemlibra,” she said, noting that she finds this viewpoint intolerable.
Hemlibra is remarkably expensive, but treatment of bleeds is also pricey. A 2021 study found that median 6-month hemostatic treatment costs in hemophilia A patients fell from more than $176,000 to barely $128,000 after they started taking the drug.
There’s another hitch. Some hematologists don’t realize that the drug can throw off certain coagulation readings. Dr. Ma recalled that a patient with hemophilia A went to a different healthcare facility for a gall bladder operation, and hematology fellows there failed to adjust his factor VIII level – an extraordinarily high 400%, suggesting high coagulation – to reflect his use of emicizumab.
“My patient bled severely and could have lost his life,” Dr. Ma said.
Despite gains, hemophilia B remains hard to treat
The much rarer hemophilia B (the type that affected members of European royal families who descended from Queen Victoria) has proved more difficult to treat than hemophilia A. An estimated 1 in 5,600 males in the United States are born with hemophilia A, compared with 1 in 19,300 males born with hemophilia B. The conditions rarely affect females.
Recombinant factor IX products that replace a missing protein have been improved and can now be given every 7 or 14 days, instead of twice a week, Dr. Key said. As for the future, so-called rebalancing therapies are in phase 3 trials and look promising: “Instead of trying to beef up the proclotting proteins, you’re trying to knock down the anticlotting proteins. ‘Rebalancing’ is a good way to think of it.”
These treatments are also agnostic – like Hemlibra – to the presence of inhibitors, he said.
These drugs could be available within a few years, Dr. Key said. “The major concern is always going to be a risk of thrombosis or clotting. Some of that has only become apparent through clinical trials and require a return to the drawing board to redesign the dosing to hit the safe, sweet spot that prevents bleeds but doesn’t cause clots.”
Dr. Ma agreed that clots are a significant risk from rebalancing agents. “I don’t know that I would put a factor IX patient without an inhibitor on a rebalancing therapy, because we already have pretty darn good therapies for them,” she said. However, factor IX patients with inhibitors do need better treatments, “and we’re all looking forward to the next approved drugs there.”
Hoopla for gene therapy, with questions, as well
The prospect of gene therapy for hemophilia, meanwhile, continues to draw attention as phase 3 trials continue. Potentially, gene therapy could be given just once to patients with hemophilia A or hemophilia B and provide bleeding control indefinitely, Dr. Ma said.
However, Dr. Key wondered whether gene therapy may be useful in hemophilia A, since emicizumab has worked so well. “I just don’t see the tsunami of patients who are wanting to undergo gene therapy in the first few years. I think there’ll be relatively slow uptake due to a lot of factors, including reimbursement.”
Hematologist Amar H. Kelkar, MD, of Dana-Farber Cancer Institute in Boston, is also skeptical that a groundswell of patients will embrace gene therapy, even if one-time treatment lasts for years. Current treatments are working well for many patients, Dr. Kelkar said in an interview, “and comfort with novel therapies may be slow within the community, especially if the treatment effect is expected to be transient. This is the same community that was hit hard by contaminated blood products during the HIV crisis, so it may be hard to convince a large number of patients to adopt a new type of therapy. There’s also the issue of the projected high upfront cost of gene therapies. Of course, I’d love to be wrong, especially if cost issues for the patients can be mitigated.”
Moving forward, both Dr. Ma and Dr. Key urged hematologists to send their hemophilia patients to Hemophilia Treatment Centers so they can get specialized care. There are about 140 of these federally funded centers around the country, according to the National Hemophilia Foundation. Many are located in children’s hospitals.
Hemophilia treatment now requires a subspecialty degree of knowledge that’s difficult for a hematologist in general practice to master, Dr. Ma said. “If you have a patient with hemophilia, and you’re in private practice for general hematology/oncology, please send them to a Hemophilia Treatment Center for something like a once-a-year check-in to make sure that the patient is getting comprehensive care.”
Dr. Ma discloses relationships with Takeda (research funding and consultation). Dr. Key discloses relationships with BioMarin and Takeda (advisory board), Novo Nordisk (grants review committee), and Uniqure (steering committee). Dr. Kelkar has no disclosures.
Phase-3 study: Leukemia patients live longer with ibrutinib
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
FROM BLOOD ADVANCES