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Drugmakers are abandoning cheap generics, and now U.S. cancer patients can’t get meds
On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.
Their decisions are likely to result in preventable deaths.
Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.
The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.
But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?
“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”
“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.
“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”
The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.
Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.
“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”
Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.
At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.
On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.
She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”
Doses remained at 80%, she said. Things hadn’t changed 10 days later.
Generics manufacturers are pulling out
The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.
As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.
The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.
Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.
The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.
Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.
Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”
Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.
“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
Should government step in?
Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.
As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.
Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”
More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.
“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.
Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.
In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.
“It would almost literally be a drop in the bucket.”
KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.
On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.
Their decisions are likely to result in preventable deaths.
Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.
The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.
But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?
“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”
“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.
“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”
The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.
Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.
“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”
Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.
At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.
On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.
She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”
Doses remained at 80%, she said. Things hadn’t changed 10 days later.
Generics manufacturers are pulling out
The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.
As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.
The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.
Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.
The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.
Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.
Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”
Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.
“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
Should government step in?
Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.
As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.
Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”
More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.
“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.
Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.
In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.
“It would almost literally be a drop in the bucket.”
KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.
On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.
Their decisions are likely to result in preventable deaths.
Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.
The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.
But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?
“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”
“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.
“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”
The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.
Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.
“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”
Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.
At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.
On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.
She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”
Doses remained at 80%, she said. Things hadn’t changed 10 days later.
Generics manufacturers are pulling out
The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.
As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.
The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.
Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.
The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.
Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.
Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”
Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.
“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
Should government step in?
Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.
As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.
Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”
More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.
“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.
Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.
In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.
“It would almost literally be a drop in the bucket.”
KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.
Consider mental health and social factors in management of sickle cell disease
Complications from sickle cell disease (SCD) can affect education and life opportunities, and these complications have been associated with social determinants of health such as socioeconomic status, depression, health literacy, and level of education, according to Kelly M. Harris, PhD, of Washington University in St. Louis, and colleagues.
Pain is a hallmark of SCD, and “the current climate around pain management and opioid use has specific implications for individuals with [SCD], especially youth,” Dr. Harris said in an interview.
In a study published in JAMA Network Open, the researchers analyzed 2,264 participants (average age, 27.9 years; 56.2% were female) in the Sickle Cell Disease Implementation Consortium a study that includes patient assessment, treatment, and creation of a longitudinal registry.
The participants completed the Adult Sickle Cell Quality of Life Measurement Information System to provide data on the frequency and severity of pain episodes related to SCD over the past 12 months. Multivariable regression analysis was used to examine the associations of education, employment, and mental health with pain frequency and severity.
Overall, 79.8% of participants reported severe pain, and 47.8% reported more than four episodes of pain in the past year.
Notably, 20% of the participants were diagnosed with depression, and increased pain frequency was significantly associated with depression, although no significant association appeared between pain severity and depression, the researchers said.
A total of 47% of the participants reported using pain medication and 49% reported using hydroxyurea. In addition, 628 participants (28.0%) underwent regular blood transfusions.
Neither education level nor income was associated with increased pain frequency or severity. Age younger than 18 years was significantly associated with both pain frequency and severity, as was daily used of pain medication. Unemployment and female sex also were associated with increased pain frequency.
The findings were limited by several factors including the cross-sectional design that prevents conclusions of causality, and by the reliance on patient reports of depression, which likely led to underreporting, the researchers noted.
However, the results are consistent with previous studies suggesting that pain and negative feelings were associated with reduced quality of life in SCD patients, especially younger patients, and support the need to screen SCD patients for depression, especially those who report more severe and/or more frequent pain, they said.
Take a comprehensive approach to a complex condition
“When treating pain, we cannot just rely on medication,” Dr. Harris said. “It is important that providers consider the full experiences of patients and pursue holistic and comprehensive treatment approaches to reducing pain. Screening for depression should be a regular practice, particularly for patients experiencing frequent and/or severe pain.
“Racial discrimination, stigma, and bias impact pain diagnosis and treatment for individuals with SCD,” said Dr. Harris. “Increasing awareness of the associations between depression and pain frequency and severity ... may help address these barriers.”
Data highlight treatment gaps
Alexander A. Boucher, MD, a member of the division of pediatric hematology and oncology at the University of Minnesota, Minneapolis, noted the researchers included patients as young as midadolescence, with a majority being under 35 years old. “The 18- to 30-year-old range is an especially high-risk age window for increased acute health care utilization, even compared with other chronic adolescent/young adult conditions. “The demographics in the study group also reasonably approximate those for young adults with SCD in urban centers. By taking a multicenter approach across a several-state region, I believe the findings offer better generalizability, since health care access and mental health access can vary state-by-state,” and the current results show a more standard experience.
“It was a bit surprising that female [sex] maintained such an association with pain across the different components of the study,” and that the pain peak was in the 25- to 34-year-old age range, said Dr. Boucher. However, anecdotally, the late teens and early 20s “can be laden with mental health concerns due to the life transitions that accompany most people at that time. The note that hydroxyurea use was associated with more pain and depression symptoms was interesting, and serves as a reminder that what is happening to the red blood cells and in the blood vessels, such as red blood cell breakdown, sickling, and vaso-occlusion are only a part of what causes pain, and hydroxyurea is not likely to play a role in mitigating mental health aspects of pain.”
The findings that overall pain frequency and related pain medication use were associated with higher depression rates “may in part reflect a blind spot for physicians and medical teams, who often resort back to physical pain-based heuristics.” Physicians may misunderstand chronic pain and its management and look for quick fixes for pain out of uncertainty or urgency, said Dr. Boucher. “This serves to diminish the perspectives of patients as people first (not embodiments of a disease) and can lead to missed opportunities to tackle mental health challenges.”
Barriers and limitations
There are barriers to mental health screening in hematology care,” Dr. Boucher said. First, most hematologists are not experts in mental health and while they may have some from their medical training in these disorders, it can be difficult to maintain the level of health literacy needed to stay up to date on treatments. Second, depression screening may not be part of regular patient intake and the Patient Health Questionnaire–2 or PHQ-9 offer only short-term (2-week) snapshots of depression.
“Perhaps most critically, even if we do successfully screen, the access to mental health specialists is severely limited, just as it is across the medical landscape, so intervention opportunities may be suboptimal,” said Dr. Boucher. The problem is magnified if, as the current study suggests, the rates of depression in SCD are approximately three times greater than the population overall.
In the current study, “the fact that only half of those who self-reported depression symptoms actually had depression documented as a diagnosis in their medical records suggests that we are missing a lot of patients affected by mental health disturbances.”
This study is limited in measurement of the contribution of social determinants of health, he said, as they were primarily focused on employment status and income. The study does not describe other factors like support systems, housing, and transportation.
“I would like to see studies that not only identify associated drivers of pain, but also offer evidence for successful interventions,” Dr. Boucher said, and these studies should include patient-centered interventions versus disease-centered interventions.
Undertreatment persists
Other concerns with sickle cell anemia include the underuse of hydroxyurea to reduce complications associated with the disease such as pain, stroke, and even early death. Another recent study in JAMA Network Open suggested that use of hydroxyurea remained low in children and youth despite the issuing of guidelines, and that underserved populations were especially affected. In that study, the researchers found that the patients’ annual days’ supply of hydroxyurea in New York state did not change significantly after the guideline update.
SCD also has been associated with increased risk of other poor outcomes, such as stillbirth and increased risk of poor COVID-19–related outcomes and COVID-19–related deaths.
The study by Dr. Harris and colleagues was supported by the National Institutes of Health through the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Harris had no financial conflicts to disclose. The hydroxyurea study was supported by the Agency for Healthcare Research and Quality and the NHLBI. The researchers had no financial conflicts to disclose. Dr. Boucher disclosed conducting research with SCL Behring, but had no relevant financial conflicts.
Complications from sickle cell disease (SCD) can affect education and life opportunities, and these complications have been associated with social determinants of health such as socioeconomic status, depression, health literacy, and level of education, according to Kelly M. Harris, PhD, of Washington University in St. Louis, and colleagues.
Pain is a hallmark of SCD, and “the current climate around pain management and opioid use has specific implications for individuals with [SCD], especially youth,” Dr. Harris said in an interview.
In a study published in JAMA Network Open, the researchers analyzed 2,264 participants (average age, 27.9 years; 56.2% were female) in the Sickle Cell Disease Implementation Consortium a study that includes patient assessment, treatment, and creation of a longitudinal registry.
The participants completed the Adult Sickle Cell Quality of Life Measurement Information System to provide data on the frequency and severity of pain episodes related to SCD over the past 12 months. Multivariable regression analysis was used to examine the associations of education, employment, and mental health with pain frequency and severity.
Overall, 79.8% of participants reported severe pain, and 47.8% reported more than four episodes of pain in the past year.
Notably, 20% of the participants were diagnosed with depression, and increased pain frequency was significantly associated with depression, although no significant association appeared between pain severity and depression, the researchers said.
A total of 47% of the participants reported using pain medication and 49% reported using hydroxyurea. In addition, 628 participants (28.0%) underwent regular blood transfusions.
Neither education level nor income was associated with increased pain frequency or severity. Age younger than 18 years was significantly associated with both pain frequency and severity, as was daily used of pain medication. Unemployment and female sex also were associated with increased pain frequency.
The findings were limited by several factors including the cross-sectional design that prevents conclusions of causality, and by the reliance on patient reports of depression, which likely led to underreporting, the researchers noted.
However, the results are consistent with previous studies suggesting that pain and negative feelings were associated with reduced quality of life in SCD patients, especially younger patients, and support the need to screen SCD patients for depression, especially those who report more severe and/or more frequent pain, they said.
Take a comprehensive approach to a complex condition
“When treating pain, we cannot just rely on medication,” Dr. Harris said. “It is important that providers consider the full experiences of patients and pursue holistic and comprehensive treatment approaches to reducing pain. Screening for depression should be a regular practice, particularly for patients experiencing frequent and/or severe pain.
“Racial discrimination, stigma, and bias impact pain diagnosis and treatment for individuals with SCD,” said Dr. Harris. “Increasing awareness of the associations between depression and pain frequency and severity ... may help address these barriers.”
Data highlight treatment gaps
Alexander A. Boucher, MD, a member of the division of pediatric hematology and oncology at the University of Minnesota, Minneapolis, noted the researchers included patients as young as midadolescence, with a majority being under 35 years old. “The 18- to 30-year-old range is an especially high-risk age window for increased acute health care utilization, even compared with other chronic adolescent/young adult conditions. “The demographics in the study group also reasonably approximate those for young adults with SCD in urban centers. By taking a multicenter approach across a several-state region, I believe the findings offer better generalizability, since health care access and mental health access can vary state-by-state,” and the current results show a more standard experience.
“It was a bit surprising that female [sex] maintained such an association with pain across the different components of the study,” and that the pain peak was in the 25- to 34-year-old age range, said Dr. Boucher. However, anecdotally, the late teens and early 20s “can be laden with mental health concerns due to the life transitions that accompany most people at that time. The note that hydroxyurea use was associated with more pain and depression symptoms was interesting, and serves as a reminder that what is happening to the red blood cells and in the blood vessels, such as red blood cell breakdown, sickling, and vaso-occlusion are only a part of what causes pain, and hydroxyurea is not likely to play a role in mitigating mental health aspects of pain.”
The findings that overall pain frequency and related pain medication use were associated with higher depression rates “may in part reflect a blind spot for physicians and medical teams, who often resort back to physical pain-based heuristics.” Physicians may misunderstand chronic pain and its management and look for quick fixes for pain out of uncertainty or urgency, said Dr. Boucher. “This serves to diminish the perspectives of patients as people first (not embodiments of a disease) and can lead to missed opportunities to tackle mental health challenges.”
Barriers and limitations
There are barriers to mental health screening in hematology care,” Dr. Boucher said. First, most hematologists are not experts in mental health and while they may have some from their medical training in these disorders, it can be difficult to maintain the level of health literacy needed to stay up to date on treatments. Second, depression screening may not be part of regular patient intake and the Patient Health Questionnaire–2 or PHQ-9 offer only short-term (2-week) snapshots of depression.
“Perhaps most critically, even if we do successfully screen, the access to mental health specialists is severely limited, just as it is across the medical landscape, so intervention opportunities may be suboptimal,” said Dr. Boucher. The problem is magnified if, as the current study suggests, the rates of depression in SCD are approximately three times greater than the population overall.
In the current study, “the fact that only half of those who self-reported depression symptoms actually had depression documented as a diagnosis in their medical records suggests that we are missing a lot of patients affected by mental health disturbances.”
This study is limited in measurement of the contribution of social determinants of health, he said, as they were primarily focused on employment status and income. The study does not describe other factors like support systems, housing, and transportation.
“I would like to see studies that not only identify associated drivers of pain, but also offer evidence for successful interventions,” Dr. Boucher said, and these studies should include patient-centered interventions versus disease-centered interventions.
Undertreatment persists
Other concerns with sickle cell anemia include the underuse of hydroxyurea to reduce complications associated with the disease such as pain, stroke, and even early death. Another recent study in JAMA Network Open suggested that use of hydroxyurea remained low in children and youth despite the issuing of guidelines, and that underserved populations were especially affected. In that study, the researchers found that the patients’ annual days’ supply of hydroxyurea in New York state did not change significantly after the guideline update.
SCD also has been associated with increased risk of other poor outcomes, such as stillbirth and increased risk of poor COVID-19–related outcomes and COVID-19–related deaths.
The study by Dr. Harris and colleagues was supported by the National Institutes of Health through the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Harris had no financial conflicts to disclose. The hydroxyurea study was supported by the Agency for Healthcare Research and Quality and the NHLBI. The researchers had no financial conflicts to disclose. Dr. Boucher disclosed conducting research with SCL Behring, but had no relevant financial conflicts.
Complications from sickle cell disease (SCD) can affect education and life opportunities, and these complications have been associated with social determinants of health such as socioeconomic status, depression, health literacy, and level of education, according to Kelly M. Harris, PhD, of Washington University in St. Louis, and colleagues.
Pain is a hallmark of SCD, and “the current climate around pain management and opioid use has specific implications for individuals with [SCD], especially youth,” Dr. Harris said in an interview.
In a study published in JAMA Network Open, the researchers analyzed 2,264 participants (average age, 27.9 years; 56.2% were female) in the Sickle Cell Disease Implementation Consortium a study that includes patient assessment, treatment, and creation of a longitudinal registry.
The participants completed the Adult Sickle Cell Quality of Life Measurement Information System to provide data on the frequency and severity of pain episodes related to SCD over the past 12 months. Multivariable regression analysis was used to examine the associations of education, employment, and mental health with pain frequency and severity.
Overall, 79.8% of participants reported severe pain, and 47.8% reported more than four episodes of pain in the past year.
Notably, 20% of the participants were diagnosed with depression, and increased pain frequency was significantly associated with depression, although no significant association appeared between pain severity and depression, the researchers said.
A total of 47% of the participants reported using pain medication and 49% reported using hydroxyurea. In addition, 628 participants (28.0%) underwent regular blood transfusions.
Neither education level nor income was associated with increased pain frequency or severity. Age younger than 18 years was significantly associated with both pain frequency and severity, as was daily used of pain medication. Unemployment and female sex also were associated with increased pain frequency.
The findings were limited by several factors including the cross-sectional design that prevents conclusions of causality, and by the reliance on patient reports of depression, which likely led to underreporting, the researchers noted.
However, the results are consistent with previous studies suggesting that pain and negative feelings were associated with reduced quality of life in SCD patients, especially younger patients, and support the need to screen SCD patients for depression, especially those who report more severe and/or more frequent pain, they said.
Take a comprehensive approach to a complex condition
“When treating pain, we cannot just rely on medication,” Dr. Harris said. “It is important that providers consider the full experiences of patients and pursue holistic and comprehensive treatment approaches to reducing pain. Screening for depression should be a regular practice, particularly for patients experiencing frequent and/or severe pain.
“Racial discrimination, stigma, and bias impact pain diagnosis and treatment for individuals with SCD,” said Dr. Harris. “Increasing awareness of the associations between depression and pain frequency and severity ... may help address these barriers.”
Data highlight treatment gaps
Alexander A. Boucher, MD, a member of the division of pediatric hematology and oncology at the University of Minnesota, Minneapolis, noted the researchers included patients as young as midadolescence, with a majority being under 35 years old. “The 18- to 30-year-old range is an especially high-risk age window for increased acute health care utilization, even compared with other chronic adolescent/young adult conditions. “The demographics in the study group also reasonably approximate those for young adults with SCD in urban centers. By taking a multicenter approach across a several-state region, I believe the findings offer better generalizability, since health care access and mental health access can vary state-by-state,” and the current results show a more standard experience.
“It was a bit surprising that female [sex] maintained such an association with pain across the different components of the study,” and that the pain peak was in the 25- to 34-year-old age range, said Dr. Boucher. However, anecdotally, the late teens and early 20s “can be laden with mental health concerns due to the life transitions that accompany most people at that time. The note that hydroxyurea use was associated with more pain and depression symptoms was interesting, and serves as a reminder that what is happening to the red blood cells and in the blood vessels, such as red blood cell breakdown, sickling, and vaso-occlusion are only a part of what causes pain, and hydroxyurea is not likely to play a role in mitigating mental health aspects of pain.”
The findings that overall pain frequency and related pain medication use were associated with higher depression rates “may in part reflect a blind spot for physicians and medical teams, who often resort back to physical pain-based heuristics.” Physicians may misunderstand chronic pain and its management and look for quick fixes for pain out of uncertainty or urgency, said Dr. Boucher. “This serves to diminish the perspectives of patients as people first (not embodiments of a disease) and can lead to missed opportunities to tackle mental health challenges.”
Barriers and limitations
There are barriers to mental health screening in hematology care,” Dr. Boucher said. First, most hematologists are not experts in mental health and while they may have some from their medical training in these disorders, it can be difficult to maintain the level of health literacy needed to stay up to date on treatments. Second, depression screening may not be part of regular patient intake and the Patient Health Questionnaire–2 or PHQ-9 offer only short-term (2-week) snapshots of depression.
“Perhaps most critically, even if we do successfully screen, the access to mental health specialists is severely limited, just as it is across the medical landscape, so intervention opportunities may be suboptimal,” said Dr. Boucher. The problem is magnified if, as the current study suggests, the rates of depression in SCD are approximately three times greater than the population overall.
In the current study, “the fact that only half of those who self-reported depression symptoms actually had depression documented as a diagnosis in their medical records suggests that we are missing a lot of patients affected by mental health disturbances.”
This study is limited in measurement of the contribution of social determinants of health, he said, as they were primarily focused on employment status and income. The study does not describe other factors like support systems, housing, and transportation.
“I would like to see studies that not only identify associated drivers of pain, but also offer evidence for successful interventions,” Dr. Boucher said, and these studies should include patient-centered interventions versus disease-centered interventions.
Undertreatment persists
Other concerns with sickle cell anemia include the underuse of hydroxyurea to reduce complications associated with the disease such as pain, stroke, and even early death. Another recent study in JAMA Network Open suggested that use of hydroxyurea remained low in children and youth despite the issuing of guidelines, and that underserved populations were especially affected. In that study, the researchers found that the patients’ annual days’ supply of hydroxyurea in New York state did not change significantly after the guideline update.
SCD also has been associated with increased risk of other poor outcomes, such as stillbirth and increased risk of poor COVID-19–related outcomes and COVID-19–related deaths.
The study by Dr. Harris and colleagues was supported by the National Institutes of Health through the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Harris had no financial conflicts to disclose. The hydroxyurea study was supported by the Agency for Healthcare Research and Quality and the NHLBI. The researchers had no financial conflicts to disclose. Dr. Boucher disclosed conducting research with SCL Behring, but had no relevant financial conflicts.
FROM JAMA NETWORK OPEN
Low-calorie tastes sweeter with a little salt
Low-calorie tastes sweeter with a little salt
Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.
That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.
Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.
The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.
The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.
Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch
Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.
LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.
P. aeruginosa: No problem. I think we can all guess what that little devil is up to.
LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?
P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.
LOTME: Beans? What do beans have to do with it?
P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.
LOTME: Sure, we knew that. Please, continue your spilling.
P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.
LOTME: The Clash? Now we’re really confused.
P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.
LOTME: And they say you guys don’t have brains.
P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”
LOTME: Pretty clever stuff, for humans, anyway.
P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.
LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.
P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.
LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
What a pain in the Butt
Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.
Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.
The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.
Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.
So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.
And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.
Low-calorie tastes sweeter with a little salt
Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.
That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.
Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.
The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.
The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.
Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch
Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.
LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.
P. aeruginosa: No problem. I think we can all guess what that little devil is up to.
LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?
P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.
LOTME: Beans? What do beans have to do with it?
P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.
LOTME: Sure, we knew that. Please, continue your spilling.
P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.
LOTME: The Clash? Now we’re really confused.
P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.
LOTME: And they say you guys don’t have brains.
P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”
LOTME: Pretty clever stuff, for humans, anyway.
P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.
LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.
P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.
LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
What a pain in the Butt
Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.
Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.
The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.
Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.
So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.
And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.
Low-calorie tastes sweeter with a little salt
Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.
That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.
Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.
The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.
The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.
Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch
Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.
LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.
P. aeruginosa: No problem. I think we can all guess what that little devil is up to.
LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?
P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.
LOTME: Beans? What do beans have to do with it?
P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.
LOTME: Sure, we knew that. Please, continue your spilling.
P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.
LOTME: The Clash? Now we’re really confused.
P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.
LOTME: And they say you guys don’t have brains.
P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”
LOTME: Pretty clever stuff, for humans, anyway.
P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.
LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.
P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.
LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
What a pain in the Butt
Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.
Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.
The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.
Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.
So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.
And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.
Gilteritinib maintenance reduces relapse in MRD+ AML
The research was presented at the European Hematology Association Hybrid Congress 2023.
For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.
The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.
However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.
While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”
“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”
Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.
He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”
Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.
“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”
He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”
Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.
He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.
As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.
He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”
This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”
Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”
He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”
“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.
Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”
He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”
“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”
Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.
The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”
They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.
Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.
Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.
He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.
MRD positivity, assessed at a cell count of ≥ 10-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.
The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.
He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”
The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.
Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).
However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”
He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10-6. “In our study, 98% of participants had samples pre- and post-[transplant].”
Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).
When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.
Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).
Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.
He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.
“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.
Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”
In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.
The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
The research was presented at the European Hematology Association Hybrid Congress 2023.
For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.
The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.
However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.
While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”
“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”
Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.
He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”
Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.
“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”
He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”
Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.
He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.
As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.
He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”
This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”
Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”
He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”
“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.
Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”
He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”
“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”
Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.
The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”
They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.
Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.
Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.
He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.
MRD positivity, assessed at a cell count of ≥ 10-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.
The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.
He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”
The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.
Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).
However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”
He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10-6. “In our study, 98% of participants had samples pre- and post-[transplant].”
Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).
When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.
Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).
Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.
He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.
“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.
Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”
In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.
The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
The research was presented at the European Hematology Association Hybrid Congress 2023.
For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.
The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.
However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.
While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”
“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”
Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.
He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”
Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.
“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”
He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”
Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.
He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.
As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.
He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”
This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”
Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”
He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”
“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.
Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”
He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”
“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”
Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.
The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”
They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.
Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.
Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.
He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.
MRD positivity, assessed at a cell count of ≥ 10-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.
The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.
He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”
The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.
Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).
However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”
He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10-6. “In our study, 98% of participants had samples pre- and post-[transplant].”
Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).
When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.
Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).
Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.
He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.
“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.
Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”
In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.
The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
AT EHA 2023
CMML: GM-CSF inhibitor lenzilumab shows early promise
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
FROM EHA 2023
Aspirin warning: Anemia may increase with daily use
, according to results from a new randomized controlled trial.
In the study, which was published in Annals of Internal Medicine, investigators analyzed data from the Aspirin in Reducing Events in the Elderly (ASPREE) trial and examined hemoglobin concentrations among 19,114 healthy, community-dwelling older patients.
“We knew from large clinical trials, including our ASPREE trial, that daily low-dose aspirin increased the risk of clinically significant bleeding,” said Zoe McQuilten, MBBS, PhD, a hematologist at Monash University in Australia and the study’s lead author. “From our study, we found that low-dose aspirin also increased the risk of anemia during the trial, and this was most likely due to bleeding that was not clinically apparent.”
Anemia is common among elderly patients. It can cause fatigue, fast or irregular heartbeat, headache, chest pain, and pounding or whooshing sounds in the ear, according to the Cleveland Clinic. It can also worsen conditions such as heart failure, cognitive impairment, and depression in people aged 65 and older.
The U.S. Preventive Services Task Force changed its recommendation on aspirin for the primary prevention of cardiovascular disease in 2022, recommending against initiating low-dose aspirin for adults aged 60 years or older. For adults aged 40-59 who have a 10% or greater 10-year risk for cardiovascular disease, the agency recommends that patients and clinicians make the decision to initiate low-dose aspirin use on a case-by-case basis, as the net benefit is small.
Dr. McQuilten said she spent the last 5 years designing substages of anemia and conditions such as blood cancer. In many cases of anemia, doctors are unable to determine the underlying cause, she said. One study published in the Journal of American Geriatrics Society in 2021 found that in about one-third of anemia cases, the etiology was not clear.
About 50% of people older than 60 who were involved in the latest study took aspirin for prevention from 2011 to 2018. That number likely dropped after changes were made to the guidelines in 2022, according to Dr. McQuilten, but long-term use may have continued among older patients. The researchers also examined ferritin levels, which serve as a proxy for iron levels, at baseline and after 3 years.
The incidence of anemia was 51 events per 1,000 person-years in the aspirin group compared with 43 events per 1,000 person-years in the placebo group, according to the researchers. The estimated probability of experiencing anemia within 5 years was 23.5% (95% confidence interval [CI], 22.4%-24.6%) in the aspirin group and 20.3% (95% CI: 19.3% to 21.4%) in the placebo group. Aspirin therapy resulted in a 20% increase in the risk for anemia (95% CI, 1.12-1.29).
People who took aspirin were more likely to have lower serum levels of ferritin at the 3-year mark than were those who received placebo. The average decrease in ferritin among participants who took aspirin was 11.5% greater (95% CI, 9.3%-13.7%) than among those who took placebo.
Basil Eldadah, MD, PhD, supervisory medical officer at the National Institute on Aging, part of the National Institutes of Health, said the findings should encourage clinicians to pay closer attention to hemoglobin levels and have conversations with patients to discuss their need for taking aspirin.
“If somebody is already taking aspirin for any reason, keep an eye on hemoglobin,” said Dr. Eldadah, who was not involved in the study. “For somebody who’s taking aspirin and who’s older, and it’s not for an indication like cardiovascular disease, consider seriously whether that’s the best treatment option.”
The study did not examine the functional consequences of anemia on participants, which Dr. Eldadah said could be fodder for future research. The researchers said one limitation was that it was not clear whether anemia was sufficient to cause symptoms that affected participants’ quality of life or whether occult bleeding caused the anemia. The researchers also did not document whether patients saw their regular physicians and received treatment for anemia over the course of the trial.
The study was funded through grants from the National Health and Medical Research Council and the Bill and Melinda Gates Foundation. The authors reported receiving consulting fees, honoraria, and stock options, and have participated on data monitoring boards not related to the study for Vifor Pharma, ITL Biomedical, Pfizer, Boehringer Ingelheim, Bayer Healthcare, AbbVie, and Abbott Diagnostics.
A version of this article originally appeared on Medscape.com.
, according to results from a new randomized controlled trial.
In the study, which was published in Annals of Internal Medicine, investigators analyzed data from the Aspirin in Reducing Events in the Elderly (ASPREE) trial and examined hemoglobin concentrations among 19,114 healthy, community-dwelling older patients.
“We knew from large clinical trials, including our ASPREE trial, that daily low-dose aspirin increased the risk of clinically significant bleeding,” said Zoe McQuilten, MBBS, PhD, a hematologist at Monash University in Australia and the study’s lead author. “From our study, we found that low-dose aspirin also increased the risk of anemia during the trial, and this was most likely due to bleeding that was not clinically apparent.”
Anemia is common among elderly patients. It can cause fatigue, fast or irregular heartbeat, headache, chest pain, and pounding or whooshing sounds in the ear, according to the Cleveland Clinic. It can also worsen conditions such as heart failure, cognitive impairment, and depression in people aged 65 and older.
The U.S. Preventive Services Task Force changed its recommendation on aspirin for the primary prevention of cardiovascular disease in 2022, recommending against initiating low-dose aspirin for adults aged 60 years or older. For adults aged 40-59 who have a 10% or greater 10-year risk for cardiovascular disease, the agency recommends that patients and clinicians make the decision to initiate low-dose aspirin use on a case-by-case basis, as the net benefit is small.
Dr. McQuilten said she spent the last 5 years designing substages of anemia and conditions such as blood cancer. In many cases of anemia, doctors are unable to determine the underlying cause, she said. One study published in the Journal of American Geriatrics Society in 2021 found that in about one-third of anemia cases, the etiology was not clear.
About 50% of people older than 60 who were involved in the latest study took aspirin for prevention from 2011 to 2018. That number likely dropped after changes were made to the guidelines in 2022, according to Dr. McQuilten, but long-term use may have continued among older patients. The researchers also examined ferritin levels, which serve as a proxy for iron levels, at baseline and after 3 years.
The incidence of anemia was 51 events per 1,000 person-years in the aspirin group compared with 43 events per 1,000 person-years in the placebo group, according to the researchers. The estimated probability of experiencing anemia within 5 years was 23.5% (95% confidence interval [CI], 22.4%-24.6%) in the aspirin group and 20.3% (95% CI: 19.3% to 21.4%) in the placebo group. Aspirin therapy resulted in a 20% increase in the risk for anemia (95% CI, 1.12-1.29).
People who took aspirin were more likely to have lower serum levels of ferritin at the 3-year mark than were those who received placebo. The average decrease in ferritin among participants who took aspirin was 11.5% greater (95% CI, 9.3%-13.7%) than among those who took placebo.
Basil Eldadah, MD, PhD, supervisory medical officer at the National Institute on Aging, part of the National Institutes of Health, said the findings should encourage clinicians to pay closer attention to hemoglobin levels and have conversations with patients to discuss their need for taking aspirin.
“If somebody is already taking aspirin for any reason, keep an eye on hemoglobin,” said Dr. Eldadah, who was not involved in the study. “For somebody who’s taking aspirin and who’s older, and it’s not for an indication like cardiovascular disease, consider seriously whether that’s the best treatment option.”
The study did not examine the functional consequences of anemia on participants, which Dr. Eldadah said could be fodder for future research. The researchers said one limitation was that it was not clear whether anemia was sufficient to cause symptoms that affected participants’ quality of life or whether occult bleeding caused the anemia. The researchers also did not document whether patients saw their regular physicians and received treatment for anemia over the course of the trial.
The study was funded through grants from the National Health and Medical Research Council and the Bill and Melinda Gates Foundation. The authors reported receiving consulting fees, honoraria, and stock options, and have participated on data monitoring boards not related to the study for Vifor Pharma, ITL Biomedical, Pfizer, Boehringer Ingelheim, Bayer Healthcare, AbbVie, and Abbott Diagnostics.
A version of this article originally appeared on Medscape.com.
, according to results from a new randomized controlled trial.
In the study, which was published in Annals of Internal Medicine, investigators analyzed data from the Aspirin in Reducing Events in the Elderly (ASPREE) trial and examined hemoglobin concentrations among 19,114 healthy, community-dwelling older patients.
“We knew from large clinical trials, including our ASPREE trial, that daily low-dose aspirin increased the risk of clinically significant bleeding,” said Zoe McQuilten, MBBS, PhD, a hematologist at Monash University in Australia and the study’s lead author. “From our study, we found that low-dose aspirin also increased the risk of anemia during the trial, and this was most likely due to bleeding that was not clinically apparent.”
Anemia is common among elderly patients. It can cause fatigue, fast or irregular heartbeat, headache, chest pain, and pounding or whooshing sounds in the ear, according to the Cleveland Clinic. It can also worsen conditions such as heart failure, cognitive impairment, and depression in people aged 65 and older.
The U.S. Preventive Services Task Force changed its recommendation on aspirin for the primary prevention of cardiovascular disease in 2022, recommending against initiating low-dose aspirin for adults aged 60 years or older. For adults aged 40-59 who have a 10% or greater 10-year risk for cardiovascular disease, the agency recommends that patients and clinicians make the decision to initiate low-dose aspirin use on a case-by-case basis, as the net benefit is small.
Dr. McQuilten said she spent the last 5 years designing substages of anemia and conditions such as blood cancer. In many cases of anemia, doctors are unable to determine the underlying cause, she said. One study published in the Journal of American Geriatrics Society in 2021 found that in about one-third of anemia cases, the etiology was not clear.
About 50% of people older than 60 who were involved in the latest study took aspirin for prevention from 2011 to 2018. That number likely dropped after changes were made to the guidelines in 2022, according to Dr. McQuilten, but long-term use may have continued among older patients. The researchers also examined ferritin levels, which serve as a proxy for iron levels, at baseline and after 3 years.
The incidence of anemia was 51 events per 1,000 person-years in the aspirin group compared with 43 events per 1,000 person-years in the placebo group, according to the researchers. The estimated probability of experiencing anemia within 5 years was 23.5% (95% confidence interval [CI], 22.4%-24.6%) in the aspirin group and 20.3% (95% CI: 19.3% to 21.4%) in the placebo group. Aspirin therapy resulted in a 20% increase in the risk for anemia (95% CI, 1.12-1.29).
People who took aspirin were more likely to have lower serum levels of ferritin at the 3-year mark than were those who received placebo. The average decrease in ferritin among participants who took aspirin was 11.5% greater (95% CI, 9.3%-13.7%) than among those who took placebo.
Basil Eldadah, MD, PhD, supervisory medical officer at the National Institute on Aging, part of the National Institutes of Health, said the findings should encourage clinicians to pay closer attention to hemoglobin levels and have conversations with patients to discuss their need for taking aspirin.
“If somebody is already taking aspirin for any reason, keep an eye on hemoglobin,” said Dr. Eldadah, who was not involved in the study. “For somebody who’s taking aspirin and who’s older, and it’s not for an indication like cardiovascular disease, consider seriously whether that’s the best treatment option.”
The study did not examine the functional consequences of anemia on participants, which Dr. Eldadah said could be fodder for future research. The researchers said one limitation was that it was not clear whether anemia was sufficient to cause symptoms that affected participants’ quality of life or whether occult bleeding caused the anemia. The researchers also did not document whether patients saw their regular physicians and received treatment for anemia over the course of the trial.
The study was funded through grants from the National Health and Medical Research Council and the Bill and Melinda Gates Foundation. The authors reported receiving consulting fees, honoraria, and stock options, and have participated on data monitoring boards not related to the study for Vifor Pharma, ITL Biomedical, Pfizer, Boehringer Ingelheim, Bayer Healthcare, AbbVie, and Abbott Diagnostics.
A version of this article originally appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
PV: Novel rusfertide shows ‘impressive’ efficacy
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
FROM EHA 2023
CLL: Venetoclax-obinutuzumab combo effective long term
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
FROM EHA 2023
FDA approves glofitamab for DLBCL
The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.
The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.
These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.
Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.
“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.
Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
Most common form of non-Hodgkin’s lymphoma
DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.
“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”
The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.
Glofitamab was given to all patients as a fixed course for 8.5 months.
More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.
The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).
Results from the NP30179 trial were published in December 2022.
The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”
The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.
The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.
These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.
Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.
“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.
Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
Most common form of non-Hodgkin’s lymphoma
DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.
“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”
The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.
Glofitamab was given to all patients as a fixed course for 8.5 months.
More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.
The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).
Results from the NP30179 trial were published in December 2022.
The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”
The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.
The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.
These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.
Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.
“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.
Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
Most common form of non-Hodgkin’s lymphoma
DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.
“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”
The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.
Glofitamab was given to all patients as a fixed course for 8.5 months.
More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.
The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).
Results from the NP30179 trial were published in December 2022.
The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”
Cancer drug shortages spur worry, rationing, and tough choices
CHICAGO – Oncologist Denise Yardley, MD, isn’t used to expressing uncertainty when she tells patients about what’s in store for them in terms of drug treatment. But things are dramatically different now amid a severe national shortage of carboplatin and cisplatin, two common and crucial cancer drugs.
“There’s a regimen I’m thinking about,” Dr. Yardley told a new patient recently, “but we’ll have to wait until you finish your staging evaluation to see whether I can deliver this. Another regimen that’s a little more toxic is my second choice.” And, she added, the alternative chemotherapy treatment – anthracycline instead of carboplatin – requires a longer treatment period.
This ambiguity is hardly ideal, said Dr. Yardley, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville. “It’s another factor in being overwhelmed in a first-time visit and wanting to know the details about what your treatment is going to look like. You’re not walking out knowing exactly what you’re going to take or the exact timing so you can start mapping out your calendar and work schedule.”
This kind of scenario is becoming all too familiar this spring, according to oncologists who gathered at the annual meeting of the American Society of Clinical Oncology (ASCO). In interviews, these physicians said the limited supply of multiple cancer drugs – including the chemotherapies carboplatin and cisplatin – is having an unprecedented negative effect since their use is so widespread in cancer care.
“Every patient could get impacted. That’s why we need to address this sooner rather than later,” said oncologist Aditya Baria, MBBS, MPH, director of the Breast Cancer Research Program at Massachusetts General Hospital, Boston.
Shortages of cancer drugs are not unusual. Three-quarters of oncology pharmacists at 68 organizations surveyed from 2019 to 2020 said shortages prompted treatment delays, reduced doses, or alternative regimens. But the current shortages are having a much wider impact.
The National Comprehensive Cancer Network recently reported that 93% of 27 member institutions surveyed in late May are short on carboplatin, and 70% have reported a shortage of cisplatin. Plus, 20% of 19 centers said they weren’t able to continue carboplatin regimens for all patients.
The drugs are mainstays of multiple types of treatment for a long list of cancer types including lung, breast, gynecologic, and many others.
Several scenarios are possible when the drugs are in short supply, said Dr. Yardley, who noted that the shortage is more severe than any she’s seen in her medical career of more than 3 decades. Patients may need to be switched to regimens with more side effects, even when they’re in the middle of a treatment, she said. Or patients might have to go longer between treatments.
In some cases, Dr. Yardley said, the shortage is forcing patients to go without an important component of a larger combination therapy regimen. “The Keynote 522 neoadjuvant regimen for triple-negative breast cancer has carboplatin given with Taxol [paclitaxel] and Keytruda [pembrolizumab]. We are just deleting the carboplatin.”
She added that carboplatin is part of the following so-called TCHP regimen for HER2+ early-stage breast cancer: Taxotere (docetaxel), carboplatin, Herceptin (trastuzumab), and Perjeta (pertuzumab).
“You can delete [carboplatin] or consider substituting cyclophosphamide for carboplatin,” she said. But she cautioned the Keynote 522 and TCHP regimens haven’t been tested without carboplatin in curative-intent trials.
At Duke University in Durham, N.C., doses of carboplatin for many patients are being lowered by a third to the level that’s commonly used for older and frail patients, said oncologist Arif Kamal, MD, MBA, MHS, who works at the academic center and is the chief patient officer at the American Cancer Society.
“We don’t know if [the lower doses will negatively affect cancer patients’ outcomes]. What’s amazing is how many patients [are understanding about having to take smaller amounts of the chemotherapy],” he said.
Medical organizations are offering guidance. The Society of Gynecologic Oncology, for example, in late April recommended that oncologists increase intervals between chemotherapy treatments when appropriate, round down vial sizes to ensure “efficient use,” and eliminate or minimize use of cisplatin and carboplatin in certain platinum-resistant cancers.
In early June, ASCO published guidance regarding alternatives to cisplatin, carboplatin, and 5-fluorouracil, which is also in short supply, in gastrointestinal cancer. As the guidance notes, some alternatives are more untested or more toxic than ideal treatments.
In addition, ASCO has a webpage devoted to news and resources about shortages of cancer drugs. It offers drug availability updates, general guidance, and breast cancer guidance. ASCO also offers ethical guidance about handling drug shortages.
Patients in clinical trials and those who hope to join them are especially vulnerable to the drug shortage, oncologists interviewed for this story said. Cisplatin and carboplatin are the backbones of many clinical trials, Dr. Yardley said. “When you can’t supply a drug in one of the [trial] arms, that puts the whole trial on pause.”
Even clinics that have managed to find adequate supplies of the drugs are planning for when they run out.
“Our institution and other institutions are trying to come up with a rationing protocol, deciding which patients are going to get access, and which ones have reasonable alternatives,” radiation oncologist Corey Speers MD, PhD, of University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, said in an interview. “In some settings, there really isn’t an effective alternative. Or the alternatives are tens of thousands of dollars more expensive.”
Oncologists also noted that cisplatin and carboplatin aren’t the only cancer drugs in short supply.
“Methotrexate is critically low, and 5FU [fluorouracil] is critically low,” Dr. Yardley said, referring to drugs that each treat several types of cancer. According to the May NCNN survey, 67% of respondents reported low supplies of methotrexate, and 26% said they were low on 5FU.
“Viscous lidocaine is a component of many supportive care mouth rinses for the stomatitis caused by our drugs but is not available at all,” Dr. Yardley said.
She added that there are also low supplies of fludarabine, which is used to treat chronic lymphocytic lymphom; clofarabine, which is used to treat acute lymphoblastic leukemia; and rasburicase, which is used to treat high levels of uric acid in patients on chemotherapy.
Dr. Speers said his institution is facing a shortage of capecitabine, which is used to treat several types of cancer.
“Numerous trials have demonstrated the improved, safety, efficacy, and convenience of oral capecitabine. With the shortage we’re having to use infusional 5FU, which not only is less convenient but also ends up being more costly and requires infusion room space or continuous infusion pumps. This impacts our ability to treat cancer patients,” he said. “Our capacity is becoming more limited to accommodate these added patients, and we have to use infusional formulations of a drug that previously was readily available via an oral formulation. Patients and caregivers now have to come to the cancer center for appointments and infusions that previously weren’t needed as they could take an oral pill.”
Dr. Speers added that his institution is rationing methotrexate. “We are now prioritizing patients being treated with curative intent and adjusting protocols to use the lowest allowable doses to conserve supply,” he said.
The roots of the platinum chemotherapy drug shortage link back to the India-based Intas Pharmaceuticals company, a major manufacturer of cisplatin and carboplatin. According to Kellyann Zuzulo, spokeperson for Accord Healthcare, an Instas U.S. subsidiary, a facility inspection in December 2022 prompted a decision to temporarily stop making the drugs. The inspection identified multiple problems.
“Intas and Accord are working with the FDA on a plan to return to manufacturing,” Ms. Zuzulo said in an interview. “This will allow for continued production of products that will be prioritized based on medical necessity. A date has not yet been confirmed in which the facility will return to manufacturing for cisplatin, carboplatin or any other products.”
Ms. Zuzulo said the company is not a health care provider and cannot offer advice to patients about alternatives.
Other companies that make cisplatin and carboplatin have also reported shortages. In interviews, representatives for Fresenius Kabi and Pfizer said the companies have limited supplies because of increased demand – not because of manufacturing problems.
On June 12, the American Society of Health-System Pharmacists (ASHP) reported that carboplatin remains in short supply, with all five companies that sell the drug listed as having limited or back-ordered supplies. Cisplatin is also in short supply, the organization reported in a June 9 update, although some is available.
In a June 12 update on methotrexate, ASHP said manufacturing delays at Accord have caused a shortage, and other companies are running low due to increased demand.
As for the future, Congress and the Biden administration, according to a report by Bloomberg, are trying to figure out what to do regarding shortages of cheap generic drugs such as cisplatin and carboplatin. The FDA is exploring a partnership with a Chinese drugmaker to make cisplatin, NBC News reported.
However, fixes will be challenging, according to former FDA commissioner and Pfizer board member, Scott Gottlieb, MD.
“This generic business, particularly for these complex drugs, these complex formulations, is not a healthy business right now. Yet it’s a vital business from a public standpoint,” he told CBS News.
In an interview, Dr. Kamal said that there is even talk about boosting the prices of cheap generic drugs “to ensure that there’s enough incentive for multiple manufacturers to be involved.”
Dr. Kamal said he is crossing his fingers that cutting chemotherapy doses at his clinic doesn’t result in worse outcomes for his patients.
“Right now, I think dropping someone by 25% or 30% is okay. And for some patients, particularly in a curative setting, we try to keep them at as much as 100% as possible. But there’s just a lot of unknowns,” he said.
CHICAGO – Oncologist Denise Yardley, MD, isn’t used to expressing uncertainty when she tells patients about what’s in store for them in terms of drug treatment. But things are dramatically different now amid a severe national shortage of carboplatin and cisplatin, two common and crucial cancer drugs.
“There’s a regimen I’m thinking about,” Dr. Yardley told a new patient recently, “but we’ll have to wait until you finish your staging evaluation to see whether I can deliver this. Another regimen that’s a little more toxic is my second choice.” And, she added, the alternative chemotherapy treatment – anthracycline instead of carboplatin – requires a longer treatment period.
This ambiguity is hardly ideal, said Dr. Yardley, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville. “It’s another factor in being overwhelmed in a first-time visit and wanting to know the details about what your treatment is going to look like. You’re not walking out knowing exactly what you’re going to take or the exact timing so you can start mapping out your calendar and work schedule.”
This kind of scenario is becoming all too familiar this spring, according to oncologists who gathered at the annual meeting of the American Society of Clinical Oncology (ASCO). In interviews, these physicians said the limited supply of multiple cancer drugs – including the chemotherapies carboplatin and cisplatin – is having an unprecedented negative effect since their use is so widespread in cancer care.
“Every patient could get impacted. That’s why we need to address this sooner rather than later,” said oncologist Aditya Baria, MBBS, MPH, director of the Breast Cancer Research Program at Massachusetts General Hospital, Boston.
Shortages of cancer drugs are not unusual. Three-quarters of oncology pharmacists at 68 organizations surveyed from 2019 to 2020 said shortages prompted treatment delays, reduced doses, or alternative regimens. But the current shortages are having a much wider impact.
The National Comprehensive Cancer Network recently reported that 93% of 27 member institutions surveyed in late May are short on carboplatin, and 70% have reported a shortage of cisplatin. Plus, 20% of 19 centers said they weren’t able to continue carboplatin regimens for all patients.
The drugs are mainstays of multiple types of treatment for a long list of cancer types including lung, breast, gynecologic, and many others.
Several scenarios are possible when the drugs are in short supply, said Dr. Yardley, who noted that the shortage is more severe than any she’s seen in her medical career of more than 3 decades. Patients may need to be switched to regimens with more side effects, even when they’re in the middle of a treatment, she said. Or patients might have to go longer between treatments.
In some cases, Dr. Yardley said, the shortage is forcing patients to go without an important component of a larger combination therapy regimen. “The Keynote 522 neoadjuvant regimen for triple-negative breast cancer has carboplatin given with Taxol [paclitaxel] and Keytruda [pembrolizumab]. We are just deleting the carboplatin.”
She added that carboplatin is part of the following so-called TCHP regimen for HER2+ early-stage breast cancer: Taxotere (docetaxel), carboplatin, Herceptin (trastuzumab), and Perjeta (pertuzumab).
“You can delete [carboplatin] or consider substituting cyclophosphamide for carboplatin,” she said. But she cautioned the Keynote 522 and TCHP regimens haven’t been tested without carboplatin in curative-intent trials.
At Duke University in Durham, N.C., doses of carboplatin for many patients are being lowered by a third to the level that’s commonly used for older and frail patients, said oncologist Arif Kamal, MD, MBA, MHS, who works at the academic center and is the chief patient officer at the American Cancer Society.
“We don’t know if [the lower doses will negatively affect cancer patients’ outcomes]. What’s amazing is how many patients [are understanding about having to take smaller amounts of the chemotherapy],” he said.
Medical organizations are offering guidance. The Society of Gynecologic Oncology, for example, in late April recommended that oncologists increase intervals between chemotherapy treatments when appropriate, round down vial sizes to ensure “efficient use,” and eliminate or minimize use of cisplatin and carboplatin in certain platinum-resistant cancers.
In early June, ASCO published guidance regarding alternatives to cisplatin, carboplatin, and 5-fluorouracil, which is also in short supply, in gastrointestinal cancer. As the guidance notes, some alternatives are more untested or more toxic than ideal treatments.
In addition, ASCO has a webpage devoted to news and resources about shortages of cancer drugs. It offers drug availability updates, general guidance, and breast cancer guidance. ASCO also offers ethical guidance about handling drug shortages.
Patients in clinical trials and those who hope to join them are especially vulnerable to the drug shortage, oncologists interviewed for this story said. Cisplatin and carboplatin are the backbones of many clinical trials, Dr. Yardley said. “When you can’t supply a drug in one of the [trial] arms, that puts the whole trial on pause.”
Even clinics that have managed to find adequate supplies of the drugs are planning for when they run out.
“Our institution and other institutions are trying to come up with a rationing protocol, deciding which patients are going to get access, and which ones have reasonable alternatives,” radiation oncologist Corey Speers MD, PhD, of University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, said in an interview. “In some settings, there really isn’t an effective alternative. Or the alternatives are tens of thousands of dollars more expensive.”
Oncologists also noted that cisplatin and carboplatin aren’t the only cancer drugs in short supply.
“Methotrexate is critically low, and 5FU [fluorouracil] is critically low,” Dr. Yardley said, referring to drugs that each treat several types of cancer. According to the May NCNN survey, 67% of respondents reported low supplies of methotrexate, and 26% said they were low on 5FU.
“Viscous lidocaine is a component of many supportive care mouth rinses for the stomatitis caused by our drugs but is not available at all,” Dr. Yardley said.
She added that there are also low supplies of fludarabine, which is used to treat chronic lymphocytic lymphom; clofarabine, which is used to treat acute lymphoblastic leukemia; and rasburicase, which is used to treat high levels of uric acid in patients on chemotherapy.
Dr. Speers said his institution is facing a shortage of capecitabine, which is used to treat several types of cancer.
“Numerous trials have demonstrated the improved, safety, efficacy, and convenience of oral capecitabine. With the shortage we’re having to use infusional 5FU, which not only is less convenient but also ends up being more costly and requires infusion room space or continuous infusion pumps. This impacts our ability to treat cancer patients,” he said. “Our capacity is becoming more limited to accommodate these added patients, and we have to use infusional formulations of a drug that previously was readily available via an oral formulation. Patients and caregivers now have to come to the cancer center for appointments and infusions that previously weren’t needed as they could take an oral pill.”
Dr. Speers added that his institution is rationing methotrexate. “We are now prioritizing patients being treated with curative intent and adjusting protocols to use the lowest allowable doses to conserve supply,” he said.
The roots of the platinum chemotherapy drug shortage link back to the India-based Intas Pharmaceuticals company, a major manufacturer of cisplatin and carboplatin. According to Kellyann Zuzulo, spokeperson for Accord Healthcare, an Instas U.S. subsidiary, a facility inspection in December 2022 prompted a decision to temporarily stop making the drugs. The inspection identified multiple problems.
“Intas and Accord are working with the FDA on a plan to return to manufacturing,” Ms. Zuzulo said in an interview. “This will allow for continued production of products that will be prioritized based on medical necessity. A date has not yet been confirmed in which the facility will return to manufacturing for cisplatin, carboplatin or any other products.”
Ms. Zuzulo said the company is not a health care provider and cannot offer advice to patients about alternatives.
Other companies that make cisplatin and carboplatin have also reported shortages. In interviews, representatives for Fresenius Kabi and Pfizer said the companies have limited supplies because of increased demand – not because of manufacturing problems.
On June 12, the American Society of Health-System Pharmacists (ASHP) reported that carboplatin remains in short supply, with all five companies that sell the drug listed as having limited or back-ordered supplies. Cisplatin is also in short supply, the organization reported in a June 9 update, although some is available.
In a June 12 update on methotrexate, ASHP said manufacturing delays at Accord have caused a shortage, and other companies are running low due to increased demand.
As for the future, Congress and the Biden administration, according to a report by Bloomberg, are trying to figure out what to do regarding shortages of cheap generic drugs such as cisplatin and carboplatin. The FDA is exploring a partnership with a Chinese drugmaker to make cisplatin, NBC News reported.
However, fixes will be challenging, according to former FDA commissioner and Pfizer board member, Scott Gottlieb, MD.
“This generic business, particularly for these complex drugs, these complex formulations, is not a healthy business right now. Yet it’s a vital business from a public standpoint,” he told CBS News.
In an interview, Dr. Kamal said that there is even talk about boosting the prices of cheap generic drugs “to ensure that there’s enough incentive for multiple manufacturers to be involved.”
Dr. Kamal said he is crossing his fingers that cutting chemotherapy doses at his clinic doesn’t result in worse outcomes for his patients.
“Right now, I think dropping someone by 25% or 30% is okay. And for some patients, particularly in a curative setting, we try to keep them at as much as 100% as possible. But there’s just a lot of unknowns,” he said.
CHICAGO – Oncologist Denise Yardley, MD, isn’t used to expressing uncertainty when she tells patients about what’s in store for them in terms of drug treatment. But things are dramatically different now amid a severe national shortage of carboplatin and cisplatin, two common and crucial cancer drugs.
“There’s a regimen I’m thinking about,” Dr. Yardley told a new patient recently, “but we’ll have to wait until you finish your staging evaluation to see whether I can deliver this. Another regimen that’s a little more toxic is my second choice.” And, she added, the alternative chemotherapy treatment – anthracycline instead of carboplatin – requires a longer treatment period.
This ambiguity is hardly ideal, said Dr. Yardley, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville. “It’s another factor in being overwhelmed in a first-time visit and wanting to know the details about what your treatment is going to look like. You’re not walking out knowing exactly what you’re going to take or the exact timing so you can start mapping out your calendar and work schedule.”
This kind of scenario is becoming all too familiar this spring, according to oncologists who gathered at the annual meeting of the American Society of Clinical Oncology (ASCO). In interviews, these physicians said the limited supply of multiple cancer drugs – including the chemotherapies carboplatin and cisplatin – is having an unprecedented negative effect since their use is so widespread in cancer care.
“Every patient could get impacted. That’s why we need to address this sooner rather than later,” said oncologist Aditya Baria, MBBS, MPH, director of the Breast Cancer Research Program at Massachusetts General Hospital, Boston.
Shortages of cancer drugs are not unusual. Three-quarters of oncology pharmacists at 68 organizations surveyed from 2019 to 2020 said shortages prompted treatment delays, reduced doses, or alternative regimens. But the current shortages are having a much wider impact.
The National Comprehensive Cancer Network recently reported that 93% of 27 member institutions surveyed in late May are short on carboplatin, and 70% have reported a shortage of cisplatin. Plus, 20% of 19 centers said they weren’t able to continue carboplatin regimens for all patients.
The drugs are mainstays of multiple types of treatment for a long list of cancer types including lung, breast, gynecologic, and many others.
Several scenarios are possible when the drugs are in short supply, said Dr. Yardley, who noted that the shortage is more severe than any she’s seen in her medical career of more than 3 decades. Patients may need to be switched to regimens with more side effects, even when they’re in the middle of a treatment, she said. Or patients might have to go longer between treatments.
In some cases, Dr. Yardley said, the shortage is forcing patients to go without an important component of a larger combination therapy regimen. “The Keynote 522 neoadjuvant regimen for triple-negative breast cancer has carboplatin given with Taxol [paclitaxel] and Keytruda [pembrolizumab]. We are just deleting the carboplatin.”
She added that carboplatin is part of the following so-called TCHP regimen for HER2+ early-stage breast cancer: Taxotere (docetaxel), carboplatin, Herceptin (trastuzumab), and Perjeta (pertuzumab).
“You can delete [carboplatin] or consider substituting cyclophosphamide for carboplatin,” she said. But she cautioned the Keynote 522 and TCHP regimens haven’t been tested without carboplatin in curative-intent trials.
At Duke University in Durham, N.C., doses of carboplatin for many patients are being lowered by a third to the level that’s commonly used for older and frail patients, said oncologist Arif Kamal, MD, MBA, MHS, who works at the academic center and is the chief patient officer at the American Cancer Society.
“We don’t know if [the lower doses will negatively affect cancer patients’ outcomes]. What’s amazing is how many patients [are understanding about having to take smaller amounts of the chemotherapy],” he said.
Medical organizations are offering guidance. The Society of Gynecologic Oncology, for example, in late April recommended that oncologists increase intervals between chemotherapy treatments when appropriate, round down vial sizes to ensure “efficient use,” and eliminate or minimize use of cisplatin and carboplatin in certain platinum-resistant cancers.
In early June, ASCO published guidance regarding alternatives to cisplatin, carboplatin, and 5-fluorouracil, which is also in short supply, in gastrointestinal cancer. As the guidance notes, some alternatives are more untested or more toxic than ideal treatments.
In addition, ASCO has a webpage devoted to news and resources about shortages of cancer drugs. It offers drug availability updates, general guidance, and breast cancer guidance. ASCO also offers ethical guidance about handling drug shortages.
Patients in clinical trials and those who hope to join them are especially vulnerable to the drug shortage, oncologists interviewed for this story said. Cisplatin and carboplatin are the backbones of many clinical trials, Dr. Yardley said. “When you can’t supply a drug in one of the [trial] arms, that puts the whole trial on pause.”
Even clinics that have managed to find adequate supplies of the drugs are planning for when they run out.
“Our institution and other institutions are trying to come up with a rationing protocol, deciding which patients are going to get access, and which ones have reasonable alternatives,” radiation oncologist Corey Speers MD, PhD, of University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, said in an interview. “In some settings, there really isn’t an effective alternative. Or the alternatives are tens of thousands of dollars more expensive.”
Oncologists also noted that cisplatin and carboplatin aren’t the only cancer drugs in short supply.
“Methotrexate is critically low, and 5FU [fluorouracil] is critically low,” Dr. Yardley said, referring to drugs that each treat several types of cancer. According to the May NCNN survey, 67% of respondents reported low supplies of methotrexate, and 26% said they were low on 5FU.
“Viscous lidocaine is a component of many supportive care mouth rinses for the stomatitis caused by our drugs but is not available at all,” Dr. Yardley said.
She added that there are also low supplies of fludarabine, which is used to treat chronic lymphocytic lymphom; clofarabine, which is used to treat acute lymphoblastic leukemia; and rasburicase, which is used to treat high levels of uric acid in patients on chemotherapy.
Dr. Speers said his institution is facing a shortage of capecitabine, which is used to treat several types of cancer.
“Numerous trials have demonstrated the improved, safety, efficacy, and convenience of oral capecitabine. With the shortage we’re having to use infusional 5FU, which not only is less convenient but also ends up being more costly and requires infusion room space or continuous infusion pumps. This impacts our ability to treat cancer patients,” he said. “Our capacity is becoming more limited to accommodate these added patients, and we have to use infusional formulations of a drug that previously was readily available via an oral formulation. Patients and caregivers now have to come to the cancer center for appointments and infusions that previously weren’t needed as they could take an oral pill.”
Dr. Speers added that his institution is rationing methotrexate. “We are now prioritizing patients being treated with curative intent and adjusting protocols to use the lowest allowable doses to conserve supply,” he said.
The roots of the platinum chemotherapy drug shortage link back to the India-based Intas Pharmaceuticals company, a major manufacturer of cisplatin and carboplatin. According to Kellyann Zuzulo, spokeperson for Accord Healthcare, an Instas U.S. subsidiary, a facility inspection in December 2022 prompted a decision to temporarily stop making the drugs. The inspection identified multiple problems.
“Intas and Accord are working with the FDA on a plan to return to manufacturing,” Ms. Zuzulo said in an interview. “This will allow for continued production of products that will be prioritized based on medical necessity. A date has not yet been confirmed in which the facility will return to manufacturing for cisplatin, carboplatin or any other products.”
Ms. Zuzulo said the company is not a health care provider and cannot offer advice to patients about alternatives.
Other companies that make cisplatin and carboplatin have also reported shortages. In interviews, representatives for Fresenius Kabi and Pfizer said the companies have limited supplies because of increased demand – not because of manufacturing problems.
On June 12, the American Society of Health-System Pharmacists (ASHP) reported that carboplatin remains in short supply, with all five companies that sell the drug listed as having limited or back-ordered supplies. Cisplatin is also in short supply, the organization reported in a June 9 update, although some is available.
In a June 12 update on methotrexate, ASHP said manufacturing delays at Accord have caused a shortage, and other companies are running low due to increased demand.
As for the future, Congress and the Biden administration, according to a report by Bloomberg, are trying to figure out what to do regarding shortages of cheap generic drugs such as cisplatin and carboplatin. The FDA is exploring a partnership with a Chinese drugmaker to make cisplatin, NBC News reported.
However, fixes will be challenging, according to former FDA commissioner and Pfizer board member, Scott Gottlieb, MD.
“This generic business, particularly for these complex drugs, these complex formulations, is not a healthy business right now. Yet it’s a vital business from a public standpoint,” he told CBS News.
In an interview, Dr. Kamal said that there is even talk about boosting the prices of cheap generic drugs “to ensure that there’s enough incentive for multiple manufacturers to be involved.”
Dr. Kamal said he is crossing his fingers that cutting chemotherapy doses at his clinic doesn’t result in worse outcomes for his patients.
“Right now, I think dropping someone by 25% or 30% is okay. And for some patients, particularly in a curative setting, we try to keep them at as much as 100% as possible. But there’s just a lot of unknowns,” he said.
AT ASCO 2023