Hematology News

In December, in what’s known as the “Take Care of Maya” case, a Florida jury returned a record $261 million verdict against Johns Hopkins All Children’s Hospital, St. Petersburg, Florida, for its treatment of a young patient and her family after an emergency room visit.

A month earlier, in New York, a jury ordered Westchester Medical Center Health Network to pay $120 million to a patient and his family following delayed stroke care that resulted in brain damage.

Mega malpractice awards like these are rising against physicians and hospitals around the country, according to new data from TransRe, an international reinsurance company that tracks large verdicts.

“2023 blew away every record previously set among high medical malpractice verdicts,” said Richard Henderson, senior vice president for TransRe. “If we look at the 50 largest verdicts in 2023 and average them out, we have a higher monetary amount than any other year.”

In 2023, there were 57 medical malpractice verdicts of $10 million or more in the United States, the data showed. Slightly more than half of those reached $25 million or more.

From 2012 to 2022, verdicts of $10 million or more ranged from 34 in 2013 to 52 in 2022, TransRe research found.

While New York, Illinois, and Florida typically saw the highest dollar verdicts in previous years, so-called “nuclear” verdicts now occur in states like Utah and Georgia where they once were uncommon, said Robert E. White Jr., president of TDC Group and The Doctors Company, a national medical liability insurer for physicians.

A rollback of tort reforms across the country is one contributor, he said. For example, Georgia’s cap on noneconomic damages is among those that have been ruled unconstitutional by courts. Utah’s cap on noneconomic damages still stands, but the limit was deemed unconstitutional in wrongful death cases. In 2019, a portion of Utah›s pre-litigation panel process was also struck down by the state’s Supreme Court.

“We used to be able to predict where these high verdicts would occur,” Mr. White said. “We can’t predict it anymore.”

Research shows a majority of malpractice cases are dropped or settled before trial, and claims that go before juries usually end in doctors’ favor. Plaintiffs’ attorneys cite large jury verdicts in similar cases to induce settlements and higher payouts, Mr. White said.

And while mega verdicts rarely stick, they can have lasting effects on future claims. The awards lead to larger settlement demands from plaintiffs and drive up the cost to resolve claims, according to Mr. Henderson and Mr. White.

“Verdicts are the yardstick by which all settlements are measured,” Mr. White said. “That’s where the damage is done.” The prospect of a mega verdict can make insurers leery of fighting some malpractice cases and motivate them to offer bigger settlements to stay out of the courtroom, he added.

Why Are Juries Awarding Higher Verdicts?

There’s no single reason for the rise in nuclear verdicts, Mr. Henderson said.

One theory is that plaintiffs’ attorneys held back on resolving high-dollar cases during the COVID pandemic and let loose with high-demand claims when courts returned to normal, he said.

Another theory is that people emerged from the pandemic angrier.

“Whether it was political dynamics, masking [mandates], or differences in opinions, people came out of it angry, and generally speaking, you don’t want an angry jury,” Mr. Henderson said. “For a while, there was the halo effect, where health professionals were seen as heroes. That went away, and all of a sudden [they] became ‘the bad guys.’ ”

“People are angry at the healthcare system, and this anger manifests itself in [liability] suits,” added Bill Burns, vice president of research for the Medical Professional Liability Association, an industry group for medical liability insurers.

Hospital and medical group consolidation also reduces the personal connection juries may have with healthcare providers, Mr. Burns said.

“Healthcare has become a big business, and the corporatization of medicine now puts companies on the stand and not your local community hospital or your family doctor that you have known since birth,” he said.

Plaintiffs’ attorneys also deploy tactics that can prompt higher verdicts, Mr. White said. They may tell a jury that the provider or hospital is a threat to the community and that awarding a large verdict will deter others in the healthcare community from repeating the same actions.

Juries may then want to punish the defendant in addition to assessing damages for economic harm or pain and suffering, Mr. White said.

“I am concerned that jurors are trying to right social wrongs rather than judging cases on the facts presented to them,” added Mike Stinson, vice president for policy and legal affairs for the Medical Professional Liability Association.

Third-party litigation financing also can lead to mega verdicts. That’s an emerging practice in which companies unrelated to a lawsuit provide capital to plaintiffs in return for a portion of any financial award. The firms essentially “invest” in the litigation.

“What this does is provide an additional financial backdrop for plaintiffs,” Mr. Henderson said. “It allows them to dig in harder on cases. They can hold out for higher numbers, and if nothing else, it can prolong litigation.”

Do High Awards Actually Stick?

Multimillion-dollar verdicts may grab headlines, but do plaintiffs actually receive them?

Rarely, said TransRe, which tracks the final outcomes of verdicts. In many cases, large verdicts are reduced on appeal.

In the Maya case, which involved child protection authorities, a judge later lowered the damages against Johns Hopkins All Children’s Hospital by $47.5 million.

A federal judge in October, for example, rejected a record $110 million medical malpractice award in Minnesota, reducing it to $10 million. The district judge ruled the award was “shockingly excessive” and that the plaintiff should either accept the $10 million award or retry the case.

After a verdict is awarded, the defendant typically challenges the award, and the case goes through the appellate pipeline, Mr. Henderson explained. A judge may reduce some elements of the verdict, he said, but more often, the plaintiff and defendant agree on a compromised figure.

Seattle medical liability defense attorney Jennifer Crisera has experienced this firsthand. She recalled a recent case where a plaintiff’s attorney demanded what she describes as an unreasonable amount to settle a claim. Ms. Crisera did not want to give exact numbers but said the plaintiff made an 8-figure demand and the defense offered a low 7-figure range.

“My impression was that plaintiff’s counsel believed that they could get a nuclear verdict from the jury, so they kept their settlement demand artificially high,” she said. “The division between the numbers was way too high. Ultimately, we had to let a jury decide the value.”

The plaintiff won the case, and the verdict was much less than the settlement demand, she said. Even so, the defense incurred trial costs, and the health provider was forced to endure the emotional stress of a trial that could have been avoided, Ms. Crisera said.

Higher medical malpractice premiums are another consequence of massive awards.

Premium rates are associated with how much insurers pay on average for cases and how frequently they are making payouts, Mr. White said.

Medical liability insurance premiums for physicians have steadily increased since 2019, according to data from the Medical Liability Monitor, a national publication that analyzes liability insurance premiums. The Monitor studies insurance premium data from insurers that cover internists, general surgeons, and obstetrician-gynecologists.

From 2019 to 2023, average premium rates for physicians increased between 1.1% and 3% each year in states without patient compensation funds, according to Monitor data.

“Nuclear verdicts are a real driver of the industry’s underwriting losses and remain top of mind for every malpractice insurance company,” said Michael Matray, editor for the Medical Liability Monitor. “Responses to this year’s rate survey questionnaire indicate that most responding companies have experienced an increase in claims greater than $1 million and claims greater than $5 million during the past 2 years.”

However, increases vary widely by region and among counties. In Montgomery County, Alabama, for instance, premiums for internists rose by 24% from 2022 to 2023, from $8,231 to $10,240. Premiums for Montgomery County general surgeons rose by 11.9% from 2022 to 2023, from $30,761 to $34,426, according to survey data.

In several counties in Illinois (Adams, Knox, Peoria, and Rock Island), premiums for some internists rose by 15% from $24,041 to $27,783, and premiums for some surgeons increased by 27% from $60,202 to $76,461, according to survey data. Some internists in Catoosa County, Georgia, meanwhile, paid $17,831 in 2023, up from $16,313 in 2022. Some surgeons in Catoosa County paid $65,616 in 2023, up from $60,032 in 2022. Inflation could be one factor behind higher liability premium rates. Claim severity is a key driver of higher premium rates, Mr. White added.

“We have not seen stability in claims severity,” he said. “It is continuing to go up and, in all likelihood, it will drive [premium] rates up further from this point.”
 

A version of this article appeared on Medscape.com.

In December, in what’s known as the “Take Care of Maya” case, a Florida jury returned a record $261 million verdict against Johns Hopkins All Children’s Hospital, St. Petersburg, Florida, for its treatment of a young patient and her family after an emergency room visit.

A month earlier, in New York, a jury ordered Westchester Medical Center Health Network to pay $120 million to a patient and his family following delayed stroke care that resulted in brain damage.

Mega malpractice awards like these are rising against physicians and hospitals around the country, according to new data from TransRe, an international reinsurance company that tracks large verdicts.

“2023 blew away every record previously set among high medical malpractice verdicts,” said Richard Henderson, senior vice president for TransRe. “If we look at the 50 largest verdicts in 2023 and average them out, we have a higher monetary amount than any other year.”

In 2023, there were 57 medical malpractice verdicts of $10 million or more in the United States, the data showed. Slightly more than half of those reached $25 million or more.

From 2012 to 2022, verdicts of $10 million or more ranged from 34 in 2013 to 52 in 2022, TransRe research found.

While New York, Illinois, and Florida typically saw the highest dollar verdicts in previous years, so-called “nuclear” verdicts now occur in states like Utah and Georgia where they once were uncommon, said Robert E. White Jr., president of TDC Group and The Doctors Company, a national medical liability insurer for physicians.

A rollback of tort reforms across the country is one contributor, he said. For example, Georgia’s cap on noneconomic damages is among those that have been ruled unconstitutional by courts. Utah’s cap on noneconomic damages still stands, but the limit was deemed unconstitutional in wrongful death cases. In 2019, a portion of Utah›s pre-litigation panel process was also struck down by the state’s Supreme Court.

“We used to be able to predict where these high verdicts would occur,” Mr. White said. “We can’t predict it anymore.”

Research shows a majority of malpractice cases are dropped or settled before trial, and claims that go before juries usually end in doctors’ favor. Plaintiffs’ attorneys cite large jury verdicts in similar cases to induce settlements and higher payouts, Mr. White said.

And while mega verdicts rarely stick, they can have lasting effects on future claims. The awards lead to larger settlement demands from plaintiffs and drive up the cost to resolve claims, according to Mr. Henderson and Mr. White.

“Verdicts are the yardstick by which all settlements are measured,” Mr. White said. “That’s where the damage is done.” The prospect of a mega verdict can make insurers leery of fighting some malpractice cases and motivate them to offer bigger settlements to stay out of the courtroom, he added.

Why Are Juries Awarding Higher Verdicts?

There’s no single reason for the rise in nuclear verdicts, Mr. Henderson said.

One theory is that plaintiffs’ attorneys held back on resolving high-dollar cases during the COVID pandemic and let loose with high-demand claims when courts returned to normal, he said.

Another theory is that people emerged from the pandemic angrier.

“Whether it was political dynamics, masking [mandates], or differences in opinions, people came out of it angry, and generally speaking, you don’t want an angry jury,” Mr. Henderson said. “For a while, there was the halo effect, where health professionals were seen as heroes. That went away, and all of a sudden [they] became ‘the bad guys.’ ”

“People are angry at the healthcare system, and this anger manifests itself in [liability] suits,” added Bill Burns, vice president of research for the Medical Professional Liability Association, an industry group for medical liability insurers.

Hospital and medical group consolidation also reduces the personal connection juries may have with healthcare providers, Mr. Burns said.

“Healthcare has become a big business, and the corporatization of medicine now puts companies on the stand and not your local community hospital or your family doctor that you have known since birth,” he said.

Plaintiffs’ attorneys also deploy tactics that can prompt higher verdicts, Mr. White said. They may tell a jury that the provider or hospital is a threat to the community and that awarding a large verdict will deter others in the healthcare community from repeating the same actions.

Juries may then want to punish the defendant in addition to assessing damages for economic harm or pain and suffering, Mr. White said.

“I am concerned that jurors are trying to right social wrongs rather than judging cases on the facts presented to them,” added Mike Stinson, vice president for policy and legal affairs for the Medical Professional Liability Association.

Third-party litigation financing also can lead to mega verdicts. That’s an emerging practice in which companies unrelated to a lawsuit provide capital to plaintiffs in return for a portion of any financial award. The firms essentially “invest” in the litigation.

“What this does is provide an additional financial backdrop for plaintiffs,” Mr. Henderson said. “It allows them to dig in harder on cases. They can hold out for higher numbers, and if nothing else, it can prolong litigation.”

Do High Awards Actually Stick?

Multimillion-dollar verdicts may grab headlines, but do plaintiffs actually receive them?

Rarely, said TransRe, which tracks the final outcomes of verdicts. In many cases, large verdicts are reduced on appeal.

In the Maya case, which involved child protection authorities, a judge later lowered the damages against Johns Hopkins All Children’s Hospital by $47.5 million.

A federal judge in October, for example, rejected a record $110 million medical malpractice award in Minnesota, reducing it to $10 million. The district judge ruled the award was “shockingly excessive” and that the plaintiff should either accept the $10 million award or retry the case.

After a verdict is awarded, the defendant typically challenges the award, and the case goes through the appellate pipeline, Mr. Henderson explained. A judge may reduce some elements of the verdict, he said, but more often, the plaintiff and defendant agree on a compromised figure.

Seattle medical liability defense attorney Jennifer Crisera has experienced this firsthand. She recalled a recent case where a plaintiff’s attorney demanded what she describes as an unreasonable amount to settle a claim. Ms. Crisera did not want to give exact numbers but said the plaintiff made an 8-figure demand and the defense offered a low 7-figure range.

“My impression was that plaintiff’s counsel believed that they could get a nuclear verdict from the jury, so they kept their settlement demand artificially high,” she said. “The division between the numbers was way too high. Ultimately, we had to let a jury decide the value.”

The plaintiff won the case, and the verdict was much less than the settlement demand, she said. Even so, the defense incurred trial costs, and the health provider was forced to endure the emotional stress of a trial that could have been avoided, Ms. Crisera said.

Higher medical malpractice premiums are another consequence of massive awards.

Premium rates are associated with how much insurers pay on average for cases and how frequently they are making payouts, Mr. White said.

Medical liability insurance premiums for physicians have steadily increased since 2019, according to data from the Medical Liability Monitor, a national publication that analyzes liability insurance premiums. The Monitor studies insurance premium data from insurers that cover internists, general surgeons, and obstetrician-gynecologists.

From 2019 to 2023, average premium rates for physicians increased between 1.1% and 3% each year in states without patient compensation funds, according to Monitor data.

“Nuclear verdicts are a real driver of the industry’s underwriting losses and remain top of mind for every malpractice insurance company,” said Michael Matray, editor for the Medical Liability Monitor. “Responses to this year’s rate survey questionnaire indicate that most responding companies have experienced an increase in claims greater than $1 million and claims greater than $5 million during the past 2 years.”

However, increases vary widely by region and among counties. In Montgomery County, Alabama, for instance, premiums for internists rose by 24% from 2022 to 2023, from $8,231 to $10,240. Premiums for Montgomery County general surgeons rose by 11.9% from 2022 to 2023, from $30,761 to $34,426, according to survey data.

In several counties in Illinois (Adams, Knox, Peoria, and Rock Island), premiums for some internists rose by 15% from $24,041 to $27,783, and premiums for some surgeons increased by 27% from $60,202 to $76,461, according to survey data. Some internists in Catoosa County, Georgia, meanwhile, paid $17,831 in 2023, up from $16,313 in 2022. Some surgeons in Catoosa County paid $65,616 in 2023, up from $60,032 in 2022. Inflation could be one factor behind higher liability premium rates. Claim severity is a key driver of higher premium rates, Mr. White added.

“We have not seen stability in claims severity,” he said. “It is continuing to go up and, in all likelihood, it will drive [premium] rates up further from this point.”
 

A version of this article appeared on Medscape.com.

In December, in what’s known as the “Take Care of Maya” case, a Florida jury returned a record $261 million verdict against Johns Hopkins All Children’s Hospital, St. Petersburg, Florida, for its treatment of a young patient and her family after an emergency room visit.

A month earlier, in New York, a jury ordered Westchester Medical Center Health Network to pay $120 million to a patient and his family following delayed stroke care that resulted in brain damage.

Mega malpractice awards like these are rising against physicians and hospitals around the country, according to new data from TransRe, an international reinsurance company that tracks large verdicts.

“2023 blew away every record previously set among high medical malpractice verdicts,” said Richard Henderson, senior vice president for TransRe. “If we look at the 50 largest verdicts in 2023 and average them out, we have a higher monetary amount than any other year.”

In 2023, there were 57 medical malpractice verdicts of $10 million or more in the United States, the data showed. Slightly more than half of those reached $25 million or more.

From 2012 to 2022, verdicts of $10 million or more ranged from 34 in 2013 to 52 in 2022, TransRe research found.

While New York, Illinois, and Florida typically saw the highest dollar verdicts in previous years, so-called “nuclear” verdicts now occur in states like Utah and Georgia where they once were uncommon, said Robert E. White Jr., president of TDC Group and The Doctors Company, a national medical liability insurer for physicians.

A rollback of tort reforms across the country is one contributor, he said. For example, Georgia’s cap on noneconomic damages is among those that have been ruled unconstitutional by courts. Utah’s cap on noneconomic damages still stands, but the limit was deemed unconstitutional in wrongful death cases. In 2019, a portion of Utah›s pre-litigation panel process was also struck down by the state’s Supreme Court.

“We used to be able to predict where these high verdicts would occur,” Mr. White said. “We can’t predict it anymore.”

Research shows a majority of malpractice cases are dropped or settled before trial, and claims that go before juries usually end in doctors’ favor. Plaintiffs’ attorneys cite large jury verdicts in similar cases to induce settlements and higher payouts, Mr. White said.

And while mega verdicts rarely stick, they can have lasting effects on future claims. The awards lead to larger settlement demands from plaintiffs and drive up the cost to resolve claims, according to Mr. Henderson and Mr. White.

“Verdicts are the yardstick by which all settlements are measured,” Mr. White said. “That’s where the damage is done.” The prospect of a mega verdict can make insurers leery of fighting some malpractice cases and motivate them to offer bigger settlements to stay out of the courtroom, he added.

Why Are Juries Awarding Higher Verdicts?

There’s no single reason for the rise in nuclear verdicts, Mr. Henderson said.

One theory is that plaintiffs’ attorneys held back on resolving high-dollar cases during the COVID pandemic and let loose with high-demand claims when courts returned to normal, he said.

Another theory is that people emerged from the pandemic angrier.

“Whether it was political dynamics, masking [mandates], or differences in opinions, people came out of it angry, and generally speaking, you don’t want an angry jury,” Mr. Henderson said. “For a while, there was the halo effect, where health professionals were seen as heroes. That went away, and all of a sudden [they] became ‘the bad guys.’ ”

“People are angry at the healthcare system, and this anger manifests itself in [liability] suits,” added Bill Burns, vice president of research for the Medical Professional Liability Association, an industry group for medical liability insurers.

Hospital and medical group consolidation also reduces the personal connection juries may have with healthcare providers, Mr. Burns said.

“Healthcare has become a big business, and the corporatization of medicine now puts companies on the stand and not your local community hospital or your family doctor that you have known since birth,” he said.

Plaintiffs’ attorneys also deploy tactics that can prompt higher verdicts, Mr. White said. They may tell a jury that the provider or hospital is a threat to the community and that awarding a large verdict will deter others in the healthcare community from repeating the same actions.

Juries may then want to punish the defendant in addition to assessing damages for economic harm or pain and suffering, Mr. White said.

“I am concerned that jurors are trying to right social wrongs rather than judging cases on the facts presented to them,” added Mike Stinson, vice president for policy and legal affairs for the Medical Professional Liability Association.

Third-party litigation financing also can lead to mega verdicts. That’s an emerging practice in which companies unrelated to a lawsuit provide capital to plaintiffs in return for a portion of any financial award. The firms essentially “invest” in the litigation.

“What this does is provide an additional financial backdrop for plaintiffs,” Mr. Henderson said. “It allows them to dig in harder on cases. They can hold out for higher numbers, and if nothing else, it can prolong litigation.”

Do High Awards Actually Stick?

Multimillion-dollar verdicts may grab headlines, but do plaintiffs actually receive them?

Rarely, said TransRe, which tracks the final outcomes of verdicts. In many cases, large verdicts are reduced on appeal.

In the Maya case, which involved child protection authorities, a judge later lowered the damages against Johns Hopkins All Children’s Hospital by $47.5 million.

A federal judge in October, for example, rejected a record $110 million medical malpractice award in Minnesota, reducing it to $10 million. The district judge ruled the award was “shockingly excessive” and that the plaintiff should either accept the $10 million award or retry the case.

After a verdict is awarded, the defendant typically challenges the award, and the case goes through the appellate pipeline, Mr. Henderson explained. A judge may reduce some elements of the verdict, he said, but more often, the plaintiff and defendant agree on a compromised figure.

Seattle medical liability defense attorney Jennifer Crisera has experienced this firsthand. She recalled a recent case where a plaintiff’s attorney demanded what she describes as an unreasonable amount to settle a claim. Ms. Crisera did not want to give exact numbers but said the plaintiff made an 8-figure demand and the defense offered a low 7-figure range.

“My impression was that plaintiff’s counsel believed that they could get a nuclear verdict from the jury, so they kept their settlement demand artificially high,” she said. “The division between the numbers was way too high. Ultimately, we had to let a jury decide the value.”

The plaintiff won the case, and the verdict was much less than the settlement demand, she said. Even so, the defense incurred trial costs, and the health provider was forced to endure the emotional stress of a trial that could have been avoided, Ms. Crisera said.

Higher medical malpractice premiums are another consequence of massive awards.

Premium rates are associated with how much insurers pay on average for cases and how frequently they are making payouts, Mr. White said.

Medical liability insurance premiums for physicians have steadily increased since 2019, according to data from the Medical Liability Monitor, a national publication that analyzes liability insurance premiums. The Monitor studies insurance premium data from insurers that cover internists, general surgeons, and obstetrician-gynecologists.

From 2019 to 2023, average premium rates for physicians increased between 1.1% and 3% each year in states without patient compensation funds, according to Monitor data.

“Nuclear verdicts are a real driver of the industry’s underwriting losses and remain top of mind for every malpractice insurance company,” said Michael Matray, editor for the Medical Liability Monitor. “Responses to this year’s rate survey questionnaire indicate that most responding companies have experienced an increase in claims greater than $1 million and claims greater than $5 million during the past 2 years.”

However, increases vary widely by region and among counties. In Montgomery County, Alabama, for instance, premiums for internists rose by 24% from 2022 to 2023, from $8,231 to $10,240. Premiums for Montgomery County general surgeons rose by 11.9% from 2022 to 2023, from $30,761 to $34,426, according to survey data.

In several counties in Illinois (Adams, Knox, Peoria, and Rock Island), premiums for some internists rose by 15% from $24,041 to $27,783, and premiums for some surgeons increased by 27% from $60,202 to $76,461, according to survey data. Some internists in Catoosa County, Georgia, meanwhile, paid $17,831 in 2023, up from $16,313 in 2022. Some surgeons in Catoosa County paid $65,616 in 2023, up from $60,032 in 2022. Inflation could be one factor behind higher liability premium rates. Claim severity is a key driver of higher premium rates, Mr. White added.

“We have not seen stability in claims severity,” he said. “It is continuing to go up and, in all likelihood, it will drive [premium] rates up further from this point.”
 

A version of this article appeared on Medscape.com.

A new study added heart failure with preserved ejection fraction (HFpEF) to the growing list of cardiovascular conditions linked to clonal hematopoiesis of indeterminate potential (CHIP), which already includes atherosclerotic cardiovascular disease (ASCVD).

But what exactly is CHIP, and what is its potential value in CVD risk and management?

CHIP is an age-related condition marked by clonal expansion of blood stem cells with leukemia-associated mutations in individuals without evidence of hematologic malignancy. CHIP is estimated to affect about 10% of people aged 70 years and older.

First described as a risk factor for hematologic, particularly myeloid, malignant neoplasms, CHIP has recently emerged as a novel CVD risk factor.

CHIP gives rise to proinflammatory immune cells, which can exacerbate ASCVD and may induce or accelerate HF.

“The association between CHIP and HFpEF may be particularly relevant, given that the prevalence of HFpEF is rising due to the progressive aging of the population,” said José J. Fuster, PhD, coordinator for the program on novel mechanisms of atherosclerosis, Spanish National Center for Cardiovascular Research, Madrid.

Yet previous studies examining CHIP and HF have either focused on overall HF without distinguishing HF subtypes of preserved vs reduced ejection fraction, or have examined its prognostic significance in the setting of established HF, rather than the development of future HF.

To help fill the gap, Boston-based researchers recently evaluated associations of CHIP and the two most common gene-specific CHIP subtypes (TET2 and DNMT3A CHIP) with incident HFpEF and HF with reduced ejection fraction (HFrEF).

In two racially diverse cohorts with a total of 8090 adults, TET2 CHIP was independently associated with > twofold higher risk of incident HFpEF. By contrast, there were no significant associations of CHIP with incident HFrEF.

“Our study’s fundings suggest that previously described associations between CHIP and future development of heart failure may be driven primarily by HFpEF,” said Michael Honigberg, MD, with the Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston.

In addition, the “clearest signal for an association with HF was observed for TET2 CHIP, the second-most common subtype of CHIP in the population. This finding aligns with a recently published study that reported relative enrichment of TET2 CHIP in a small human HFpEF cohort,” Dr. Honigberg said.

Dr. Fuster said the connection between CHIP and aging “enhances the potential clinical relevance of this study, as CHIP is frequent in elderly individuals and, therefore, may contribute to the pathophysiology of HFpEF in a high proportion of patients.”

He cautioned, however, that the findings need to be validated in other studies.

“In addition, there is a growing recognition that the effects of CHIP are heterogeneous, as mutations in different genes have different effects on cardiovascular and act through different mechanisms. Additional studies will be needed to dissect gene-specific effects in HFpEF. It will also be important to explore whether CHIP influences the clinical progression of the disease,” Dr. Fuster said.

Targeted Treatment?

Dr. Honigberg said the findings may aid in the development of new targeted-treatment strategies for at least the subset of patients with HFpEF.

Based on multiple lines of evidence, the mechanism linking TET2 CHIP to CVD appears to be heightened inflammation, he explained.

For example, in a substudy of the CANTOS trial, patients with atherosclerosis and TET2 CHIP who received canakinumab appeared to derive “outsized benefit” in preventing CV events compared with the overall trial population, Dr. Honigberg said.

“HFpEF is a particularly challenging disease with limited effective therapies. Our findings support the premise that targeted anti-inflammatory therapies may prevent and/or treat HFpEF driven by TET2 CHIP. Of course, this hypothesis will require testing in prospective randomized trials,” Dr. Honigberg said.

“The field of CHIP has developed rapidly, and it is an exciting area of research,” Dr. Fuster added. “However, I personally believe that much work lies ahead before it is ready for prime time in the clinical setting.

“Although the link between CHIP and CVD is solid, we still lack evidence-based interventions to mitigate the elevated CVD risk associated with these mutations. In the absence of effective interventions, the added value of screening for CHIP as a risk factor may be limited,” Dr. Fuster noted.

“For instance, in the setting of HFpEF, we don’t really know whether CHIP mutation carriers may respond favorably to contemporary HF medications or may require new personalized approaches. Additional research and, eventually, clinical trials, are needed,” he added. 

Dr. Honigberg has disclosed relationships with Genentech, Miga Health, CRISPR Therapeutics, and Comanche Biopharma. Dr. Fuster has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

A new study added heart failure with preserved ejection fraction (HFpEF) to the growing list of cardiovascular conditions linked to clonal hematopoiesis of indeterminate potential (CHIP), which already includes atherosclerotic cardiovascular disease (ASCVD).

But what exactly is CHIP, and what is its potential value in CVD risk and management?

CHIP is an age-related condition marked by clonal expansion of blood stem cells with leukemia-associated mutations in individuals without evidence of hematologic malignancy. CHIP is estimated to affect about 10% of people aged 70 years and older.

First described as a risk factor for hematologic, particularly myeloid, malignant neoplasms, CHIP has recently emerged as a novel CVD risk factor.

CHIP gives rise to proinflammatory immune cells, which can exacerbate ASCVD and may induce or accelerate HF.

“The association between CHIP and HFpEF may be particularly relevant, given that the prevalence of HFpEF is rising due to the progressive aging of the population,” said José J. Fuster, PhD, coordinator for the program on novel mechanisms of atherosclerosis, Spanish National Center for Cardiovascular Research, Madrid.

Yet previous studies examining CHIP and HF have either focused on overall HF without distinguishing HF subtypes of preserved vs reduced ejection fraction, or have examined its prognostic significance in the setting of established HF, rather than the development of future HF.

To help fill the gap, Boston-based researchers recently evaluated associations of CHIP and the two most common gene-specific CHIP subtypes (TET2 and DNMT3A CHIP) with incident HFpEF and HF with reduced ejection fraction (HFrEF).

In two racially diverse cohorts with a total of 8090 adults, TET2 CHIP was independently associated with > twofold higher risk of incident HFpEF. By contrast, there were no significant associations of CHIP with incident HFrEF.

“Our study’s fundings suggest that previously described associations between CHIP and future development of heart failure may be driven primarily by HFpEF,” said Michael Honigberg, MD, with the Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston.

In addition, the “clearest signal for an association with HF was observed for TET2 CHIP, the second-most common subtype of CHIP in the population. This finding aligns with a recently published study that reported relative enrichment of TET2 CHIP in a small human HFpEF cohort,” Dr. Honigberg said.

Dr. Fuster said the connection between CHIP and aging “enhances the potential clinical relevance of this study, as CHIP is frequent in elderly individuals and, therefore, may contribute to the pathophysiology of HFpEF in a high proportion of patients.”

He cautioned, however, that the findings need to be validated in other studies.

“In addition, there is a growing recognition that the effects of CHIP are heterogeneous, as mutations in different genes have different effects on cardiovascular and act through different mechanisms. Additional studies will be needed to dissect gene-specific effects in HFpEF. It will also be important to explore whether CHIP influences the clinical progression of the disease,” Dr. Fuster said.

Targeted Treatment?

Dr. Honigberg said the findings may aid in the development of new targeted-treatment strategies for at least the subset of patients with HFpEF.

Based on multiple lines of evidence, the mechanism linking TET2 CHIP to CVD appears to be heightened inflammation, he explained.

For example, in a substudy of the CANTOS trial, patients with atherosclerosis and TET2 CHIP who received canakinumab appeared to derive “outsized benefit” in preventing CV events compared with the overall trial population, Dr. Honigberg said.

“HFpEF is a particularly challenging disease with limited effective therapies. Our findings support the premise that targeted anti-inflammatory therapies may prevent and/or treat HFpEF driven by TET2 CHIP. Of course, this hypothesis will require testing in prospective randomized trials,” Dr. Honigberg said.

“The field of CHIP has developed rapidly, and it is an exciting area of research,” Dr. Fuster added. “However, I personally believe that much work lies ahead before it is ready for prime time in the clinical setting.

“Although the link between CHIP and CVD is solid, we still lack evidence-based interventions to mitigate the elevated CVD risk associated with these mutations. In the absence of effective interventions, the added value of screening for CHIP as a risk factor may be limited,” Dr. Fuster noted.

“For instance, in the setting of HFpEF, we don’t really know whether CHIP mutation carriers may respond favorably to contemporary HF medications or may require new personalized approaches. Additional research and, eventually, clinical trials, are needed,” he added. 

Dr. Honigberg has disclosed relationships with Genentech, Miga Health, CRISPR Therapeutics, and Comanche Biopharma. Dr. Fuster has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

A new study added heart failure with preserved ejection fraction (HFpEF) to the growing list of cardiovascular conditions linked to clonal hematopoiesis of indeterminate potential (CHIP), which already includes atherosclerotic cardiovascular disease (ASCVD).

But what exactly is CHIP, and what is its potential value in CVD risk and management?

CHIP is an age-related condition marked by clonal expansion of blood stem cells with leukemia-associated mutations in individuals without evidence of hematologic malignancy. CHIP is estimated to affect about 10% of people aged 70 years and older.

First described as a risk factor for hematologic, particularly myeloid, malignant neoplasms, CHIP has recently emerged as a novel CVD risk factor.

CHIP gives rise to proinflammatory immune cells, which can exacerbate ASCVD and may induce or accelerate HF.

“The association between CHIP and HFpEF may be particularly relevant, given that the prevalence of HFpEF is rising due to the progressive aging of the population,” said José J. Fuster, PhD, coordinator for the program on novel mechanisms of atherosclerosis, Spanish National Center for Cardiovascular Research, Madrid.

Yet previous studies examining CHIP and HF have either focused on overall HF without distinguishing HF subtypes of preserved vs reduced ejection fraction, or have examined its prognostic significance in the setting of established HF, rather than the development of future HF.

To help fill the gap, Boston-based researchers recently evaluated associations of CHIP and the two most common gene-specific CHIP subtypes (TET2 and DNMT3A CHIP) with incident HFpEF and HF with reduced ejection fraction (HFrEF).

In two racially diverse cohorts with a total of 8090 adults, TET2 CHIP was independently associated with > twofold higher risk of incident HFpEF. By contrast, there were no significant associations of CHIP with incident HFrEF.

“Our study’s fundings suggest that previously described associations between CHIP and future development of heart failure may be driven primarily by HFpEF,” said Michael Honigberg, MD, with the Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston.

In addition, the “clearest signal for an association with HF was observed for TET2 CHIP, the second-most common subtype of CHIP in the population. This finding aligns with a recently published study that reported relative enrichment of TET2 CHIP in a small human HFpEF cohort,” Dr. Honigberg said.

Dr. Fuster said the connection between CHIP and aging “enhances the potential clinical relevance of this study, as CHIP is frequent in elderly individuals and, therefore, may contribute to the pathophysiology of HFpEF in a high proportion of patients.”

He cautioned, however, that the findings need to be validated in other studies.

“In addition, there is a growing recognition that the effects of CHIP are heterogeneous, as mutations in different genes have different effects on cardiovascular and act through different mechanisms. Additional studies will be needed to dissect gene-specific effects in HFpEF. It will also be important to explore whether CHIP influences the clinical progression of the disease,” Dr. Fuster said.

Targeted Treatment?

Dr. Honigberg said the findings may aid in the development of new targeted-treatment strategies for at least the subset of patients with HFpEF.

Based on multiple lines of evidence, the mechanism linking TET2 CHIP to CVD appears to be heightened inflammation, he explained.

For example, in a substudy of the CANTOS trial, patients with atherosclerosis and TET2 CHIP who received canakinumab appeared to derive “outsized benefit” in preventing CV events compared with the overall trial population, Dr. Honigberg said.

“HFpEF is a particularly challenging disease with limited effective therapies. Our findings support the premise that targeted anti-inflammatory therapies may prevent and/or treat HFpEF driven by TET2 CHIP. Of course, this hypothesis will require testing in prospective randomized trials,” Dr. Honigberg said.

“The field of CHIP has developed rapidly, and it is an exciting area of research,” Dr. Fuster added. “However, I personally believe that much work lies ahead before it is ready for prime time in the clinical setting.

“Although the link between CHIP and CVD is solid, we still lack evidence-based interventions to mitigate the elevated CVD risk associated with these mutations. In the absence of effective interventions, the added value of screening for CHIP as a risk factor may be limited,” Dr. Fuster noted.

“For instance, in the setting of HFpEF, we don’t really know whether CHIP mutation carriers may respond favorably to contemporary HF medications or may require new personalized approaches. Additional research and, eventually, clinical trials, are needed,” he added. 

Dr. Honigberg has disclosed relationships with Genentech, Miga Health, CRISPR Therapeutics, and Comanche Biopharma. Dr. Fuster has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

A recent study sheds light on the heightened risk for burnout among physicians who take infrequent vacations and engage in patient-related work during their time off.

Conducted by the American Medical Association (AMA), the study focuses on the United States, where labor regulations regarding vacation days and compensation differ from German norms. Despite this distinction, it provides valuable insights into the vacation behavior of doctors and its potential impact on burnout risk.

Christine A. Sinsky, MD, study author and senior physician advisor for physician satisfaction at the AMA, and her colleagues invited more than 90,000 physicians to participate in a survey that used postal and computer-based methods. In all, 3024 physicians, mainly those contacted by mail, filled out the questionnaire.
 

Limited Vacation Days

A significant proportion (59.6%) of respondents reported having taken fewer than 15 vacation days in the previous year, with nearly 20% taking fewer than 5 days off. Even when officially on vacation, most (70.4%) found themselves dealing with patient-related tasks. For one-third, these tasks consumed at least 30 minutes on a typical vacation day, often longer. This phenomenon was noted especially among female physicians.

Doctors who took less vacation and worked during their time off displayed higher emotional exhaustion and reported feeling less fulfilled in their profession.
 

Administrative Tasks 

Administrative tasks, though no longer confined to paper, significantly influenced physicians’ vacation behavior. In the United States, handling messages from patients through the electronic health records (EHR) inbox demands a considerable amount of time.

Courses and tutorials on EHR inbox management are on the rise. A 2023 review linked electronic health records management to an increased burnout risk in the US medical community.
 

Lack of Coverage 

Many physicians lack coverage for their EHR inbox during their absence. Less than half (49.1%) stated that someone else manages their inbox while they are on vacation.

Difficulty in finding coverage, whether for the EHR inbox or patient care, is a leading reason why many physicians seldom take more than 3 weeks of vacation per year. Financial considerations also contribute to this decision, as revealed in the survey.
 

Vacation Lowers Risk

Further analysis showed that doctors who took more than 3 weeks of vacation per year, which is not common, had a lower risk of developing burnout. Having coverage for vacation was also associated with reduced burnout risk and increased professional fulfillment.

However, these benefits applied only when physicians truly took a break during their vacation. Respondents who spent 30 minutes or more per day on patient-related work had a higher burnout risk. The risk was 1.58 times greater for 30-60 minutes, 1.97 times greater for 60-90 minutes, and 1.92 times greater for more than 90 minutes.
 

System-Level Interventions

The vacation behavior observed in this study likely exacerbates the effects of chronic workplace overload that are associated with long working hours, thus increasing the risk for burnout, according to the researchers.

“System-level measures must be implemented to ensure physicians take an appropriate number of vacation days,” wrote the researchers. “This includes having coverage available to handle clinical activities and administrative tasks, such as managing the EHR inbox. This could potentially reduce the burnout rate among physicians.”

This article was translated from the Medscape German edition. A version of this article appeared on Medscape.com.

A recent study sheds light on the heightened risk for burnout among physicians who take infrequent vacations and engage in patient-related work during their time off.

Conducted by the American Medical Association (AMA), the study focuses on the United States, where labor regulations regarding vacation days and compensation differ from German norms. Despite this distinction, it provides valuable insights into the vacation behavior of doctors and its potential impact on burnout risk.

Christine A. Sinsky, MD, study author and senior physician advisor for physician satisfaction at the AMA, and her colleagues invited more than 90,000 physicians to participate in a survey that used postal and computer-based methods. In all, 3024 physicians, mainly those contacted by mail, filled out the questionnaire.
 

Limited Vacation Days

A significant proportion (59.6%) of respondents reported having taken fewer than 15 vacation days in the previous year, with nearly 20% taking fewer than 5 days off. Even when officially on vacation, most (70.4%) found themselves dealing with patient-related tasks. For one-third, these tasks consumed at least 30 minutes on a typical vacation day, often longer. This phenomenon was noted especially among female physicians.

Doctors who took less vacation and worked during their time off displayed higher emotional exhaustion and reported feeling less fulfilled in their profession.
 

Administrative Tasks 

Administrative tasks, though no longer confined to paper, significantly influenced physicians’ vacation behavior. In the United States, handling messages from patients through the electronic health records (EHR) inbox demands a considerable amount of time.

Courses and tutorials on EHR inbox management are on the rise. A 2023 review linked electronic health records management to an increased burnout risk in the US medical community.
 

Lack of Coverage 

Many physicians lack coverage for their EHR inbox during their absence. Less than half (49.1%) stated that someone else manages their inbox while they are on vacation.

Difficulty in finding coverage, whether for the EHR inbox or patient care, is a leading reason why many physicians seldom take more than 3 weeks of vacation per year. Financial considerations also contribute to this decision, as revealed in the survey.
 

Vacation Lowers Risk

Further analysis showed that doctors who took more than 3 weeks of vacation per year, which is not common, had a lower risk of developing burnout. Having coverage for vacation was also associated with reduced burnout risk and increased professional fulfillment.

However, these benefits applied only when physicians truly took a break during their vacation. Respondents who spent 30 minutes or more per day on patient-related work had a higher burnout risk. The risk was 1.58 times greater for 30-60 minutes, 1.97 times greater for 60-90 minutes, and 1.92 times greater for more than 90 minutes.
 

System-Level Interventions

The vacation behavior observed in this study likely exacerbates the effects of chronic workplace overload that are associated with long working hours, thus increasing the risk for burnout, according to the researchers.

“System-level measures must be implemented to ensure physicians take an appropriate number of vacation days,” wrote the researchers. “This includes having coverage available to handle clinical activities and administrative tasks, such as managing the EHR inbox. This could potentially reduce the burnout rate among physicians.”

This article was translated from the Medscape German edition. A version of this article appeared on Medscape.com.

A recent study sheds light on the heightened risk for burnout among physicians who take infrequent vacations and engage in patient-related work during their time off.

Conducted by the American Medical Association (AMA), the study focuses on the United States, where labor regulations regarding vacation days and compensation differ from German norms. Despite this distinction, it provides valuable insights into the vacation behavior of doctors and its potential impact on burnout risk.

Christine A. Sinsky, MD, study author and senior physician advisor for physician satisfaction at the AMA, and her colleagues invited more than 90,000 physicians to participate in a survey that used postal and computer-based methods. In all, 3024 physicians, mainly those contacted by mail, filled out the questionnaire.
 

Limited Vacation Days

A significant proportion (59.6%) of respondents reported having taken fewer than 15 vacation days in the previous year, with nearly 20% taking fewer than 5 days off. Even when officially on vacation, most (70.4%) found themselves dealing with patient-related tasks. For one-third, these tasks consumed at least 30 minutes on a typical vacation day, often longer. This phenomenon was noted especially among female physicians.

Doctors who took less vacation and worked during their time off displayed higher emotional exhaustion and reported feeling less fulfilled in their profession.
 

Administrative Tasks 

Administrative tasks, though no longer confined to paper, significantly influenced physicians’ vacation behavior. In the United States, handling messages from patients through the electronic health records (EHR) inbox demands a considerable amount of time.

Courses and tutorials on EHR inbox management are on the rise. A 2023 review linked electronic health records management to an increased burnout risk in the US medical community.
 

Lack of Coverage 

Many physicians lack coverage for their EHR inbox during their absence. Less than half (49.1%) stated that someone else manages their inbox while they are on vacation.

Difficulty in finding coverage, whether for the EHR inbox or patient care, is a leading reason why many physicians seldom take more than 3 weeks of vacation per year. Financial considerations also contribute to this decision, as revealed in the survey.
 

Vacation Lowers Risk

Further analysis showed that doctors who took more than 3 weeks of vacation per year, which is not common, had a lower risk of developing burnout. Having coverage for vacation was also associated with reduced burnout risk and increased professional fulfillment.

However, these benefits applied only when physicians truly took a break during their vacation. Respondents who spent 30 minutes or more per day on patient-related work had a higher burnout risk. The risk was 1.58 times greater for 30-60 minutes, 1.97 times greater for 60-90 minutes, and 1.92 times greater for more than 90 minutes.
 

System-Level Interventions

The vacation behavior observed in this study likely exacerbates the effects of chronic workplace overload that are associated with long working hours, thus increasing the risk for burnout, according to the researchers.

“System-level measures must be implemented to ensure physicians take an appropriate number of vacation days,” wrote the researchers. “This includes having coverage available to handle clinical activities and administrative tasks, such as managing the EHR inbox. This could potentially reduce the burnout rate among physicians.”

This article was translated from the Medscape German edition. A version of this article appeared on Medscape.com.

Once the standard treatment for adult patients with acute lymphocytic leukemia (ALL), stem cell transplants have fallen out of favor somewhat in recent years, with immunotherapy and pediatric-inspired chemotherapy regimens moving to the forefront. But hematologists differ on how to treat relapsed/refractory patients with Philadelphia-chromosome negative (Ph-negative) ALL who are minimal residual disease (MRD)-negative.

Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”

Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.

A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.

However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.

As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”

As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”

Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”

He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.

As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.

In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”

If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”

How can hematologists make the best decision about HSCT?

In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”

The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.

In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”

In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”

The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.

Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”

If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”

As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”

What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”

Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.

Once the standard treatment for adult patients with acute lymphocytic leukemia (ALL), stem cell transplants have fallen out of favor somewhat in recent years, with immunotherapy and pediatric-inspired chemotherapy regimens moving to the forefront. But hematologists differ on how to treat relapsed/refractory patients with Philadelphia-chromosome negative (Ph-negative) ALL who are minimal residual disease (MRD)-negative.

Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”

Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.

A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.

However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.

As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”

As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”

Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”

He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.

As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.

In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”

If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”

How can hematologists make the best decision about HSCT?

In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”

The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.

In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”

In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”

The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.

Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”

If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”

As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”

What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”

Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.

Once the standard treatment for adult patients with acute lymphocytic leukemia (ALL), stem cell transplants have fallen out of favor somewhat in recent years, with immunotherapy and pediatric-inspired chemotherapy regimens moving to the forefront. But hematologists differ on how to treat relapsed/refractory patients with Philadelphia-chromosome negative (Ph-negative) ALL who are minimal residual disease (MRD)-negative.

Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”

Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.

A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.

However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.

As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”

As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”

Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”

He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.

As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.

In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”

If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”

How can hematologists make the best decision about HSCT?

In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”

The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.

In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”

In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”

The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.

Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”

If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”

As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”

What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”

Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the Division of Medical Ethics at the NYU Grossman School of Medicine. There has been an explosion of interest recently in bills that propose to extend medical assistance in dying to more Americans as states begin to contemplate legalization.

Right now, there are 10 states and the District of Columbia that have had some version of medical assistance in dying approved and on the books. That basically means that about 20% of Americans have access where they live to a physician who can prescribe a lethal dose of medication to them if they’re terminally ill and can ingest the medication themselves. That leaves many Americans not covered by this kind of access to this kind of service.

Many of you watching this may live in states where it is legal, like Oregon, Washington, New Jersey, Colorado, and Hawaii. I know many doctors say, “I’m not going to do that.” It’s not something that anyone is compelling a doctor to do. For some Americans, access is not just about where they live but whether there is a doctor willing to participate with them in bringing about their accelerated death, knowing that they’re inevitably going to die.

There’s not much we can do about that. It’s up to the conscience of each physician as to what they’re comfortable with. Certainly, there are other things that can be done to extend the possibility of having this available.

One thing that’s taking place is that, after lawsuits were filed, Vermont and Oregon have given up on their residency requirement, so you don’t have to be there 6 months or a year in order to use this opportunity. It’s legal now to move to the state or visit the state, and as soon as you get there, sign up for this kind of end-of-life intervention.

New Jersey is also being sued. I’ll predict that every state that has a residency requirement, when sued in court, is going to lose because we’ve long recognized the right of Americans to seek out healthcare in the United States, wherever they want to go.

If some states have made this a legitimate medical procedure, courts are going to say you can’t restrict it only to state residents. If someone wants to use a service, they’re entitled to show up from another state or another place and use it. I’m not sure about foreign nationals, but I’m very sure that Americans can go state to state in search of legitimate medical procedures.

The other bills that are out there, however, are basically saying they want to emulate Oregon, Washington, and the other states and say that the terminally ill, with severe restrictions, are going to be able to get this service without going anywhere.

The restrictions include a diagnosis of terminal illness and that you have to be deemed mentally competent. You can’t use this if you have Alzheimer’s or severe depression. You have to make a request twice with a week or two in between to make sure that your request is authentic. And obviously, everyone is on board to make sure that you’re not being coerced or pushed somehow into requesting a somewhat earlier death than you would have experienced without having the availability of the pills.

You also have to take the pills yourself or be able to pull a switch so that you could use a feeding tube–type administration. If you can’t do that, say due to ALS, you’re not eligible to use medical aid in dying. It’s a pretty restricted intervention.

Many people who get pills after going through these restrictions in the states that permit it don’t use it. As many as one third say they like having it there as a safety valve or a parachute, but once they know they could end their life sooner, then they’re going to stick it out.

Should states make this legal? New York, Massachusetts, Florida, and many other states have bills that are moving through. I’m going to say yes. We’ve had Oregon and Washington since the late 1990s with medical aid in dying on the books. There doesn’t seem to be any evidence of pushing people to use this, of bias against the disabled, or bigotry against particular ethnic or racial groups being used to encourage people to end their life sooner.

I think it is an option that Americans want. I think it’s an option that makes some sense. I’m well aware that we also have to make sure that people know about hospice. In some of these states, medical aid in dying is offered as a part of hospice — not all, but a few. Not everybody wants hospice once they realize that they’re dying and that it is coming relatively soon. They may want to leave with family present, with a ceremony, or with a quality of life that they desire.

Past experience says let’s continue to expand availability in each state. Let’s also realize that we have to keep the restrictions in place on how it’s used because they have protected us against abuse. Let’s understand that every doctor has an option to do this or not do this. It’s a matter of conscience and a matter of comfort.

I think legalization is the direction we’re going to be going in. Getting rid of the residency requirements that have been around, as I think courts are going to overturn them, also gives a push to the idea that once the service is in this many states, it’s something that should be available if there are doctors willing to do it.

I’m Art Caplan at the Division of Medical Ethics at NYU Grossman School of Medicine. New York, NY. Thank you for watching.

Arthur L. Caplan, PhD, has disclosed the following relevant financial relationships:

• Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position)
• Serves as a contributing author and adviser for: Medscape

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the Division of Medical Ethics at the NYU Grossman School of Medicine. There has been an explosion of interest recently in bills that propose to extend medical assistance in dying to more Americans as states begin to contemplate legalization.

Right now, there are 10 states and the District of Columbia that have had some version of medical assistance in dying approved and on the books. That basically means that about 20% of Americans have access where they live to a physician who can prescribe a lethal dose of medication to them if they’re terminally ill and can ingest the medication themselves. That leaves many Americans not covered by this kind of access to this kind of service.

Many of you watching this may live in states where it is legal, like Oregon, Washington, New Jersey, Colorado, and Hawaii. I know many doctors say, “I’m not going to do that.” It’s not something that anyone is compelling a doctor to do. For some Americans, access is not just about where they live but whether there is a doctor willing to participate with them in bringing about their accelerated death, knowing that they’re inevitably going to die.

There’s not much we can do about that. It’s up to the conscience of each physician as to what they’re comfortable with. Certainly, there are other things that can be done to extend the possibility of having this available.

One thing that’s taking place is that, after lawsuits were filed, Vermont and Oregon have given up on their residency requirement, so you don’t have to be there 6 months or a year in order to use this opportunity. It’s legal now to move to the state or visit the state, and as soon as you get there, sign up for this kind of end-of-life intervention.

New Jersey is also being sued. I’ll predict that every state that has a residency requirement, when sued in court, is going to lose because we’ve long recognized the right of Americans to seek out healthcare in the United States, wherever they want to go.

If some states have made this a legitimate medical procedure, courts are going to say you can’t restrict it only to state residents. If someone wants to use a service, they’re entitled to show up from another state or another place and use it. I’m not sure about foreign nationals, but I’m very sure that Americans can go state to state in search of legitimate medical procedures.

The other bills that are out there, however, are basically saying they want to emulate Oregon, Washington, and the other states and say that the terminally ill, with severe restrictions, are going to be able to get this service without going anywhere.

The restrictions include a diagnosis of terminal illness and that you have to be deemed mentally competent. You can’t use this if you have Alzheimer’s or severe depression. You have to make a request twice with a week or two in between to make sure that your request is authentic. And obviously, everyone is on board to make sure that you’re not being coerced or pushed somehow into requesting a somewhat earlier death than you would have experienced without having the availability of the pills.

You also have to take the pills yourself or be able to pull a switch so that you could use a feeding tube–type administration. If you can’t do that, say due to ALS, you’re not eligible to use medical aid in dying. It’s a pretty restricted intervention.

Many people who get pills after going through these restrictions in the states that permit it don’t use it. As many as one third say they like having it there as a safety valve or a parachute, but once they know they could end their life sooner, then they’re going to stick it out.

Should states make this legal? New York, Massachusetts, Florida, and many other states have bills that are moving through. I’m going to say yes. We’ve had Oregon and Washington since the late 1990s with medical aid in dying on the books. There doesn’t seem to be any evidence of pushing people to use this, of bias against the disabled, or bigotry against particular ethnic or racial groups being used to encourage people to end their life sooner.

I think it is an option that Americans want. I think it’s an option that makes some sense. I’m well aware that we also have to make sure that people know about hospice. In some of these states, medical aid in dying is offered as a part of hospice — not all, but a few. Not everybody wants hospice once they realize that they’re dying and that it is coming relatively soon. They may want to leave with family present, with a ceremony, or with a quality of life that they desire.

Past experience says let’s continue to expand availability in each state. Let’s also realize that we have to keep the restrictions in place on how it’s used because they have protected us against abuse. Let’s understand that every doctor has an option to do this or not do this. It’s a matter of conscience and a matter of comfort.

I think legalization is the direction we’re going to be going in. Getting rid of the residency requirements that have been around, as I think courts are going to overturn them, also gives a push to the idea that once the service is in this many states, it’s something that should be available if there are doctors willing to do it.

I’m Art Caplan at the Division of Medical Ethics at NYU Grossman School of Medicine. New York, NY. Thank you for watching.

Arthur L. Caplan, PhD, has disclosed the following relevant financial relationships:

• Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position)
• Serves as a contributing author and adviser for: Medscape

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the Division of Medical Ethics at the NYU Grossman School of Medicine. There has been an explosion of interest recently in bills that propose to extend medical assistance in dying to more Americans as states begin to contemplate legalization.

Right now, there are 10 states and the District of Columbia that have had some version of medical assistance in dying approved and on the books. That basically means that about 20% of Americans have access where they live to a physician who can prescribe a lethal dose of medication to them if they’re terminally ill and can ingest the medication themselves. That leaves many Americans not covered by this kind of access to this kind of service.

Many of you watching this may live in states where it is legal, like Oregon, Washington, New Jersey, Colorado, and Hawaii. I know many doctors say, “I’m not going to do that.” It’s not something that anyone is compelling a doctor to do. For some Americans, access is not just about where they live but whether there is a doctor willing to participate with them in bringing about their accelerated death, knowing that they’re inevitably going to die.

There’s not much we can do about that. It’s up to the conscience of each physician as to what they’re comfortable with. Certainly, there are other things that can be done to extend the possibility of having this available.

One thing that’s taking place is that, after lawsuits were filed, Vermont and Oregon have given up on their residency requirement, so you don’t have to be there 6 months or a year in order to use this opportunity. It’s legal now to move to the state or visit the state, and as soon as you get there, sign up for this kind of end-of-life intervention.

New Jersey is also being sued. I’ll predict that every state that has a residency requirement, when sued in court, is going to lose because we’ve long recognized the right of Americans to seek out healthcare in the United States, wherever they want to go.

If some states have made this a legitimate medical procedure, courts are going to say you can’t restrict it only to state residents. If someone wants to use a service, they’re entitled to show up from another state or another place and use it. I’m not sure about foreign nationals, but I’m very sure that Americans can go state to state in search of legitimate medical procedures.

The other bills that are out there, however, are basically saying they want to emulate Oregon, Washington, and the other states and say that the terminally ill, with severe restrictions, are going to be able to get this service without going anywhere.

The restrictions include a diagnosis of terminal illness and that you have to be deemed mentally competent. You can’t use this if you have Alzheimer’s or severe depression. You have to make a request twice with a week or two in between to make sure that your request is authentic. And obviously, everyone is on board to make sure that you’re not being coerced or pushed somehow into requesting a somewhat earlier death than you would have experienced without having the availability of the pills.

You also have to take the pills yourself or be able to pull a switch so that you could use a feeding tube–type administration. If you can’t do that, say due to ALS, you’re not eligible to use medical aid in dying. It’s a pretty restricted intervention.

Many people who get pills after going through these restrictions in the states that permit it don’t use it. As many as one third say they like having it there as a safety valve or a parachute, but once they know they could end their life sooner, then they’re going to stick it out.

Should states make this legal? New York, Massachusetts, Florida, and many other states have bills that are moving through. I’m going to say yes. We’ve had Oregon and Washington since the late 1990s with medical aid in dying on the books. There doesn’t seem to be any evidence of pushing people to use this, of bias against the disabled, or bigotry against particular ethnic or racial groups being used to encourage people to end their life sooner.

I think it is an option that Americans want. I think it’s an option that makes some sense. I’m well aware that we also have to make sure that people know about hospice. In some of these states, medical aid in dying is offered as a part of hospice — not all, but a few. Not everybody wants hospice once they realize that they’re dying and that it is coming relatively soon. They may want to leave with family present, with a ceremony, or with a quality of life that they desire.

Past experience says let’s continue to expand availability in each state. Let’s also realize that we have to keep the restrictions in place on how it’s used because they have protected us against abuse. Let’s understand that every doctor has an option to do this or not do this. It’s a matter of conscience and a matter of comfort.

I think legalization is the direction we’re going to be going in. Getting rid of the residency requirements that have been around, as I think courts are going to overturn them, also gives a push to the idea that once the service is in this many states, it’s something that should be available if there are doctors willing to do it.

I’m Art Caplan at the Division of Medical Ethics at NYU Grossman School of Medicine. New York, NY. Thank you for watching.

Arthur L. Caplan, PhD, has disclosed the following relevant financial relationships:

• Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position)
• Serves as a contributing author and adviser for: Medscape

A version of this article appeared on Medscape.com.

Recent reporting has shown that the number of physician-scientists — doctors who both practice medicine and perform scientific research — in the United States is dropping rapidly. That’s a problem, because physician-scientists are uniquely equipped to make scientific discoveries in the laboratory and translate them to the clinic. Indeed, many of the discoveries that have transformed medicine for the better were made by physician-scientists. For example, Jonas Salk developed the polio vaccine, Timothy Ley sequenced the first cancer genome, and Anthony Fauci coordinated public health responses to both the HIV/AIDS and COVID-19 pandemics. Indicative of their sheer impact, at least a third and as many as half of all Nobel Prizes and Lasker Awards in physiology/medicine have gone to physician-scientists.

So why is the supply of physician-scientists shrinking so precipitously at a time when medical discoveries are being made at a record-high rate? Immunotherapy and proton therapy are transforming cancer care; RNA technology led to COVID vaccines; CRISPR is facilitating gene editing and treatment of diseases like sickle cell anemia. Yet, as exciting as medical science has become, only 1.5% of American doctors work as physician-scientists, more than a threefold drop compared with 30 years ago when the figure was a more robust 4.7%. What’s going on?

Residency training programs at prestigious academic medical centers have standard infolded research years; for example, neurosurgery residents at academic medical centers will often get 2 years of protected research time. And the National Institutes of Health has training grants dedicated to physician-scientists, such as the K08 award program. Several foundations are also dedicated to supporting early-career physician-scientists. Yet, the number of physicians deciding to become physician-scientists remains low, and, more troubling, the attrition rate of those who do decide to go this route is quite high.

The underlying issue is multifold. First, funding rates from the federal government for grants have become competitive to the point of being unrealistic. For example, the current funding rate for the flagship R01 program from the National Cancer Institute is only 12%. Promotions are typically tied to these grant awards, which means physician-scientists who are unable to acquire substantial grant funding are unable to pay for their research or win promotion — and often exit the physician-scientist track altogether.

Compounding this issue is a lack of mentorship for early-career physician-scientists. With the rise of “careerism” in medicine, senior-level physician-scientists may have less incentive to mentor those who are earlier in their careers. Rather, there seems to be greater reward to “managing up” — that is, spending time to please hospital administrators and departmental leadership. Being involved in countless committees appears to carry more value in advancing an established investigator’s career than does mentorship.

Finally, physician-scientists typically earn less than their clinician colleagues, despite juggling both scientific and clinical responsibilities. While many are comfortable with this arrangement when embarking on this track, the disparity may become untenable after a while, especially as departmental leadership will often turn to physician-scientists to fill clinical coverage gaps when faculty leave the department, or as the medical center expands to satellite centers outside the primary hospital. Indeed, physician-scientists get pulled in several directions, which can lead to burnout and attrition, with many who are highly equipped for this track ultimately hanging up their cleats and seeking more clinical or private industry–oriented opportunities.

Every academic medical center operates differently. Some clearly have done a better job than others promoting and fostering physician-scientists. What we find in the centers that manage to retain physician-scientists is leadership plays a major role: If a medical center values the importance of physician-scientists, they will do things to foster the success of those people, such as assembling mentorship committees, establishing clear criteria for promotion and career advancement, protecting research time while maintaining some level of pay equity, advocating for team science approaches, and supporting investigators in cases of gaps in federal funding. Different countries also have different models for physician-scientist training, with Germany, for example, allowing medical residents to have 3 years of protected time to engage in research after their second year of residency.

The stakes here are high. If we can’t address the physician-scientist recruitment and retention crisis in America now, we risk falling behind other countries in our ability to innovate and deliver world-class care.

Dr Chaudhuri is a tenure-track physician-scientist at Washington University in St. Louis, a Paul and Daisy Soros Fellow, and a Public Voices Fellow of The OpEd Project.

Aadel Chaudhuri, MD, PhD, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Recent reporting has shown that the number of physician-scientists — doctors who both practice medicine and perform scientific research — in the United States is dropping rapidly. That’s a problem, because physician-scientists are uniquely equipped to make scientific discoveries in the laboratory and translate them to the clinic. Indeed, many of the discoveries that have transformed medicine for the better were made by physician-scientists. For example, Jonas Salk developed the polio vaccine, Timothy Ley sequenced the first cancer genome, and Anthony Fauci coordinated public health responses to both the HIV/AIDS and COVID-19 pandemics. Indicative of their sheer impact, at least a third and as many as half of all Nobel Prizes and Lasker Awards in physiology/medicine have gone to physician-scientists.

So why is the supply of physician-scientists shrinking so precipitously at a time when medical discoveries are being made at a record-high rate? Immunotherapy and proton therapy are transforming cancer care; RNA technology led to COVID vaccines; CRISPR is facilitating gene editing and treatment of diseases like sickle cell anemia. Yet, as exciting as medical science has become, only 1.5% of American doctors work as physician-scientists, more than a threefold drop compared with 30 years ago when the figure was a more robust 4.7%. What’s going on?

Residency training programs at prestigious academic medical centers have standard infolded research years; for example, neurosurgery residents at academic medical centers will often get 2 years of protected research time. And the National Institutes of Health has training grants dedicated to physician-scientists, such as the K08 award program. Several foundations are also dedicated to supporting early-career physician-scientists. Yet, the number of physicians deciding to become physician-scientists remains low, and, more troubling, the attrition rate of those who do decide to go this route is quite high.

The underlying issue is multifold. First, funding rates from the federal government for grants have become competitive to the point of being unrealistic. For example, the current funding rate for the flagship R01 program from the National Cancer Institute is only 12%. Promotions are typically tied to these grant awards, which means physician-scientists who are unable to acquire substantial grant funding are unable to pay for their research or win promotion — and often exit the physician-scientist track altogether.

Compounding this issue is a lack of mentorship for early-career physician-scientists. With the rise of “careerism” in medicine, senior-level physician-scientists may have less incentive to mentor those who are earlier in their careers. Rather, there seems to be greater reward to “managing up” — that is, spending time to please hospital administrators and departmental leadership. Being involved in countless committees appears to carry more value in advancing an established investigator’s career than does mentorship.

Finally, physician-scientists typically earn less than their clinician colleagues, despite juggling both scientific and clinical responsibilities. While many are comfortable with this arrangement when embarking on this track, the disparity may become untenable after a while, especially as departmental leadership will often turn to physician-scientists to fill clinical coverage gaps when faculty leave the department, or as the medical center expands to satellite centers outside the primary hospital. Indeed, physician-scientists get pulled in several directions, which can lead to burnout and attrition, with many who are highly equipped for this track ultimately hanging up their cleats and seeking more clinical or private industry–oriented opportunities.

Every academic medical center operates differently. Some clearly have done a better job than others promoting and fostering physician-scientists. What we find in the centers that manage to retain physician-scientists is leadership plays a major role: If a medical center values the importance of physician-scientists, they will do things to foster the success of those people, such as assembling mentorship committees, establishing clear criteria for promotion and career advancement, protecting research time while maintaining some level of pay equity, advocating for team science approaches, and supporting investigators in cases of gaps in federal funding. Different countries also have different models for physician-scientist training, with Germany, for example, allowing medical residents to have 3 years of protected time to engage in research after their second year of residency.

The stakes here are high. If we can’t address the physician-scientist recruitment and retention crisis in America now, we risk falling behind other countries in our ability to innovate and deliver world-class care.

Dr Chaudhuri is a tenure-track physician-scientist at Washington University in St. Louis, a Paul and Daisy Soros Fellow, and a Public Voices Fellow of The OpEd Project.

Aadel Chaudhuri, MD, PhD, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Recent reporting has shown that the number of physician-scientists — doctors who both practice medicine and perform scientific research — in the United States is dropping rapidly. That’s a problem, because physician-scientists are uniquely equipped to make scientific discoveries in the laboratory and translate them to the clinic. Indeed, many of the discoveries that have transformed medicine for the better were made by physician-scientists. For example, Jonas Salk developed the polio vaccine, Timothy Ley sequenced the first cancer genome, and Anthony Fauci coordinated public health responses to both the HIV/AIDS and COVID-19 pandemics. Indicative of their sheer impact, at least a third and as many as half of all Nobel Prizes and Lasker Awards in physiology/medicine have gone to physician-scientists.

So why is the supply of physician-scientists shrinking so precipitously at a time when medical discoveries are being made at a record-high rate? Immunotherapy and proton therapy are transforming cancer care; RNA technology led to COVID vaccines; CRISPR is facilitating gene editing and treatment of diseases like sickle cell anemia. Yet, as exciting as medical science has become, only 1.5% of American doctors work as physician-scientists, more than a threefold drop compared with 30 years ago when the figure was a more robust 4.7%. What’s going on?

Residency training programs at prestigious academic medical centers have standard infolded research years; for example, neurosurgery residents at academic medical centers will often get 2 years of protected research time. And the National Institutes of Health has training grants dedicated to physician-scientists, such as the K08 award program. Several foundations are also dedicated to supporting early-career physician-scientists. Yet, the number of physicians deciding to become physician-scientists remains low, and, more troubling, the attrition rate of those who do decide to go this route is quite high.

The underlying issue is multifold. First, funding rates from the federal government for grants have become competitive to the point of being unrealistic. For example, the current funding rate for the flagship R01 program from the National Cancer Institute is only 12%. Promotions are typically tied to these grant awards, which means physician-scientists who are unable to acquire substantial grant funding are unable to pay for their research or win promotion — and often exit the physician-scientist track altogether.

Compounding this issue is a lack of mentorship for early-career physician-scientists. With the rise of “careerism” in medicine, senior-level physician-scientists may have less incentive to mentor those who are earlier in their careers. Rather, there seems to be greater reward to “managing up” — that is, spending time to please hospital administrators and departmental leadership. Being involved in countless committees appears to carry more value in advancing an established investigator’s career than does mentorship.

Finally, physician-scientists typically earn less than their clinician colleagues, despite juggling both scientific and clinical responsibilities. While many are comfortable with this arrangement when embarking on this track, the disparity may become untenable after a while, especially as departmental leadership will often turn to physician-scientists to fill clinical coverage gaps when faculty leave the department, or as the medical center expands to satellite centers outside the primary hospital. Indeed, physician-scientists get pulled in several directions, which can lead to burnout and attrition, with many who are highly equipped for this track ultimately hanging up their cleats and seeking more clinical or private industry–oriented opportunities.

Every academic medical center operates differently. Some clearly have done a better job than others promoting and fostering physician-scientists. What we find in the centers that manage to retain physician-scientists is leadership plays a major role: If a medical center values the importance of physician-scientists, they will do things to foster the success of those people, such as assembling mentorship committees, establishing clear criteria for promotion and career advancement, protecting research time while maintaining some level of pay equity, advocating for team science approaches, and supporting investigators in cases of gaps in federal funding. Different countries also have different models for physician-scientist training, with Germany, for example, allowing medical residents to have 3 years of protected time to engage in research after their second year of residency.

The stakes here are high. If we can’t address the physician-scientist recruitment and retention crisis in America now, we risk falling behind other countries in our ability to innovate and deliver world-class care.

Dr Chaudhuri is a tenure-track physician-scientist at Washington University in St. Louis, a Paul and Daisy Soros Fellow, and a Public Voices Fellow of The OpEd Project.

Aadel Chaudhuri, MD, PhD, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

With last month’s American Society of Hematology (ASH) annual conference in the rearview mirror, Ghulam Rehman “Manni” Mohyuddin, MD, a young medical oncologist who reaches out to colleagues via social media, hopes his efforts to support and inspire trainees at ASH 2023 will help propel them forward in their chosen field of medicine.

Ahead of the conference held in San Diego in December, Dr. Mohyuddin, a blood cancer specialist with a focus on multiple myeloma and medical education, put out a heartfelt appeal on X (formerly Twitter): “If you’re a trainee and interested in meeting me at #ASH23, please reach out … (especially if [international medical graduate]) I’d love to meet and offer support in whatever capacity I can! I can’t have a research project for each one of you, but happy to help/mentor in any other way possible,” he posted on X back in late November.

An international medical graduate himself, Dr. Mohyuddin recalls how overwhelmed he felt when he first attended an annual ASH conference as a trainee, so he aims to reassure others that they “don’t have to know everything.”

“It’s about networking and broadening horizons,” he said in an interview that took place between ASH sessions, his own research presentations, and meetings with the many trainees who took him up on the offer he made via X. “I’ve spent most of this ASH meeting trainees — it’s the most rewarding thing for me at these meetings.

“Reassurance is a lot of what we do in oncology,” he continued, drawing a connection between his affinity for helping trainees and providing compassionate care to patients. “For an oncologist, the single most important thing is having excellent communication skills and being able to express support and empathy. The ability to connect deeply with your patients during their time of need is profoundly important.

“You can compensate for lack of knowledge, because we have so many other sources of support for knowledge, but you simply cannot compensate for poor communication skills, and your patient suffers as a result,” he said.
 

Relationship Building

In addition to the guidance he received from mentors, Dr. Mohyuddin noted that it was the chance to build supportive, empathetic relationships that drew him to specialize in blood cancer and, in particular, to caring for patients with multiple myeloma and conducting research focused on improving the patient experience.

Dr. Mohyuddin attended medical school at the Aga Khan University in Pakistan, then completed his internal medicine residency and fellowship at the University of Kansas in Kansas City. As a chief resident there, he focused on novel approaches to education delivery and improving access to research for trainees. As a fellow, he developed clinical and research interests in multiple myeloma, which he describes as an “incredibly rewarding field” marked by “truly spectacular advances over the last two decades.”

“There are some cancers you can cure, which means you don’t get to see patients often, and there are some you can’t cure, where patients die early, and there’s not a lot of time to build a relationship,” he said. “But there are some where patients can do well even though they aren’t currently cured, and you get to form really amazing and meaningful relationships over a long period of time.

“Multiple myeloma occupies that space, and that’s why I’m drawn to it,” Dr. Mohyuddin added, noting that he doesn’t shy away from forging emotional connections with patients. “I recognize that makes me vulnerable, but I think that is essentially what your patients deserve from you — to be invested at an emotional level with them through their suffering.”
 

Improving value and the patient experience

“One thing, philosophically, that I research is value in multiple myeloma care: identifying areas where we are overtreating patients and where we can do less and get away with it,” he said.

Despite the major advances in multiple myeloma in recent years, which “represent a lot of what is going right with oncology,” this blood cancer still “also represents a lot of what is wrong with oncology,” he noted. As an example, he cited “the approval of low-value drugs, the sequencing of drugs, adding more and more drugs without responsibly addressing quality-of-life questions, and identifying more responsible ways to provide high-value efficacious care without bankrupting the economy.

“So my research and policy work apply to that,” he explained. “What can we do better? What sort of trials should we be doing? What populations do we enroll? Are we asking the right questions or looking at trivialities? Are we serving patients foremost?”

Sometimes, this means comparing multiple myeloma staging systems in a real-world cohort, or assessing whether a widely available, cheap, and safe drug like budesonide can help patients avoid diarrhea during chemotherapy, whether control arms in myeloma randomized trials are fair, whether drugs ever get approved in low- or middle-income countries after their approval in the United States, and whether smoldering myeloma, a multiple myeloma precursor, really requires treatment, as current guidelines suggest, or if patients would do just as well — or perhaps better — with a close surveillance protocol.

“Pharma won’t do those studies and many key opinion leaders feel the question [about whether smoldering myeloma needs to be treated] has already been answered, so we are launching a prospective study that will define the natural history of smoldering myeloma and allow for patients to stay off therapy while undergoing rigorous surveillance with imaging,” he said.

Another study Dr. Mohyuddin hopes to launch soon will look at a “start low, go slow” treatment approach for the frailest patients with newly diagnosed myeloma.

His upbringing in Pakistan, where there are “mind-boggling” differences in health care access, affordability, and outcomes when compared with the United States, provided a foundation for both his “enthusiasm for cost-effective care” and his desire to give back, he said.

Another aspect of life in Pakistan — an across-the-board sense of closeness and solidarity in families and communities that is sometimes lacking in the United States — contributed to his desire to build relationships.

“That is something I dearly miss,” he said. “I am very privileged and so thankful to be here in the US, but that is one thing I do deeply miss.”
 

Connecting and Making a Difference

Dr. Mohyuddin seeks connection through his relationships with patients, trainees, and his many followers on social media platforms like X, where he frequently shares his thoughts on research quality and findings, heme/onc trends, and treatment-related insight.

“How to treat myeloma after #ASH23,” he posted on X as the conference came to a close. His takeaways: Don’t treat smoldering myeloma, do quadruple therapy for transplant-eligible patients (but no cd38 maintenance therapy afterward), don’t do quads for carfilzomib in newly diagnosed frail or older patients, and don’t do a salvage autologous transplant, no matter how good the first transplant was.

Dr. Mohyuddin also works to make a difference through his research and involvement in helping to launch initiatives like Common Sense Oncology, an ambitious global effort to reform cancer clinical trials and care, and through a current project with colleagues in India and Pakistan to create a consortium for pooling data on hematologic malignancies from South Asian countries. The hope is that such a collaborative effort will lead to good prospective research relevant to the needs of participating countries, he explained.

“Those are things where I want to make a difference. Taking care of patients is number one, but more than research, the number two thing for me is teaching and hopefully inspiring trainees and others to think differently, to look at data differently,” he said, noting that despite the major advances in myeloma, the reality is that “a lot of what we offer in oncology is very marginal.”

The effect sizes of interventions are often very small, and outcomes can still be really bad, he explained, adding that “[i]t really hits you when you see a lot of death and suffering. It’s a huge wake-up call … we have so many advances, but the reality is very, very sobering.

“Critically understanding and interpreting data is something where education really fails us. I’m incredibly passionate about it. I’ve found great resources to help me interpret data better, and I want to make them more accessible and inspire others to understand better,” he said. “We need to know how to defend ourselves from the hype.”

His efforts have not gone unnoticed. Dr. Mohyuddin was the recipient of the 2023 Hematology and Medical Oncology Fellowship Faculty Teaching Award at the University of Utah, Salt Lake City, where he is currently a faculty member.

“The recognition means more than any publication or grant award,” he said. “It’s great to know that medical education is appreciated, because so often we are in a rat race of getting more papers and grants out, but teaching and inspiring people is what is really, really important to me.”

With last month’s American Society of Hematology (ASH) annual conference in the rearview mirror, Ghulam Rehman “Manni” Mohyuddin, MD, a young medical oncologist who reaches out to colleagues via social media, hopes his efforts to support and inspire trainees at ASH 2023 will help propel them forward in their chosen field of medicine.

Ahead of the conference held in San Diego in December, Dr. Mohyuddin, a blood cancer specialist with a focus on multiple myeloma and medical education, put out a heartfelt appeal on X (formerly Twitter): “If you’re a trainee and interested in meeting me at #ASH23, please reach out … (especially if [international medical graduate]) I’d love to meet and offer support in whatever capacity I can! I can’t have a research project for each one of you, but happy to help/mentor in any other way possible,” he posted on X back in late November.

An international medical graduate himself, Dr. Mohyuddin recalls how overwhelmed he felt when he first attended an annual ASH conference as a trainee, so he aims to reassure others that they “don’t have to know everything.”

“It’s about networking and broadening horizons,” he said in an interview that took place between ASH sessions, his own research presentations, and meetings with the many trainees who took him up on the offer he made via X. “I’ve spent most of this ASH meeting trainees — it’s the most rewarding thing for me at these meetings.

“Reassurance is a lot of what we do in oncology,” he continued, drawing a connection between his affinity for helping trainees and providing compassionate care to patients. “For an oncologist, the single most important thing is having excellent communication skills and being able to express support and empathy. The ability to connect deeply with your patients during their time of need is profoundly important.

“You can compensate for lack of knowledge, because we have so many other sources of support for knowledge, but you simply cannot compensate for poor communication skills, and your patient suffers as a result,” he said.
 

Relationship Building

In addition to the guidance he received from mentors, Dr. Mohyuddin noted that it was the chance to build supportive, empathetic relationships that drew him to specialize in blood cancer and, in particular, to caring for patients with multiple myeloma and conducting research focused on improving the patient experience.

Dr. Mohyuddin attended medical school at the Aga Khan University in Pakistan, then completed his internal medicine residency and fellowship at the University of Kansas in Kansas City. As a chief resident there, he focused on novel approaches to education delivery and improving access to research for trainees. As a fellow, he developed clinical and research interests in multiple myeloma, which he describes as an “incredibly rewarding field” marked by “truly spectacular advances over the last two decades.”

“There are some cancers you can cure, which means you don’t get to see patients often, and there are some you can’t cure, where patients die early, and there’s not a lot of time to build a relationship,” he said. “But there are some where patients can do well even though they aren’t currently cured, and you get to form really amazing and meaningful relationships over a long period of time.

“Multiple myeloma occupies that space, and that’s why I’m drawn to it,” Dr. Mohyuddin added, noting that he doesn’t shy away from forging emotional connections with patients. “I recognize that makes me vulnerable, but I think that is essentially what your patients deserve from you — to be invested at an emotional level with them through their suffering.”
 

Improving value and the patient experience

“One thing, philosophically, that I research is value in multiple myeloma care: identifying areas where we are overtreating patients and where we can do less and get away with it,” he said.

Despite the major advances in multiple myeloma in recent years, which “represent a lot of what is going right with oncology,” this blood cancer still “also represents a lot of what is wrong with oncology,” he noted. As an example, he cited “the approval of low-value drugs, the sequencing of drugs, adding more and more drugs without responsibly addressing quality-of-life questions, and identifying more responsible ways to provide high-value efficacious care without bankrupting the economy.

“So my research and policy work apply to that,” he explained. “What can we do better? What sort of trials should we be doing? What populations do we enroll? Are we asking the right questions or looking at trivialities? Are we serving patients foremost?”

Sometimes, this means comparing multiple myeloma staging systems in a real-world cohort, or assessing whether a widely available, cheap, and safe drug like budesonide can help patients avoid diarrhea during chemotherapy, whether control arms in myeloma randomized trials are fair, whether drugs ever get approved in low- or middle-income countries after their approval in the United States, and whether smoldering myeloma, a multiple myeloma precursor, really requires treatment, as current guidelines suggest, or if patients would do just as well — or perhaps better — with a close surveillance protocol.

“Pharma won’t do those studies and many key opinion leaders feel the question [about whether smoldering myeloma needs to be treated] has already been answered, so we are launching a prospective study that will define the natural history of smoldering myeloma and allow for patients to stay off therapy while undergoing rigorous surveillance with imaging,” he said.

Another study Dr. Mohyuddin hopes to launch soon will look at a “start low, go slow” treatment approach for the frailest patients with newly diagnosed myeloma.

His upbringing in Pakistan, where there are “mind-boggling” differences in health care access, affordability, and outcomes when compared with the United States, provided a foundation for both his “enthusiasm for cost-effective care” and his desire to give back, he said.

Another aspect of life in Pakistan — an across-the-board sense of closeness and solidarity in families and communities that is sometimes lacking in the United States — contributed to his desire to build relationships.

“That is something I dearly miss,” he said. “I am very privileged and so thankful to be here in the US, but that is one thing I do deeply miss.”
 

Connecting and Making a Difference

Dr. Mohyuddin seeks connection through his relationships with patients, trainees, and his many followers on social media platforms like X, where he frequently shares his thoughts on research quality and findings, heme/onc trends, and treatment-related insight.

“How to treat myeloma after #ASH23,” he posted on X as the conference came to a close. His takeaways: Don’t treat smoldering myeloma, do quadruple therapy for transplant-eligible patients (but no cd38 maintenance therapy afterward), don’t do quads for carfilzomib in newly diagnosed frail or older patients, and don’t do a salvage autologous transplant, no matter how good the first transplant was.

Dr. Mohyuddin also works to make a difference through his research and involvement in helping to launch initiatives like Common Sense Oncology, an ambitious global effort to reform cancer clinical trials and care, and through a current project with colleagues in India and Pakistan to create a consortium for pooling data on hematologic malignancies from South Asian countries. The hope is that such a collaborative effort will lead to good prospective research relevant to the needs of participating countries, he explained.

“Those are things where I want to make a difference. Taking care of patients is number one, but more than research, the number two thing for me is teaching and hopefully inspiring trainees and others to think differently, to look at data differently,” he said, noting that despite the major advances in myeloma, the reality is that “a lot of what we offer in oncology is very marginal.”

The effect sizes of interventions are often very small, and outcomes can still be really bad, he explained, adding that “[i]t really hits you when you see a lot of death and suffering. It’s a huge wake-up call … we have so many advances, but the reality is very, very sobering.

“Critically understanding and interpreting data is something where education really fails us. I’m incredibly passionate about it. I’ve found great resources to help me interpret data better, and I want to make them more accessible and inspire others to understand better,” he said. “We need to know how to defend ourselves from the hype.”

His efforts have not gone unnoticed. Dr. Mohyuddin was the recipient of the 2023 Hematology and Medical Oncology Fellowship Faculty Teaching Award at the University of Utah, Salt Lake City, where he is currently a faculty member.

“The recognition means more than any publication or grant award,” he said. “It’s great to know that medical education is appreciated, because so often we are in a rat race of getting more papers and grants out, but teaching and inspiring people is what is really, really important to me.”

With last month’s American Society of Hematology (ASH) annual conference in the rearview mirror, Ghulam Rehman “Manni” Mohyuddin, MD, a young medical oncologist who reaches out to colleagues via social media, hopes his efforts to support and inspire trainees at ASH 2023 will help propel them forward in their chosen field of medicine.

Ahead of the conference held in San Diego in December, Dr. Mohyuddin, a blood cancer specialist with a focus on multiple myeloma and medical education, put out a heartfelt appeal on X (formerly Twitter): “If you’re a trainee and interested in meeting me at #ASH23, please reach out … (especially if [international medical graduate]) I’d love to meet and offer support in whatever capacity I can! I can’t have a research project for each one of you, but happy to help/mentor in any other way possible,” he posted on X back in late November.

An international medical graduate himself, Dr. Mohyuddin recalls how overwhelmed he felt when he first attended an annual ASH conference as a trainee, so he aims to reassure others that they “don’t have to know everything.”

“It’s about networking and broadening horizons,” he said in an interview that took place between ASH sessions, his own research presentations, and meetings with the many trainees who took him up on the offer he made via X. “I’ve spent most of this ASH meeting trainees — it’s the most rewarding thing for me at these meetings.

“Reassurance is a lot of what we do in oncology,” he continued, drawing a connection between his affinity for helping trainees and providing compassionate care to patients. “For an oncologist, the single most important thing is having excellent communication skills and being able to express support and empathy. The ability to connect deeply with your patients during their time of need is profoundly important.

“You can compensate for lack of knowledge, because we have so many other sources of support for knowledge, but you simply cannot compensate for poor communication skills, and your patient suffers as a result,” he said.
 

Relationship Building

In addition to the guidance he received from mentors, Dr. Mohyuddin noted that it was the chance to build supportive, empathetic relationships that drew him to specialize in blood cancer and, in particular, to caring for patients with multiple myeloma and conducting research focused on improving the patient experience.

Dr. Mohyuddin attended medical school at the Aga Khan University in Pakistan, then completed his internal medicine residency and fellowship at the University of Kansas in Kansas City. As a chief resident there, he focused on novel approaches to education delivery and improving access to research for trainees. As a fellow, he developed clinical and research interests in multiple myeloma, which he describes as an “incredibly rewarding field” marked by “truly spectacular advances over the last two decades.”

“There are some cancers you can cure, which means you don’t get to see patients often, and there are some you can’t cure, where patients die early, and there’s not a lot of time to build a relationship,” he said. “But there are some where patients can do well even though they aren’t currently cured, and you get to form really amazing and meaningful relationships over a long period of time.

“Multiple myeloma occupies that space, and that’s why I’m drawn to it,” Dr. Mohyuddin added, noting that he doesn’t shy away from forging emotional connections with patients. “I recognize that makes me vulnerable, but I think that is essentially what your patients deserve from you — to be invested at an emotional level with them through their suffering.”
 

Improving value and the patient experience

“One thing, philosophically, that I research is value in multiple myeloma care: identifying areas where we are overtreating patients and where we can do less and get away with it,” he said.

Despite the major advances in multiple myeloma in recent years, which “represent a lot of what is going right with oncology,” this blood cancer still “also represents a lot of what is wrong with oncology,” he noted. As an example, he cited “the approval of low-value drugs, the sequencing of drugs, adding more and more drugs without responsibly addressing quality-of-life questions, and identifying more responsible ways to provide high-value efficacious care without bankrupting the economy.

“So my research and policy work apply to that,” he explained. “What can we do better? What sort of trials should we be doing? What populations do we enroll? Are we asking the right questions or looking at trivialities? Are we serving patients foremost?”

Sometimes, this means comparing multiple myeloma staging systems in a real-world cohort, or assessing whether a widely available, cheap, and safe drug like budesonide can help patients avoid diarrhea during chemotherapy, whether control arms in myeloma randomized trials are fair, whether drugs ever get approved in low- or middle-income countries after their approval in the United States, and whether smoldering myeloma, a multiple myeloma precursor, really requires treatment, as current guidelines suggest, or if patients would do just as well — or perhaps better — with a close surveillance protocol.

“Pharma won’t do those studies and many key opinion leaders feel the question [about whether smoldering myeloma needs to be treated] has already been answered, so we are launching a prospective study that will define the natural history of smoldering myeloma and allow for patients to stay off therapy while undergoing rigorous surveillance with imaging,” he said.

Another study Dr. Mohyuddin hopes to launch soon will look at a “start low, go slow” treatment approach for the frailest patients with newly diagnosed myeloma.

His upbringing in Pakistan, where there are “mind-boggling” differences in health care access, affordability, and outcomes when compared with the United States, provided a foundation for both his “enthusiasm for cost-effective care” and his desire to give back, he said.

Another aspect of life in Pakistan — an across-the-board sense of closeness and solidarity in families and communities that is sometimes lacking in the United States — contributed to his desire to build relationships.

“That is something I dearly miss,” he said. “I am very privileged and so thankful to be here in the US, but that is one thing I do deeply miss.”
 

Connecting and Making a Difference

Dr. Mohyuddin seeks connection through his relationships with patients, trainees, and his many followers on social media platforms like X, where he frequently shares his thoughts on research quality and findings, heme/onc trends, and treatment-related insight.

“How to treat myeloma after #ASH23,” he posted on X as the conference came to a close. His takeaways: Don’t treat smoldering myeloma, do quadruple therapy for transplant-eligible patients (but no cd38 maintenance therapy afterward), don’t do quads for carfilzomib in newly diagnosed frail or older patients, and don’t do a salvage autologous transplant, no matter how good the first transplant was.

Dr. Mohyuddin also works to make a difference through his research and involvement in helping to launch initiatives like Common Sense Oncology, an ambitious global effort to reform cancer clinical trials and care, and through a current project with colleagues in India and Pakistan to create a consortium for pooling data on hematologic malignancies from South Asian countries. The hope is that such a collaborative effort will lead to good prospective research relevant to the needs of participating countries, he explained.

“Those are things where I want to make a difference. Taking care of patients is number one, but more than research, the number two thing for me is teaching and hopefully inspiring trainees and others to think differently, to look at data differently,” he said, noting that despite the major advances in myeloma, the reality is that “a lot of what we offer in oncology is very marginal.”

The effect sizes of interventions are often very small, and outcomes can still be really bad, he explained, adding that “[i]t really hits you when you see a lot of death and suffering. It’s a huge wake-up call … we have so many advances, but the reality is very, very sobering.

“Critically understanding and interpreting data is something where education really fails us. I’m incredibly passionate about it. I’ve found great resources to help me interpret data better, and I want to make them more accessible and inspire others to understand better,” he said. “We need to know how to defend ourselves from the hype.”

His efforts have not gone unnoticed. Dr. Mohyuddin was the recipient of the 2023 Hematology and Medical Oncology Fellowship Faculty Teaching Award at the University of Utah, Salt Lake City, where he is currently a faculty member.

“The recognition means more than any publication or grant award,” he said. “It’s great to know that medical education is appreciated, because so often we are in a rat race of getting more papers and grants out, but teaching and inspiring people is what is really, really important to me.”

In treating young patients with T-cell acute lymphoblastic leukemia (T-ALL), prophylactic central nervous system (CNS)-directed cranial radiotherapy (CRT) can safely be omitted even for those with the greatest CNS involvement,i.e., CNS-3 disease. Doing so spares patients the treatment’s toxic effects without heightening the risk of relapse.

“Overall, comparison of these cohorts provides a strong indication that CRT provides minimal benefit to patients with CNS-3 disease at diagnosis,” first author Ajay Vora, MD, a consultant hematologist with Great Ormond Street Hospital, in London, and his colleagues report in a research letter published recently in Blood Advances.

“Given the high rates of neurocognitive impairment and secondary CNS malignancies, we believe strong consideration should be given to eliminating CRT in first-line treatment for all patients with T-ALL,” they wrote.

More aggressive than B-cell ALL, T-ALL is characterized by a higher likelihood of infiltration of the CNS at diagnosis, which increases the risk of relapse after treatment.

Until recently, treatment of T-ALL long entailed CNS-directed therapy using prophylactic CRT. Now, however, due to the risks of significant toxicity, including neurocognitive defects and secondary cancers, CRT is usually either omitted or limited to key subgroups, such as those with CNS-3 disease. As an alternative, intrathecal chemotherapy is used, the authors explain.

In a 2023 study evaluating the consecutive Children’s Oncology Group (COG) AALL0434 and AALL1231 phase 3 trials of 2,164 patients with T-ALL, patients with CNS-3 at diagnosis were found to have worse outcomes, compared with CNS-1 and 2.

Importantly, the outcomes in both of those two trials were similar, despite the use of CRT in more than 90% of patients in the AALL0434 trial--but in only 10% of patients AALL1231 trial (mainly those with CNS-3 and at high-risk). These outcomes suggested that CRT can safely be eliminated for CNS-1 and 2 patients.

With CRT used in both trials among patients with CNS-3, conclusions about eliminating CRT among those patients could not be drawn. However, with other large groups (including the Dutch Childhood Oncology Group), eliminating CRT in the frontline treatment of all patients with T-ALL, including those with CNS-3, is what Dr. Vora and colleagues sought to further investigate.

For the current study, they evaluated outcomes in the UKALL2003 and UKALL2011 trials conducted by the UK National Cancer Research Institute, in which CRT was eliminated for all patients — including those with CNS-3 — and compared them with the COG AALL0434 and AALL1231 trials.

In the UK trials, involving 665 patients with T-ALL aged 1 to 24, treatment included a dexamethasone-based backbone chemotherapy consisting of a 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation, interim maintenance, delayed intensification, and maintenance therapy, with the treatment stratified based on morphological early response and minimal residual disease at the end of induction.

While the UKALL2003 trial initially recommended CRT for patients with CNS-3, that practice ended in 2009, and CNS-directed therapy subsequently consisted of intrathecal methotrexate (MTX) at regular intervals throughout treatment. Additional weekly intrathecal MTX treatments were recommended throughout induction for patients with CNS-3.

In the UKALL2011 trial, the weekly intrathecal MTX treatments were recommended for patients with CNS-2, as well as CNS-3.

Overall, among those with CNS data available, 557 patients had CNS-1 (87.4%), 44 CNS-2 (6.9%), and 36 CNS-3 (5.7%).

For the outcomes of 4-year cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) in the combined cohort of the 2 UK trials, there were no significant differences between CNS-1, 2 or 3 groups.

Specifically, the mean rates of 4-year CIR in the CNS-1, 2, and 3 groups were 13.6%, 25.9% and 24.6%, respectively (P = .241); mean EFS rates were 82.9%, 74.1% and 77.8% (P = .623), and OS rates were 88.6%, 80.9% and 91.8%, (P = .453).

“Most importantly, outcomes are not significantly different for the patients with CNS-3, despite omission of CRT in the UK cohort,” the authors underscored.

Comparatively, in the cohort of the 2 COG trials, there were significant differences based on CNS status for 4-year CIR (P = .0002); EFS (P = .0004) and OS (P = .005).

The 4-year relapse rates among those with CNS-3 in the UK cohort were slightly higher compared with those in the COG cohort (24.6% UK vs 17.9%, COG). However, the difference did not translate to poorer long-term survival in the UK cohort (91.8% vs 82.7%, respectively).

Those findings are consistent with a previous meta-analysis that Dr. Vora and his colleagues conducted of more than 16,000 patients with mainly B-cell ALL, which showed that CRT reduced the risk of isolated and combined CNS relapse in patients with CNS-3. However, that risk had no impact on EFS and OS.

Of note, patients in the UK cohort with CNS-2 had worse outcomes compared with the COG group, with double the rate of relapse and lower EFS and OS. However, the authors speculate that factors including a lower proportion of patients with CNS-2 in the UK cohort and differences in methodologies may explain those different outcomes and may preclude their generalizability to other groups.

Overall, “these findings corroborate those of earlier studies that CRT has marginal, if any benefit, for any sub-group of ALL, especially as part of contemporary treatment,” Dr. Vora said in an interview.

In terms of therapies that do appear to make a difference in the treatment of CNS-3, Dr. Vora noted that the addition of nelarabine in the COG AALL0434 trial showed “remarkable benefit” in the CNS-3 group, with a 93.1% rate of disease-free survival in those patients versus 70.2% without nelarabine.

Importantly, those patients did also receive CRT. However, Dr. Vora and colleagues underscore that “the improvement is impressive and raises the question of whether nelarabine would have a similar beneficial effect in the absence of CRT.”

In an editorial published with the COG trials, Josep-Maria Ribera, MD, of the Josep Carreras Leukemia Research Institute, in Barcelona, Spain, agrees that “better approaches clearly are needed to treat CNS-3 T-ALL, especially if omission of CRT is a priority.”

Noting the improvements observed with nelarabine, as well as Capizzi escalating-dose methotrexate (C-MTX), and dexamethasone in reducing the risk of CNS relapse, he speculates that “it is possible that the additional use of C-MTX and induction dexamethasone could eliminate the need for CRT in these patients.”

The authors and Dr. Ribera had no disclosures to report.

In treating young patients with T-cell acute lymphoblastic leukemia (T-ALL), prophylactic central nervous system (CNS)-directed cranial radiotherapy (CRT) can safely be omitted even for those with the greatest CNS involvement,i.e., CNS-3 disease. Doing so spares patients the treatment’s toxic effects without heightening the risk of relapse.

“Overall, comparison of these cohorts provides a strong indication that CRT provides minimal benefit to patients with CNS-3 disease at diagnosis,” first author Ajay Vora, MD, a consultant hematologist with Great Ormond Street Hospital, in London, and his colleagues report in a research letter published recently in Blood Advances.

“Given the high rates of neurocognitive impairment and secondary CNS malignancies, we believe strong consideration should be given to eliminating CRT in first-line treatment for all patients with T-ALL,” they wrote.

More aggressive than B-cell ALL, T-ALL is characterized by a higher likelihood of infiltration of the CNS at diagnosis, which increases the risk of relapse after treatment.

Until recently, treatment of T-ALL long entailed CNS-directed therapy using prophylactic CRT. Now, however, due to the risks of significant toxicity, including neurocognitive defects and secondary cancers, CRT is usually either omitted or limited to key subgroups, such as those with CNS-3 disease. As an alternative, intrathecal chemotherapy is used, the authors explain.

In a 2023 study evaluating the consecutive Children’s Oncology Group (COG) AALL0434 and AALL1231 phase 3 trials of 2,164 patients with T-ALL, patients with CNS-3 at diagnosis were found to have worse outcomes, compared with CNS-1 and 2.

Importantly, the outcomes in both of those two trials were similar, despite the use of CRT in more than 90% of patients in the AALL0434 trial--but in only 10% of patients AALL1231 trial (mainly those with CNS-3 and at high-risk). These outcomes suggested that CRT can safely be eliminated for CNS-1 and 2 patients.

With CRT used in both trials among patients with CNS-3, conclusions about eliminating CRT among those patients could not be drawn. However, with other large groups (including the Dutch Childhood Oncology Group), eliminating CRT in the frontline treatment of all patients with T-ALL, including those with CNS-3, is what Dr. Vora and colleagues sought to further investigate.

For the current study, they evaluated outcomes in the UKALL2003 and UKALL2011 trials conducted by the UK National Cancer Research Institute, in which CRT was eliminated for all patients — including those with CNS-3 — and compared them with the COG AALL0434 and AALL1231 trials.

In the UK trials, involving 665 patients with T-ALL aged 1 to 24, treatment included a dexamethasone-based backbone chemotherapy consisting of a 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation, interim maintenance, delayed intensification, and maintenance therapy, with the treatment stratified based on morphological early response and minimal residual disease at the end of induction.

While the UKALL2003 trial initially recommended CRT for patients with CNS-3, that practice ended in 2009, and CNS-directed therapy subsequently consisted of intrathecal methotrexate (MTX) at regular intervals throughout treatment. Additional weekly intrathecal MTX treatments were recommended throughout induction for patients with CNS-3.

In the UKALL2011 trial, the weekly intrathecal MTX treatments were recommended for patients with CNS-2, as well as CNS-3.

Overall, among those with CNS data available, 557 patients had CNS-1 (87.4%), 44 CNS-2 (6.9%), and 36 CNS-3 (5.7%).

For the outcomes of 4-year cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) in the combined cohort of the 2 UK trials, there were no significant differences between CNS-1, 2 or 3 groups.

Specifically, the mean rates of 4-year CIR in the CNS-1, 2, and 3 groups were 13.6%, 25.9% and 24.6%, respectively (P = .241); mean EFS rates were 82.9%, 74.1% and 77.8% (P = .623), and OS rates were 88.6%, 80.9% and 91.8%, (P = .453).

“Most importantly, outcomes are not significantly different for the patients with CNS-3, despite omission of CRT in the UK cohort,” the authors underscored.

Comparatively, in the cohort of the 2 COG trials, there were significant differences based on CNS status for 4-year CIR (P = .0002); EFS (P = .0004) and OS (P = .005).

The 4-year relapse rates among those with CNS-3 in the UK cohort were slightly higher compared with those in the COG cohort (24.6% UK vs 17.9%, COG). However, the difference did not translate to poorer long-term survival in the UK cohort (91.8% vs 82.7%, respectively).

Those findings are consistent with a previous meta-analysis that Dr. Vora and his colleagues conducted of more than 16,000 patients with mainly B-cell ALL, which showed that CRT reduced the risk of isolated and combined CNS relapse in patients with CNS-3. However, that risk had no impact on EFS and OS.

Of note, patients in the UK cohort with CNS-2 had worse outcomes compared with the COG group, with double the rate of relapse and lower EFS and OS. However, the authors speculate that factors including a lower proportion of patients with CNS-2 in the UK cohort and differences in methodologies may explain those different outcomes and may preclude their generalizability to other groups.

Overall, “these findings corroborate those of earlier studies that CRT has marginal, if any benefit, for any sub-group of ALL, especially as part of contemporary treatment,” Dr. Vora said in an interview.

In terms of therapies that do appear to make a difference in the treatment of CNS-3, Dr. Vora noted that the addition of nelarabine in the COG AALL0434 trial showed “remarkable benefit” in the CNS-3 group, with a 93.1% rate of disease-free survival in those patients versus 70.2% without nelarabine.

Importantly, those patients did also receive CRT. However, Dr. Vora and colleagues underscore that “the improvement is impressive and raises the question of whether nelarabine would have a similar beneficial effect in the absence of CRT.”

In an editorial published with the COG trials, Josep-Maria Ribera, MD, of the Josep Carreras Leukemia Research Institute, in Barcelona, Spain, agrees that “better approaches clearly are needed to treat CNS-3 T-ALL, especially if omission of CRT is a priority.”

Noting the improvements observed with nelarabine, as well as Capizzi escalating-dose methotrexate (C-MTX), and dexamethasone in reducing the risk of CNS relapse, he speculates that “it is possible that the additional use of C-MTX and induction dexamethasone could eliminate the need for CRT in these patients.”

The authors and Dr. Ribera had no disclosures to report.

In treating young patients with T-cell acute lymphoblastic leukemia (T-ALL), prophylactic central nervous system (CNS)-directed cranial radiotherapy (CRT) can safely be omitted even for those with the greatest CNS involvement,i.e., CNS-3 disease. Doing so spares patients the treatment’s toxic effects without heightening the risk of relapse.

“Overall, comparison of these cohorts provides a strong indication that CRT provides minimal benefit to patients with CNS-3 disease at diagnosis,” first author Ajay Vora, MD, a consultant hematologist with Great Ormond Street Hospital, in London, and his colleagues report in a research letter published recently in Blood Advances.

“Given the high rates of neurocognitive impairment and secondary CNS malignancies, we believe strong consideration should be given to eliminating CRT in first-line treatment for all patients with T-ALL,” they wrote.

More aggressive than B-cell ALL, T-ALL is characterized by a higher likelihood of infiltration of the CNS at diagnosis, which increases the risk of relapse after treatment.

Until recently, treatment of T-ALL long entailed CNS-directed therapy using prophylactic CRT. Now, however, due to the risks of significant toxicity, including neurocognitive defects and secondary cancers, CRT is usually either omitted or limited to key subgroups, such as those with CNS-3 disease. As an alternative, intrathecal chemotherapy is used, the authors explain.

In a 2023 study evaluating the consecutive Children’s Oncology Group (COG) AALL0434 and AALL1231 phase 3 trials of 2,164 patients with T-ALL, patients with CNS-3 at diagnosis were found to have worse outcomes, compared with CNS-1 and 2.

Importantly, the outcomes in both of those two trials were similar, despite the use of CRT in more than 90% of patients in the AALL0434 trial--but in only 10% of patients AALL1231 trial (mainly those with CNS-3 and at high-risk). These outcomes suggested that CRT can safely be eliminated for CNS-1 and 2 patients.

With CRT used in both trials among patients with CNS-3, conclusions about eliminating CRT among those patients could not be drawn. However, with other large groups (including the Dutch Childhood Oncology Group), eliminating CRT in the frontline treatment of all patients with T-ALL, including those with CNS-3, is what Dr. Vora and colleagues sought to further investigate.

For the current study, they evaluated outcomes in the UKALL2003 and UKALL2011 trials conducted by the UK National Cancer Research Institute, in which CRT was eliminated for all patients — including those with CNS-3 — and compared them with the COG AALL0434 and AALL1231 trials.

In the UK trials, involving 665 patients with T-ALL aged 1 to 24, treatment included a dexamethasone-based backbone chemotherapy consisting of a 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation, interim maintenance, delayed intensification, and maintenance therapy, with the treatment stratified based on morphological early response and minimal residual disease at the end of induction.

While the UKALL2003 trial initially recommended CRT for patients with CNS-3, that practice ended in 2009, and CNS-directed therapy subsequently consisted of intrathecal methotrexate (MTX) at regular intervals throughout treatment. Additional weekly intrathecal MTX treatments were recommended throughout induction for patients with CNS-3.

In the UKALL2011 trial, the weekly intrathecal MTX treatments were recommended for patients with CNS-2, as well as CNS-3.

Overall, among those with CNS data available, 557 patients had CNS-1 (87.4%), 44 CNS-2 (6.9%), and 36 CNS-3 (5.7%).

For the outcomes of 4-year cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) in the combined cohort of the 2 UK trials, there were no significant differences between CNS-1, 2 or 3 groups.

Specifically, the mean rates of 4-year CIR in the CNS-1, 2, and 3 groups were 13.6%, 25.9% and 24.6%, respectively (P = .241); mean EFS rates were 82.9%, 74.1% and 77.8% (P = .623), and OS rates were 88.6%, 80.9% and 91.8%, (P = .453).

“Most importantly, outcomes are not significantly different for the patients with CNS-3, despite omission of CRT in the UK cohort,” the authors underscored.

Comparatively, in the cohort of the 2 COG trials, there were significant differences based on CNS status for 4-year CIR (P = .0002); EFS (P = .0004) and OS (P = .005).

The 4-year relapse rates among those with CNS-3 in the UK cohort were slightly higher compared with those in the COG cohort (24.6% UK vs 17.9%, COG). However, the difference did not translate to poorer long-term survival in the UK cohort (91.8% vs 82.7%, respectively).

Those findings are consistent with a previous meta-analysis that Dr. Vora and his colleagues conducted of more than 16,000 patients with mainly B-cell ALL, which showed that CRT reduced the risk of isolated and combined CNS relapse in patients with CNS-3. However, that risk had no impact on EFS and OS.

Of note, patients in the UK cohort with CNS-2 had worse outcomes compared with the COG group, with double the rate of relapse and lower EFS and OS. However, the authors speculate that factors including a lower proportion of patients with CNS-2 in the UK cohort and differences in methodologies may explain those different outcomes and may preclude their generalizability to other groups.

Overall, “these findings corroborate those of earlier studies that CRT has marginal, if any benefit, for any sub-group of ALL, especially as part of contemporary treatment,” Dr. Vora said in an interview.

In terms of therapies that do appear to make a difference in the treatment of CNS-3, Dr. Vora noted that the addition of nelarabine in the COG AALL0434 trial showed “remarkable benefit” in the CNS-3 group, with a 93.1% rate of disease-free survival in those patients versus 70.2% without nelarabine.

Importantly, those patients did also receive CRT. However, Dr. Vora and colleagues underscore that “the improvement is impressive and raises the question of whether nelarabine would have a similar beneficial effect in the absence of CRT.”

In an editorial published with the COG trials, Josep-Maria Ribera, MD, of the Josep Carreras Leukemia Research Institute, in Barcelona, Spain, agrees that “better approaches clearly are needed to treat CNS-3 T-ALL, especially if omission of CRT is a priority.”

Noting the improvements observed with nelarabine, as well as Capizzi escalating-dose methotrexate (C-MTX), and dexamethasone in reducing the risk of CNS relapse, he speculates that “it is possible that the additional use of C-MTX and induction dexamethasone could eliminate the need for CRT in these patients.”

The authors and Dr. Ribera had no disclosures to report.

Using an advanced microscopic technique, American researchers have detected 100,000 nanoplastic molecules per liter of water in plastic bottles. Because of their small size, these particles can enter the bloodstream, cells, and the brain, thus posing potential health risks. The study, recently published in the Proceedings of the National Academy of Sciences, raises concerns about the impact of these nanoparticles.

An Unknown Realm

In recent years, the global presence of tiny particles known as microplastics has raised concerns. The particles are found in polar ice, soil, drinking water, and food. Formed as plastics break down into increasingly small pieces, these particles are consumed by humans and other organisms, with unknown effects on health and ecosystems. Whereas macroplastics have been found in various organs, including the lungs and liver, the study marks a unique exploration into the world of nanoplastics.

Concerns about nanoplastic presence in humans intensified when a 2018 study revealed contamination signs in 93% of 259 examined bottles from nine countries.

The novelty of this research lies in its focus, using a refined spectrometry method, on the poorly understood world of nanoplastics, which derive from the decomposition of microplastics. For the first time, American researchers, including biophysicists and chemists, counted and identified these tiny particles in bottled water. On average, they found around 240,000 detectable plastic fragments per liter, which is 10-100 times more than previous estimates based on larger sizes.

Microplastics are defined as fragments ranging from 5 mm to 1 µm, whereas nanoplastics, particles < 1 µm, are measured in billionths of a meter.

In contrast to microplastics, nanoplastics are so small that they can traverse the intestines and lungs and move directly into the bloodstream, reaching organs such as the heart or brain or even the fetus via the placenta.

“This was previously an obscure, unexplored area. Toxicity studies could only speculate about what was in there,” said Beizhan Yan, PhD, coauthor of the study and environmental chemist at the Lamont–Doherty Earth Observatory of Columbia University, New York. “This study opens a window for us to observe a world we were not exposed to before.”
 

90% Nanoplastics Found

The new study employed a technique called stimulated Raman scattering microscopy, which was invented by study coauthor Wei Min, a biophysicist at Columbia. This method involves probing samples simultaneously with two lasers tuned to resonate specific molecules.

Researchers tested three bottled water brands that are popular in the United States, analyzing plastic particles up to 100 nm in size. They identified 110,000-370,000 plastic particles per liter. About 90% were nanoplastics — which are invisible by standard imaging techniques — and the rest were microplastics. The study also identified the seven plastics involved.

The most common is polyamide, a type of nylon, likely from plastic filters purportedly used to purify water before bottling. Next is polyethylene terephthalate, which is commonly used for water bottles and other food containers. Researchers also found other common plastics, including polystyrene, polyvinyl chloride, and methyl methacrylate, used in various industrial processes.
 

Not Size But Quantity

What’s more concerning is that the seven types of plastics accounted for only about 10% of all nanoparticles found in the samples. Researchers have no idea about the composition of the remaining 90%. If these are all nanoparticles, their number could reach tens of millions per liter, representing the complex composition of seemingly simple water samples, as noted by the authors.

Researchers now plan to expand beyond bottled water, exploring the vast realm of nanoplastics. They emphasize that, in terms of mass, nanoplastics are far smaller than microplastics, but “it’s not about size. It’s about the numbers as smaller things can easily penetrate us.”

The team aims to study tap water, which also contains microplastics but in much smaller proportions than bottled water.

This article was translated from the Medscape French edition. 

Using an advanced microscopic technique, American researchers have detected 100,000 nanoplastic molecules per liter of water in plastic bottles. Because of their small size, these particles can enter the bloodstream, cells, and the brain, thus posing potential health risks. The study, recently published in the Proceedings of the National Academy of Sciences, raises concerns about the impact of these nanoparticles.

An Unknown Realm

In recent years, the global presence of tiny particles known as microplastics has raised concerns. The particles are found in polar ice, soil, drinking water, and food. Formed as plastics break down into increasingly small pieces, these particles are consumed by humans and other organisms, with unknown effects on health and ecosystems. Whereas macroplastics have been found in various organs, including the lungs and liver, the study marks a unique exploration into the world of nanoplastics.

Concerns about nanoplastic presence in humans intensified when a 2018 study revealed contamination signs in 93% of 259 examined bottles from nine countries.

The novelty of this research lies in its focus, using a refined spectrometry method, on the poorly understood world of nanoplastics, which derive from the decomposition of microplastics. For the first time, American researchers, including biophysicists and chemists, counted and identified these tiny particles in bottled water. On average, they found around 240,000 detectable plastic fragments per liter, which is 10-100 times more than previous estimates based on larger sizes.

Microplastics are defined as fragments ranging from 5 mm to 1 µm, whereas nanoplastics, particles < 1 µm, are measured in billionths of a meter.

In contrast to microplastics, nanoplastics are so small that they can traverse the intestines and lungs and move directly into the bloodstream, reaching organs such as the heart or brain or even the fetus via the placenta.

“This was previously an obscure, unexplored area. Toxicity studies could only speculate about what was in there,” said Beizhan Yan, PhD, coauthor of the study and environmental chemist at the Lamont–Doherty Earth Observatory of Columbia University, New York. “This study opens a window for us to observe a world we were not exposed to before.”
 

90% Nanoplastics Found

The new study employed a technique called stimulated Raman scattering microscopy, which was invented by study coauthor Wei Min, a biophysicist at Columbia. This method involves probing samples simultaneously with two lasers tuned to resonate specific molecules.

Researchers tested three bottled water brands that are popular in the United States, analyzing plastic particles up to 100 nm in size. They identified 110,000-370,000 plastic particles per liter. About 90% were nanoplastics — which are invisible by standard imaging techniques — and the rest were microplastics. The study also identified the seven plastics involved.

The most common is polyamide, a type of nylon, likely from plastic filters purportedly used to purify water before bottling. Next is polyethylene terephthalate, which is commonly used for water bottles and other food containers. Researchers also found other common plastics, including polystyrene, polyvinyl chloride, and methyl methacrylate, used in various industrial processes.
 

Not Size But Quantity

What’s more concerning is that the seven types of plastics accounted for only about 10% of all nanoparticles found in the samples. Researchers have no idea about the composition of the remaining 90%. If these are all nanoparticles, their number could reach tens of millions per liter, representing the complex composition of seemingly simple water samples, as noted by the authors.

Researchers now plan to expand beyond bottled water, exploring the vast realm of nanoplastics. They emphasize that, in terms of mass, nanoplastics are far smaller than microplastics, but “it’s not about size. It’s about the numbers as smaller things can easily penetrate us.”

The team aims to study tap water, which also contains microplastics but in much smaller proportions than bottled water.

This article was translated from the Medscape French edition. 

Using an advanced microscopic technique, American researchers have detected 100,000 nanoplastic molecules per liter of water in plastic bottles. Because of their small size, these particles can enter the bloodstream, cells, and the brain, thus posing potential health risks. The study, recently published in the Proceedings of the National Academy of Sciences, raises concerns about the impact of these nanoparticles.

An Unknown Realm

In recent years, the global presence of tiny particles known as microplastics has raised concerns. The particles are found in polar ice, soil, drinking water, and food. Formed as plastics break down into increasingly small pieces, these particles are consumed by humans and other organisms, with unknown effects on health and ecosystems. Whereas macroplastics have been found in various organs, including the lungs and liver, the study marks a unique exploration into the world of nanoplastics.

Concerns about nanoplastic presence in humans intensified when a 2018 study revealed contamination signs in 93% of 259 examined bottles from nine countries.

The novelty of this research lies in its focus, using a refined spectrometry method, on the poorly understood world of nanoplastics, which derive from the decomposition of microplastics. For the first time, American researchers, including biophysicists and chemists, counted and identified these tiny particles in bottled water. On average, they found around 240,000 detectable plastic fragments per liter, which is 10-100 times more than previous estimates based on larger sizes.

Microplastics are defined as fragments ranging from 5 mm to 1 µm, whereas nanoplastics, particles < 1 µm, are measured in billionths of a meter.

In contrast to microplastics, nanoplastics are so small that they can traverse the intestines and lungs and move directly into the bloodstream, reaching organs such as the heart or brain or even the fetus via the placenta.

“This was previously an obscure, unexplored area. Toxicity studies could only speculate about what was in there,” said Beizhan Yan, PhD, coauthor of the study and environmental chemist at the Lamont–Doherty Earth Observatory of Columbia University, New York. “This study opens a window for us to observe a world we were not exposed to before.”
 

90% Nanoplastics Found

The new study employed a technique called stimulated Raman scattering microscopy, which was invented by study coauthor Wei Min, a biophysicist at Columbia. This method involves probing samples simultaneously with two lasers tuned to resonate specific molecules.

Researchers tested three bottled water brands that are popular in the United States, analyzing plastic particles up to 100 nm in size. They identified 110,000-370,000 plastic particles per liter. About 90% were nanoplastics — which are invisible by standard imaging techniques — and the rest were microplastics. The study also identified the seven plastics involved.

The most common is polyamide, a type of nylon, likely from plastic filters purportedly used to purify water before bottling. Next is polyethylene terephthalate, which is commonly used for water bottles and other food containers. Researchers also found other common plastics, including polystyrene, polyvinyl chloride, and methyl methacrylate, used in various industrial processes.
 

Not Size But Quantity

What’s more concerning is that the seven types of plastics accounted for only about 10% of all nanoparticles found in the samples. Researchers have no idea about the composition of the remaining 90%. If these are all nanoparticles, their number could reach tens of millions per liter, representing the complex composition of seemingly simple water samples, as noted by the authors.

Researchers now plan to expand beyond bottled water, exploring the vast realm of nanoplastics. They emphasize that, in terms of mass, nanoplastics are far smaller than microplastics, but “it’s not about size. It’s about the numbers as smaller things can easily penetrate us.”

The team aims to study tap water, which also contains microplastics but in much smaller proportions than bottled water.

This article was translated from the Medscape French edition.