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New Cancer Drugs: Do Patients Prefer Faster Access or Clinical Benefit?
When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them.
The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials.
During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities.
In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.
Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.
But is that really the case?
The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works.
In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios.
The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).
The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).
The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios.
Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty.
Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.
“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.
Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview.
In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.
“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.
Bishal Gyawali, MD, PhD, was not surprised by the findings.
“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview.
“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”
However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added.
What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.
The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.
A version of this article first appeared on Medscape.com.
When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them.
The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials.
During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities.
In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.
Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.
But is that really the case?
The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works.
In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios.
The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).
The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).
The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios.
Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty.
Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.
“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.
Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview.
In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.
“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.
Bishal Gyawali, MD, PhD, was not surprised by the findings.
“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview.
“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”
However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added.
What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.
The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.
A version of this article first appeared on Medscape.com.
When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them.
The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials.
During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities.
In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.
Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.
But is that really the case?
The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works.
In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios.
The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).
The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).
The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios.
Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty.
Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.
“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.
Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview.
In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.
“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.
Bishal Gyawali, MD, PhD, was not surprised by the findings.
“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview.
“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”
However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added.
What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.
The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.
A version of this article first appeared on Medscape.com.
FROM THE LANCET ONCOLOGY
Smoking Linked to More Genetic Havoc in MDS
The prospective National MDS Natural History Study evaluated 1898 patients with recently diagnosed or suspected MDS. An adjusted analysis linked higher number of pack-years to more mutations (P = .006), with those at the 90th percentile with 3.5 times the number of mutations as nonsmokers, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.
The findings “suggest that smoking potentially contributes to the multistep molecular genetic pathogenesis that ultimately results in diagnosis of the cancer,” said corresponding author Mikkael A. Sekeres, MD, of the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida, at a news briefing. “The more you smoke, the more likely you are to acquire more mutations and even develop a higher risk of myelodysplastic syndromes. [More smoking] was also associated with progression and survival.”
While numbers are uncertain, an estimated 10,000 or more people in the United States each year are diagnosed with MDS, also known as preleukemia, according to the American Cancer Society. Median survival ranges from 1 to 10.6 years based on risk group, although the cancer society says the statistics are dated and mainly from Europe.
Multiple studies have linked smoking to MDS. The new study aims to understand the possible effects of smoking on genetic mutations.
The research analyzed 1898 patients enrolled from 2016 to 2023 (52% who had ever smoked; 18% current smokers; mean smoking years, 29.8 ± 16.9 years). The patients had diagnoses of MDSs, MDS/myeloproliferative neoplasm overlap, or precursor conditions such as clonal cytopenia of undetermined significance (CCUS).
Smokers were more likely than nonsmokers to be men (68% vs 54%; P < .001) and aged 70-79 years (45% vs 34%; P < .001).
After adjustment for confounders, smokers had more average mutations linked to MDS than nonsmokers (2.0 vs 1.4; P = .04). Those at the 75th percentile of pack-years had 1.8 times as many MDS-linked mutations as nonsmokers.
The 5-year cumulative incidence of disease progression was higher in long-term smokers than in nonsmokers and those with shorter smoking history (mean proportion progressed, 20+ years vs < 20 years smoking/nonsmoking, 27% [19%-36%] vs 18% [13%-24%]; P < .05, respectively).
Also, overall survival was lower in smokers than in nonsmokers for patients with CCUS (hazard ratio [HR], 1.91; 95% CI, 1.03-3.55; P = .04) but not for those with MDS (HR, 1.21; 95% CI, 0.53-1.30; P = .41).
“The data suggests that a patient with a new diagnosis of MDS who also smokes should be counseled to stop smoking,” Sekeres said.
This may seem counterintuitive to patients, he acknowledged. When Sekeres was a medical student, he counseled a female patient with advanced lung cancer to quit smoking. “The patient looked at me like I had three heads and she said: ‘Why should I stop smoking? The cats are already out of the bag. I have lung cancer.’ ”
But the new study points to a possible benefit from quitting smoking while sick. “It appears that smoking contributes to the acquisition of new genetic mutations that can lead to worsening of the myelodysplastic syndromes and even evolution of the cancer into acute myeloid leukemia,” Sekeres said.
He added: “One thing to understand about these cancers of the bone marrow is they can take years or decades to develop. They’re not one-hit wonders. Smoking caused very specific genetic mutations. The cool part of this is that they’re the same genetic mutations smoking has been shown to cause in cancers like lung cancer, so we’re seeing consistency across cancers.”
Sekeres said he himself will counsel patients with MDS or acute myeloid leukemia to stop smoking. “If there’s anything we can do to intervene to prevent myelodysplastic syndrome from evolving into acute leukemia, my word, I sure I’m going to try it.”
In an interview, Peter Greenberg, MD, professor of medicine at Stanford Cancer Center in California, who’s familiar with the study but didn’t take part in the research, said the study suggests that smoking in MDS isn’t just related to exposure to fumes “but appears to be a much more widespread problem” related to its impact on generating hematologic stem cell mutations.
Most clinicians don’t warn patients with MDS about the dangers of smoking because they’re not aware of tobacco’s connection to the disease, Greenberg said. But there’s another reason to bring up smoking, he said: It boosts the risk for cardiovascular disease, which may be partially responsible for decreased survival in smokers.
Sekeres disclosed ties with Kurome, Schrödinger, and Bristol-Myers Squibb. Other authors reported multiple and various relationships with industry. Greenberg had no disclosures.
A version of this article appeared on Medscape.com.
The prospective National MDS Natural History Study evaluated 1898 patients with recently diagnosed or suspected MDS. An adjusted analysis linked higher number of pack-years to more mutations (P = .006), with those at the 90th percentile with 3.5 times the number of mutations as nonsmokers, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.
The findings “suggest that smoking potentially contributes to the multistep molecular genetic pathogenesis that ultimately results in diagnosis of the cancer,” said corresponding author Mikkael A. Sekeres, MD, of the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida, at a news briefing. “The more you smoke, the more likely you are to acquire more mutations and even develop a higher risk of myelodysplastic syndromes. [More smoking] was also associated with progression and survival.”
While numbers are uncertain, an estimated 10,000 or more people in the United States each year are diagnosed with MDS, also known as preleukemia, according to the American Cancer Society. Median survival ranges from 1 to 10.6 years based on risk group, although the cancer society says the statistics are dated and mainly from Europe.
Multiple studies have linked smoking to MDS. The new study aims to understand the possible effects of smoking on genetic mutations.
The research analyzed 1898 patients enrolled from 2016 to 2023 (52% who had ever smoked; 18% current smokers; mean smoking years, 29.8 ± 16.9 years). The patients had diagnoses of MDSs, MDS/myeloproliferative neoplasm overlap, or precursor conditions such as clonal cytopenia of undetermined significance (CCUS).
Smokers were more likely than nonsmokers to be men (68% vs 54%; P < .001) and aged 70-79 years (45% vs 34%; P < .001).
After adjustment for confounders, smokers had more average mutations linked to MDS than nonsmokers (2.0 vs 1.4; P = .04). Those at the 75th percentile of pack-years had 1.8 times as many MDS-linked mutations as nonsmokers.
The 5-year cumulative incidence of disease progression was higher in long-term smokers than in nonsmokers and those with shorter smoking history (mean proportion progressed, 20+ years vs < 20 years smoking/nonsmoking, 27% [19%-36%] vs 18% [13%-24%]; P < .05, respectively).
Also, overall survival was lower in smokers than in nonsmokers for patients with CCUS (hazard ratio [HR], 1.91; 95% CI, 1.03-3.55; P = .04) but not for those with MDS (HR, 1.21; 95% CI, 0.53-1.30; P = .41).
“The data suggests that a patient with a new diagnosis of MDS who also smokes should be counseled to stop smoking,” Sekeres said.
This may seem counterintuitive to patients, he acknowledged. When Sekeres was a medical student, he counseled a female patient with advanced lung cancer to quit smoking. “The patient looked at me like I had three heads and she said: ‘Why should I stop smoking? The cats are already out of the bag. I have lung cancer.’ ”
But the new study points to a possible benefit from quitting smoking while sick. “It appears that smoking contributes to the acquisition of new genetic mutations that can lead to worsening of the myelodysplastic syndromes and even evolution of the cancer into acute myeloid leukemia,” Sekeres said.
He added: “One thing to understand about these cancers of the bone marrow is they can take years or decades to develop. They’re not one-hit wonders. Smoking caused very specific genetic mutations. The cool part of this is that they’re the same genetic mutations smoking has been shown to cause in cancers like lung cancer, so we’re seeing consistency across cancers.”
Sekeres said he himself will counsel patients with MDS or acute myeloid leukemia to stop smoking. “If there’s anything we can do to intervene to prevent myelodysplastic syndrome from evolving into acute leukemia, my word, I sure I’m going to try it.”
In an interview, Peter Greenberg, MD, professor of medicine at Stanford Cancer Center in California, who’s familiar with the study but didn’t take part in the research, said the study suggests that smoking in MDS isn’t just related to exposure to fumes “but appears to be a much more widespread problem” related to its impact on generating hematologic stem cell mutations.
Most clinicians don’t warn patients with MDS about the dangers of smoking because they’re not aware of tobacco’s connection to the disease, Greenberg said. But there’s another reason to bring up smoking, he said: It boosts the risk for cardiovascular disease, which may be partially responsible for decreased survival in smokers.
Sekeres disclosed ties with Kurome, Schrödinger, and Bristol-Myers Squibb. Other authors reported multiple and various relationships with industry. Greenberg had no disclosures.
A version of this article appeared on Medscape.com.
The prospective National MDS Natural History Study evaluated 1898 patients with recently diagnosed or suspected MDS. An adjusted analysis linked higher number of pack-years to more mutations (P = .006), with those at the 90th percentile with 3.5 times the number of mutations as nonsmokers, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.
The findings “suggest that smoking potentially contributes to the multistep molecular genetic pathogenesis that ultimately results in diagnosis of the cancer,” said corresponding author Mikkael A. Sekeres, MD, of the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida, at a news briefing. “The more you smoke, the more likely you are to acquire more mutations and even develop a higher risk of myelodysplastic syndromes. [More smoking] was also associated with progression and survival.”
While numbers are uncertain, an estimated 10,000 or more people in the United States each year are diagnosed with MDS, also known as preleukemia, according to the American Cancer Society. Median survival ranges from 1 to 10.6 years based on risk group, although the cancer society says the statistics are dated and mainly from Europe.
Multiple studies have linked smoking to MDS. The new study aims to understand the possible effects of smoking on genetic mutations.
The research analyzed 1898 patients enrolled from 2016 to 2023 (52% who had ever smoked; 18% current smokers; mean smoking years, 29.8 ± 16.9 years). The patients had diagnoses of MDSs, MDS/myeloproliferative neoplasm overlap, or precursor conditions such as clonal cytopenia of undetermined significance (CCUS).
Smokers were more likely than nonsmokers to be men (68% vs 54%; P < .001) and aged 70-79 years (45% vs 34%; P < .001).
After adjustment for confounders, smokers had more average mutations linked to MDS than nonsmokers (2.0 vs 1.4; P = .04). Those at the 75th percentile of pack-years had 1.8 times as many MDS-linked mutations as nonsmokers.
The 5-year cumulative incidence of disease progression was higher in long-term smokers than in nonsmokers and those with shorter smoking history (mean proportion progressed, 20+ years vs < 20 years smoking/nonsmoking, 27% [19%-36%] vs 18% [13%-24%]; P < .05, respectively).
Also, overall survival was lower in smokers than in nonsmokers for patients with CCUS (hazard ratio [HR], 1.91; 95% CI, 1.03-3.55; P = .04) but not for those with MDS (HR, 1.21; 95% CI, 0.53-1.30; P = .41).
“The data suggests that a patient with a new diagnosis of MDS who also smokes should be counseled to stop smoking,” Sekeres said.
This may seem counterintuitive to patients, he acknowledged. When Sekeres was a medical student, he counseled a female patient with advanced lung cancer to quit smoking. “The patient looked at me like I had three heads and she said: ‘Why should I stop smoking? The cats are already out of the bag. I have lung cancer.’ ”
But the new study points to a possible benefit from quitting smoking while sick. “It appears that smoking contributes to the acquisition of new genetic mutations that can lead to worsening of the myelodysplastic syndromes and even evolution of the cancer into acute myeloid leukemia,” Sekeres said.
He added: “One thing to understand about these cancers of the bone marrow is they can take years or decades to develop. They’re not one-hit wonders. Smoking caused very specific genetic mutations. The cool part of this is that they’re the same genetic mutations smoking has been shown to cause in cancers like lung cancer, so we’re seeing consistency across cancers.”
Sekeres said he himself will counsel patients with MDS or acute myeloid leukemia to stop smoking. “If there’s anything we can do to intervene to prevent myelodysplastic syndrome from evolving into acute leukemia, my word, I sure I’m going to try it.”
In an interview, Peter Greenberg, MD, professor of medicine at Stanford Cancer Center in California, who’s familiar with the study but didn’t take part in the research, said the study suggests that smoking in MDS isn’t just related to exposure to fumes “but appears to be a much more widespread problem” related to its impact on generating hematologic stem cell mutations.
Most clinicians don’t warn patients with MDS about the dangers of smoking because they’re not aware of tobacco’s connection to the disease, Greenberg said. But there’s another reason to bring up smoking, he said: It boosts the risk for cardiovascular disease, which may be partially responsible for decreased survival in smokers.
Sekeres disclosed ties with Kurome, Schrödinger, and Bristol-Myers Squibb. Other authors reported multiple and various relationships with industry. Greenberg had no disclosures.
A version of this article appeared on Medscape.com.
FROM ASH 2024
High-Fiber Diet Linked to Improved Stem Cell Transplant, GvHD Outcomes
Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits.
“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.
Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.
Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.
However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.
For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.
Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration.
Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).
After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health.
Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).
Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD.
Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).
However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).
A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.
The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.
“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview.
“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.
“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”
Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.
The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.
“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.
“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.
Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned.
“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said.
High-Fiber Diet Slows MM Disease Progression?
The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).
NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.
Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m2 or higher.
The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI.
Notably, two patients in the study had stabilization of disease progression.
“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement.
“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.
The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.
Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not.
“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.
The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.
A version of this article first appeared on Medscape.com.
Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits.
“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.
Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.
Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.
However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.
For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.
Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration.
Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).
After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health.
Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).
Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD.
Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).
However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).
A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.
The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.
“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview.
“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.
“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”
Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.
The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.
“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.
“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.
Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned.
“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said.
High-Fiber Diet Slows MM Disease Progression?
The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).
NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.
Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m2 or higher.
The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI.
Notably, two patients in the study had stabilization of disease progression.
“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement.
“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.
The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.
Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not.
“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.
The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.
A version of this article first appeared on Medscape.com.
Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits.
“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.
Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.
Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.
However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.
For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.
Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration.
Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).
After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health.
Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).
Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD.
Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).
However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).
A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.
The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.
“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview.
“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.
“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”
Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.
The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.
“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.
“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.
Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned.
“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said.
High-Fiber Diet Slows MM Disease Progression?
The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).
NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.
Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m2 or higher.
The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI.
Notably, two patients in the study had stabilization of disease progression.
“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement.
“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.
The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.
Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not.
“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.
The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
Agent Orange and Myelodysplastic Syndrome: A Single VAMC Experience
Background
Agent Orange (AO) exposure may be linked to development of myeloid malignancies, including myelodysplastic syndrome (MDS). This is not yet definitive, though, and, unlike several other malignancies, MDS is not yet a service-connected diagnosis for AO. Although recent studies have not revealed AO associated specific mutations in MDS, other clinical and pathological potential differences have not been well described. In addition, determination of AO exposure is often not reported. Purpose: To assess for differences between AO versus non-AO exposed veterans with MDS.
Methods
All veterans diagnosed with MDS at the Cleveland VAMC from 2012-2023 were identified. Prior AO exposure was determined by Military Exposure tab in the EMR (CPRS) and confirmed with direct patient contact. Data collected included age and IPSS-R score at diagnosis; ring sideroblast percentage; mutations (on NGS); progression to AML and overall survival (OS).
Results
129 veterans were identified, 48 of whom had AO exposure. The mean age was 70.7 years in the AO group and 73.3 in the non-AO group (p=0.098); average IPSS-R score was 3.14 in AO and 2.75 in non-AO group (p= 0.32). In the AO group 4/48 (8.3%) progressed to AML vs 10/81 (12.3%) in the non-AO group; median OS was 39 months in AO vs 33 months in non-AO group (p=0.93). The most common mutations seen were TP53, SF3B1, SRSF2, DNMT, ASXL1, and U2AF1, with no differences between the 2 groups. 50% of those in the AO group had 2 or more genetic mutations vs. 61% for the non-AO group. Average variant allele frequency (VAF) was 40.2% in the AO group vs. 44% in the non-AO group. The average ring sideroblasts seen was 6% for the AO group compared to 5.7% for the non-AO group, p = 0.89.
Conclusions
This small retrospective study did not reveal statistically significant differences between AO vs non-AO exposed veterans with MDS, in terms of age at diagnosis, IPSS-R score, RS %, mutations (type, number or VAF load), progression to AML or OS. There were trends for AO exposed veterans presenting at a younger age and having a lower rate of progression to AML.
Background
Agent Orange (AO) exposure may be linked to development of myeloid malignancies, including myelodysplastic syndrome (MDS). This is not yet definitive, though, and, unlike several other malignancies, MDS is not yet a service-connected diagnosis for AO. Although recent studies have not revealed AO associated specific mutations in MDS, other clinical and pathological potential differences have not been well described. In addition, determination of AO exposure is often not reported. Purpose: To assess for differences between AO versus non-AO exposed veterans with MDS.
Methods
All veterans diagnosed with MDS at the Cleveland VAMC from 2012-2023 were identified. Prior AO exposure was determined by Military Exposure tab in the EMR (CPRS) and confirmed with direct patient contact. Data collected included age and IPSS-R score at diagnosis; ring sideroblast percentage; mutations (on NGS); progression to AML and overall survival (OS).
Results
129 veterans were identified, 48 of whom had AO exposure. The mean age was 70.7 years in the AO group and 73.3 in the non-AO group (p=0.098); average IPSS-R score was 3.14 in AO and 2.75 in non-AO group (p= 0.32). In the AO group 4/48 (8.3%) progressed to AML vs 10/81 (12.3%) in the non-AO group; median OS was 39 months in AO vs 33 months in non-AO group (p=0.93). The most common mutations seen were TP53, SF3B1, SRSF2, DNMT, ASXL1, and U2AF1, with no differences between the 2 groups. 50% of those in the AO group had 2 or more genetic mutations vs. 61% for the non-AO group. Average variant allele frequency (VAF) was 40.2% in the AO group vs. 44% in the non-AO group. The average ring sideroblasts seen was 6% for the AO group compared to 5.7% for the non-AO group, p = 0.89.
Conclusions
This small retrospective study did not reveal statistically significant differences between AO vs non-AO exposed veterans with MDS, in terms of age at diagnosis, IPSS-R score, RS %, mutations (type, number or VAF load), progression to AML or OS. There were trends for AO exposed veterans presenting at a younger age and having a lower rate of progression to AML.
Background
Agent Orange (AO) exposure may be linked to development of myeloid malignancies, including myelodysplastic syndrome (MDS). This is not yet definitive, though, and, unlike several other malignancies, MDS is not yet a service-connected diagnosis for AO. Although recent studies have not revealed AO associated specific mutations in MDS, other clinical and pathological potential differences have not been well described. In addition, determination of AO exposure is often not reported. Purpose: To assess for differences between AO versus non-AO exposed veterans with MDS.
Methods
All veterans diagnosed with MDS at the Cleveland VAMC from 2012-2023 were identified. Prior AO exposure was determined by Military Exposure tab in the EMR (CPRS) and confirmed with direct patient contact. Data collected included age and IPSS-R score at diagnosis; ring sideroblast percentage; mutations (on NGS); progression to AML and overall survival (OS).
Results
129 veterans were identified, 48 of whom had AO exposure. The mean age was 70.7 years in the AO group and 73.3 in the non-AO group (p=0.098); average IPSS-R score was 3.14 in AO and 2.75 in non-AO group (p= 0.32). In the AO group 4/48 (8.3%) progressed to AML vs 10/81 (12.3%) in the non-AO group; median OS was 39 months in AO vs 33 months in non-AO group (p=0.93). The most common mutations seen were TP53, SF3B1, SRSF2, DNMT, ASXL1, and U2AF1, with no differences between the 2 groups. 50% of those in the AO group had 2 or more genetic mutations vs. 61% for the non-AO group. Average variant allele frequency (VAF) was 40.2% in the AO group vs. 44% in the non-AO group. The average ring sideroblasts seen was 6% for the AO group compared to 5.7% for the non-AO group, p = 0.89.
Conclusions
This small retrospective study did not reveal statistically significant differences between AO vs non-AO exposed veterans with MDS, in terms of age at diagnosis, IPSS-R score, RS %, mutations (type, number or VAF load), progression to AML or OS. There were trends for AO exposed veterans presenting at a younger age and having a lower rate of progression to AML.
A Clonal Complete Remission Induced by IDH1 Inhibitor Ivosidenib in a Myelodysplastic Syndrome (MDS) With Co-Mutations of IDH1 and the ZRSR2 RNA Splicing Gene
Background
IDH1 mutations are detected in 3-4% of MDS, nearly always with one or more co-mutations. Treatment with IDH1 inhibitor ivosidenib typically resulted in regression of the abnormal clone in 15 reported responders. However, in a few cases differentiation was restored from the abnormal clone. Here we report a durable MDS remission despite sustained proliferation of a clone with IDH1 and ZRSR2 mutations.
Case Presentation
A 49-year-old man developed severe neutropenia and macrocytic anemia in January 2019. Mild marrow dysplasia developed by March 2020 with IDH1 (31.1%) and splicing gene ZRSR2 (55.7%) mutations. In October 2022 biopsy showed MDS with 4% blasts, megakaryocytic/granulocytic hypoplasia, normal cytogenetics and 43% IDH1/89% ZRSR2. After azacytidine failure, ivosidenib was started in November 2023 following FDA approval. Within weeks ANCs increased from 170 to 1580 and hemoglobin from 7.9 to 11.6 with MCV 115, reticulocytes 1.72%. At 3 months a CBC was normal except for MCV 111. IDH1 and ZRSR2 were 36.4% and 71%. After 6 months, ANC was 2380, hemoglobin 14.7, MCV 108.6, reticulo-cytes 1.77%. IDH1 PCR showed a 33.1% allele frequency consistent with a clonal remission.
Discussion
IDH1 mutations in MDS/AML frequently co-occur with mutations in RNA splicing genes SRSF2 or ZRSR2. For ZRSR2, we previously reported that isolated mutations of this gene cause refractory macrocytic anemias without dysplasia, thus presenting as clonal cytopenias of undetermined significance (Fleischman et al., Leuk Res, 2017). In this MDS case, after ivosidenib treatment the ZRSR2 splicing defect sustained clonal dominance over polyclonal hematopoiesis while accounting for macrocytosis. Longitudinal data for two ivosidenib-treated IDH1/SRSF2 MDS cases are incomplete, but one case of IDH2/SRSF2 MDS treated with the inhibitor enasidenib similarly achieved complete remission without regression of the mutated clone for 12 months.
Conclusions
Following the FDA approval of ivosidenib, all cases of MDS should have DNA sequencing performed at diagnosis to identify IDH1 mutations. Treatment induces high rates of remission even when polyclonal hematopoiesis does not recover. Moreover, the restoration of hematopoietic differentiation by the abnormal clone provides unique insights into the clinical phenotype and fitness advantage conferred by the co-existing driver mutations.
Background
IDH1 mutations are detected in 3-4% of MDS, nearly always with one or more co-mutations. Treatment with IDH1 inhibitor ivosidenib typically resulted in regression of the abnormal clone in 15 reported responders. However, in a few cases differentiation was restored from the abnormal clone. Here we report a durable MDS remission despite sustained proliferation of a clone with IDH1 and ZRSR2 mutations.
Case Presentation
A 49-year-old man developed severe neutropenia and macrocytic anemia in January 2019. Mild marrow dysplasia developed by March 2020 with IDH1 (31.1%) and splicing gene ZRSR2 (55.7%) mutations. In October 2022 biopsy showed MDS with 4% blasts, megakaryocytic/granulocytic hypoplasia, normal cytogenetics and 43% IDH1/89% ZRSR2. After azacytidine failure, ivosidenib was started in November 2023 following FDA approval. Within weeks ANCs increased from 170 to 1580 and hemoglobin from 7.9 to 11.6 with MCV 115, reticulocytes 1.72%. At 3 months a CBC was normal except for MCV 111. IDH1 and ZRSR2 were 36.4% and 71%. After 6 months, ANC was 2380, hemoglobin 14.7, MCV 108.6, reticulo-cytes 1.77%. IDH1 PCR showed a 33.1% allele frequency consistent with a clonal remission.
Discussion
IDH1 mutations in MDS/AML frequently co-occur with mutations in RNA splicing genes SRSF2 or ZRSR2. For ZRSR2, we previously reported that isolated mutations of this gene cause refractory macrocytic anemias without dysplasia, thus presenting as clonal cytopenias of undetermined significance (Fleischman et al., Leuk Res, 2017). In this MDS case, after ivosidenib treatment the ZRSR2 splicing defect sustained clonal dominance over polyclonal hematopoiesis while accounting for macrocytosis. Longitudinal data for two ivosidenib-treated IDH1/SRSF2 MDS cases are incomplete, but one case of IDH2/SRSF2 MDS treated with the inhibitor enasidenib similarly achieved complete remission without regression of the mutated clone for 12 months.
Conclusions
Following the FDA approval of ivosidenib, all cases of MDS should have DNA sequencing performed at diagnosis to identify IDH1 mutations. Treatment induces high rates of remission even when polyclonal hematopoiesis does not recover. Moreover, the restoration of hematopoietic differentiation by the abnormal clone provides unique insights into the clinical phenotype and fitness advantage conferred by the co-existing driver mutations.
Background
IDH1 mutations are detected in 3-4% of MDS, nearly always with one or more co-mutations. Treatment with IDH1 inhibitor ivosidenib typically resulted in regression of the abnormal clone in 15 reported responders. However, in a few cases differentiation was restored from the abnormal clone. Here we report a durable MDS remission despite sustained proliferation of a clone with IDH1 and ZRSR2 mutations.
Case Presentation
A 49-year-old man developed severe neutropenia and macrocytic anemia in January 2019. Mild marrow dysplasia developed by March 2020 with IDH1 (31.1%) and splicing gene ZRSR2 (55.7%) mutations. In October 2022 biopsy showed MDS with 4% blasts, megakaryocytic/granulocytic hypoplasia, normal cytogenetics and 43% IDH1/89% ZRSR2. After azacytidine failure, ivosidenib was started in November 2023 following FDA approval. Within weeks ANCs increased from 170 to 1580 and hemoglobin from 7.9 to 11.6 with MCV 115, reticulocytes 1.72%. At 3 months a CBC was normal except for MCV 111. IDH1 and ZRSR2 were 36.4% and 71%. After 6 months, ANC was 2380, hemoglobin 14.7, MCV 108.6, reticulo-cytes 1.77%. IDH1 PCR showed a 33.1% allele frequency consistent with a clonal remission.
Discussion
IDH1 mutations in MDS/AML frequently co-occur with mutations in RNA splicing genes SRSF2 or ZRSR2. For ZRSR2, we previously reported that isolated mutations of this gene cause refractory macrocytic anemias without dysplasia, thus presenting as clonal cytopenias of undetermined significance (Fleischman et al., Leuk Res, 2017). In this MDS case, after ivosidenib treatment the ZRSR2 splicing defect sustained clonal dominance over polyclonal hematopoiesis while accounting for macrocytosis. Longitudinal data for two ivosidenib-treated IDH1/SRSF2 MDS cases are incomplete, but one case of IDH2/SRSF2 MDS treated with the inhibitor enasidenib similarly achieved complete remission without regression of the mutated clone for 12 months.
Conclusions
Following the FDA approval of ivosidenib, all cases of MDS should have DNA sequencing performed at diagnosis to identify IDH1 mutations. Treatment induces high rates of remission even when polyclonal hematopoiesis does not recover. Moreover, the restoration of hematopoietic differentiation by the abnormal clone provides unique insights into the clinical phenotype and fitness advantage conferred by the co-existing driver mutations.
From Baghdad to Boston: The Making of a Blood Cancer Specialist
Today, she practices hematology at Massachusetts General Hospital, Boston, and is a leading advocate for palliative care in oncology.
In an interview, Dr. El-Jawahri spoke about her journey from Baghdad to Boston and the future of palliative medicine in hematology.
Question: Where did you grow up?
Dr. El-Jawahri: My family is from Baghdad, Iraq, and I was born there. We moved to the States when I was 14. I came to Michigan not speaking a word of English. My parents — my father is a mechanical engineer, and my mom is a computer engineer — chose to live in a very white neighborhood in Farmington Hills, in the suburbs of Detroit. The neighborhood did not have any immigrants or Arab Americans. There are a lot of Arab Americans in Michigan, but they chose for me not to hang out with them early on so that I could learn the language. It was a really good choice.
Question: What happened to your college friend?
Dr. El-Jawahri: She had a brain tumor and ended up receiving intensive care at the end of life. We had a lot of conversations about her wishes and desires, but none of those were honored. Her ending was not something that she wanted, nor did it honor her memory.
Question: What do you think went wrong?
Dr. El-Jawahri: She was getting treatment for her family’s sake. The idea of losing her was too hard for them. I remember vividly the conversations where she would say, “I just hope I don’t end up in the hospital at the end of life.” We had that conversation explicitly. But because we were young, her family was very involved in her care. A lot of the decision-making was very complicated.
Question: How did this experience change your career path?
Dr. El-Jawahri: I went into medicine specifically to become an oncologist and cure cancer. The naive 20-year-old in me said, “Nobody should die this miserable death. I’m going to go in, and I’m going to cure it.”
Question: How did palliative medicine become your major focus?
Dr. El-Jawahri: During my first year at Harvard Medical School, I took a course that’s called “Living With Life-Threatening Illness.” It allows medical students to spend their entire first year getting to know a patient living with a serious illness. We’d spend weekly coffee or lunch breaks with them, where we’d hear about their experiences. After every weekly meeting with a patient, we also had a group meeting with several students and group facilitators to talk about — and process — the interactions we had with patients. I was assigned a woman who was living with metastatic breast cancer. I was also introduced to the field of palliative care and how it helps patients manage complex symptoms and process and cope with a difficult diagnosis. It also cultivates the understanding to make informed decisions about their care. That’s when I knew what I wanted to do for the rest of my life — figure out ways to integrate these palliative and supportive care concepts and improve the lived experience of patients and families within the oncology setting.
Question: What happened next?
Dr. El-Jawahri: When I was a first-year intern, I went to residency at Massachusetts General Hospital. I was on an oncology service and admitted a young college student who was diagnosed with acute myeloid leukemia. She was an athlete, and every time she went up the stairs to her dorm, she was getting very short of breath. She went to a walk-in clinic because when you’re 20 and you’re healthy, you don’t think you need anything. They did some blood work, and 2 hours later, they called her and said, “You probably have leukemia. You need to go to the emergency department immediately.” There she saw an emergency doctor who said, “You will be admitted to the hospital. You have leukemia. I’m calling an oncologist, and you’ll probably have to start chemotherapy within the next day or two.”
Question: What was that experience like for the patient?
Dr. El-Jawahri: I’ve never seen someone so scared. The first question she asked me was about her family, who were from North Carolina. She said, “It feels like everybody thinks that I’m dying. Do you think my family will have time to get here?” They were in a car driving over. This is not a unique story in this population. Unfortunately, these patients experience the most traumatic way of being diagnosed and probably the most traumatic experience in oncology. They’re being abducted into a hospital environment, losing all control and starting immediate therapy. Then, for the first 4-6 weeks, they experience immense toxicity, side effects like nausea, vomiting, diarrhea, and mucositis, where they have painful mouth and throat sores that require intravenous pain medications. This causes real posttraumatic stress. After seeing that woman, I made the decision to work in leukemia and transplants to try to make things a little bit better for these patients.
Question: How did the patient fare?
Dr. El-Jawahri: She actually did great and was cured of her disease. Many of our patients with leukemia, especially younger ones, do well in terms of survival. But they struggle with the trauma of their diagnosis and the distress of the acute treatment period. Even in the curative setting, helping patients to cope with a traumatic diagnosis can have a big impact on their quality of life, how they feel, and their long-term outcomes in terms of psychological stress, depression, anxiety, and posttraumatic stress. But so often, our patients with leukemia are not offered palliative care and supportive care because they’re going to be cured.
Question: What is an important lesson from your research into palliative care in hematology?
Dr. El-Jawahri: We can make things better for patients and families by integrating palliative care clinicians into the care of patients. Patients receiving palliative care are more likely to document their end-of-life preferences and discuss them with their clinicians, and they’re less likely to be hospitalized at the end of life. When you ask patients with cancer where do they want to die, many of patients say, “I want to die at home. I don’t want to be in a hospital.” A lot of the work I’m doing now is focused on creating digital apps with components of palliative care and supportive care interventions. Patients can administer these interventions to themselves and learn how to effectively cope and deal with their illness. Some patients may do well with a digital app, but others may actually need the in-person touch. Some may need a hybrid approach. One of the other future directions for us is thinking about how we optimize supportive care interventions. Which ones do we give to which patient?
Question: Considering all that you’ve learned since college, how do you think your sick friend should have been treated?
Dr. El-Jawahri: She was neither introduced to the term palliative care nor to palliative care specialists. Now the standard of care — especially in patients with advanced cancer — is to integrate palliative care clinicians early in the course of illness. We would have loved for her to have a palliative care clinician who didn’t replace the oncologist but rather helped the patient, family, and oncologist communicate more effectively with one another. We hear all the time from patients who say different things to their oncologist than to their palliative care clinician. It’s not like my friend wasn’t able to communicate with her oncologist. But maybe part of it was that she wanted to not disappoint her oncologist [by ending treatment].
Question: Could you tell me about the research you presented at ASCO 2024 regarding 115 adult patients with acute myeloid leukemia and high-risk myelodysplastic syndrome who were receiving non-intensive chemotherapy?
Dr. El-Jawahri: These patients receive therapy that requires frequent clinic visits and often substantially impairs their quality of life. We know this population often does not engage in any timely discussion with their clinicians about their end-of-life care preferences. This multisite randomized clinical trial assigned patients to receive usual oncology care [with palliative care consultations only upon request] vs to see palliative care clinicians monthly in the outpatient setting and twice weekly every time they were hospitalized. The intervention focused on how to help patients manage their symptoms and end-of-life communication in particular. The primary outcome of the study was time from the documentation of end-of-life care preferences to death.
Question: What did you learn?
Dr. El-Jawahri: This is one of the first studies to highlight the impact of palliative care integration on end-of-life care preferences and discussions and documentation in this population. Patients receiving the palliative care intervention were much more likely to discuss their end-of-life care preferences (96.5% vs 68.4%; P < .001). More importantly, those receiving the intervention had a much longer time from documentation of end-of-life care preferences to death. On average, patients in the palliative care intervention group vs the usual care group had a mean of 41 vs 1.5 days from documentation of their preferences to death (P < .001). In the intervention group, these conversations were happening early enough for patients to plan, talk to their families, and discuss their wishes. In the usual care group, they were happening acutely while these patients were dying. We also learned that patients receiving palliative care intervention were less likely to be hospitalized at the end of life (70.6% vs 91.9%; P = .031) and had better quality of life (138.6 vs 125.5; P = .010).
Question: What’s next for your research in this area?
Dr. El-Jawahri: We are doing a large-scale randomized, comparative effectiveness trial of specialty palliative care vs primary palliative care in 11,150 patients with acute myeloid leukemia across 20 institutions in the United States. We expect results in 2028.
Question: What are you hoping to understand?
Dr. El-Jawahri: We will never have enough specialty palliative care clinicians to take care of all patients with serious illness. As a result, we have to learn how palliative care works: How does it improve outcomes? How do we potentially take what palliative care clinicians do and try to integrate it into regular oncology practice? A lot of the work that I’m excited about now regards what we call primary palliative care. How do we train oncology clinicians to incorporate palliative care skills in their practices so we’re able to better meet the needs of our patients and their families? What we’d love to understand from future research is which patient populations need specialty palliative care and which patients can do just fine with an oncology clinician who has a lot of good palliative care skills integrated into their practice.
Dr. El-Jawahri disclosed consulting for Incyte and Novartis.
A version of this article first appeared on Medscape.com.
Today, she practices hematology at Massachusetts General Hospital, Boston, and is a leading advocate for palliative care in oncology.
In an interview, Dr. El-Jawahri spoke about her journey from Baghdad to Boston and the future of palliative medicine in hematology.
Question: Where did you grow up?
Dr. El-Jawahri: My family is from Baghdad, Iraq, and I was born there. We moved to the States when I was 14. I came to Michigan not speaking a word of English. My parents — my father is a mechanical engineer, and my mom is a computer engineer — chose to live in a very white neighborhood in Farmington Hills, in the suburbs of Detroit. The neighborhood did not have any immigrants or Arab Americans. There are a lot of Arab Americans in Michigan, but they chose for me not to hang out with them early on so that I could learn the language. It was a really good choice.
Question: What happened to your college friend?
Dr. El-Jawahri: She had a brain tumor and ended up receiving intensive care at the end of life. We had a lot of conversations about her wishes and desires, but none of those were honored. Her ending was not something that she wanted, nor did it honor her memory.
Question: What do you think went wrong?
Dr. El-Jawahri: She was getting treatment for her family’s sake. The idea of losing her was too hard for them. I remember vividly the conversations where she would say, “I just hope I don’t end up in the hospital at the end of life.” We had that conversation explicitly. But because we were young, her family was very involved in her care. A lot of the decision-making was very complicated.
Question: How did this experience change your career path?
Dr. El-Jawahri: I went into medicine specifically to become an oncologist and cure cancer. The naive 20-year-old in me said, “Nobody should die this miserable death. I’m going to go in, and I’m going to cure it.”
Question: How did palliative medicine become your major focus?
Dr. El-Jawahri: During my first year at Harvard Medical School, I took a course that’s called “Living With Life-Threatening Illness.” It allows medical students to spend their entire first year getting to know a patient living with a serious illness. We’d spend weekly coffee or lunch breaks with them, where we’d hear about their experiences. After every weekly meeting with a patient, we also had a group meeting with several students and group facilitators to talk about — and process — the interactions we had with patients. I was assigned a woman who was living with metastatic breast cancer. I was also introduced to the field of palliative care and how it helps patients manage complex symptoms and process and cope with a difficult diagnosis. It also cultivates the understanding to make informed decisions about their care. That’s when I knew what I wanted to do for the rest of my life — figure out ways to integrate these palliative and supportive care concepts and improve the lived experience of patients and families within the oncology setting.
Question: What happened next?
Dr. El-Jawahri: When I was a first-year intern, I went to residency at Massachusetts General Hospital. I was on an oncology service and admitted a young college student who was diagnosed with acute myeloid leukemia. She was an athlete, and every time she went up the stairs to her dorm, she was getting very short of breath. She went to a walk-in clinic because when you’re 20 and you’re healthy, you don’t think you need anything. They did some blood work, and 2 hours later, they called her and said, “You probably have leukemia. You need to go to the emergency department immediately.” There she saw an emergency doctor who said, “You will be admitted to the hospital. You have leukemia. I’m calling an oncologist, and you’ll probably have to start chemotherapy within the next day or two.”
Question: What was that experience like for the patient?
Dr. El-Jawahri: I’ve never seen someone so scared. The first question she asked me was about her family, who were from North Carolina. She said, “It feels like everybody thinks that I’m dying. Do you think my family will have time to get here?” They were in a car driving over. This is not a unique story in this population. Unfortunately, these patients experience the most traumatic way of being diagnosed and probably the most traumatic experience in oncology. They’re being abducted into a hospital environment, losing all control and starting immediate therapy. Then, for the first 4-6 weeks, they experience immense toxicity, side effects like nausea, vomiting, diarrhea, and mucositis, where they have painful mouth and throat sores that require intravenous pain medications. This causes real posttraumatic stress. After seeing that woman, I made the decision to work in leukemia and transplants to try to make things a little bit better for these patients.
Question: How did the patient fare?
Dr. El-Jawahri: She actually did great and was cured of her disease. Many of our patients with leukemia, especially younger ones, do well in terms of survival. But they struggle with the trauma of their diagnosis and the distress of the acute treatment period. Even in the curative setting, helping patients to cope with a traumatic diagnosis can have a big impact on their quality of life, how they feel, and their long-term outcomes in terms of psychological stress, depression, anxiety, and posttraumatic stress. But so often, our patients with leukemia are not offered palliative care and supportive care because they’re going to be cured.
Question: What is an important lesson from your research into palliative care in hematology?
Dr. El-Jawahri: We can make things better for patients and families by integrating palliative care clinicians into the care of patients. Patients receiving palliative care are more likely to document their end-of-life preferences and discuss them with their clinicians, and they’re less likely to be hospitalized at the end of life. When you ask patients with cancer where do they want to die, many of patients say, “I want to die at home. I don’t want to be in a hospital.” A lot of the work I’m doing now is focused on creating digital apps with components of palliative care and supportive care interventions. Patients can administer these interventions to themselves and learn how to effectively cope and deal with their illness. Some patients may do well with a digital app, but others may actually need the in-person touch. Some may need a hybrid approach. One of the other future directions for us is thinking about how we optimize supportive care interventions. Which ones do we give to which patient?
Question: Considering all that you’ve learned since college, how do you think your sick friend should have been treated?
Dr. El-Jawahri: She was neither introduced to the term palliative care nor to palliative care specialists. Now the standard of care — especially in patients with advanced cancer — is to integrate palliative care clinicians early in the course of illness. We would have loved for her to have a palliative care clinician who didn’t replace the oncologist but rather helped the patient, family, and oncologist communicate more effectively with one another. We hear all the time from patients who say different things to their oncologist than to their palliative care clinician. It’s not like my friend wasn’t able to communicate with her oncologist. But maybe part of it was that she wanted to not disappoint her oncologist [by ending treatment].
Question: Could you tell me about the research you presented at ASCO 2024 regarding 115 adult patients with acute myeloid leukemia and high-risk myelodysplastic syndrome who were receiving non-intensive chemotherapy?
Dr. El-Jawahri: These patients receive therapy that requires frequent clinic visits and often substantially impairs their quality of life. We know this population often does not engage in any timely discussion with their clinicians about their end-of-life care preferences. This multisite randomized clinical trial assigned patients to receive usual oncology care [with palliative care consultations only upon request] vs to see palliative care clinicians monthly in the outpatient setting and twice weekly every time they were hospitalized. The intervention focused on how to help patients manage their symptoms and end-of-life communication in particular. The primary outcome of the study was time from the documentation of end-of-life care preferences to death.
Question: What did you learn?
Dr. El-Jawahri: This is one of the first studies to highlight the impact of palliative care integration on end-of-life care preferences and discussions and documentation in this population. Patients receiving the palliative care intervention were much more likely to discuss their end-of-life care preferences (96.5% vs 68.4%; P < .001). More importantly, those receiving the intervention had a much longer time from documentation of end-of-life care preferences to death. On average, patients in the palliative care intervention group vs the usual care group had a mean of 41 vs 1.5 days from documentation of their preferences to death (P < .001). In the intervention group, these conversations were happening early enough for patients to plan, talk to their families, and discuss their wishes. In the usual care group, they were happening acutely while these patients were dying. We also learned that patients receiving palliative care intervention were less likely to be hospitalized at the end of life (70.6% vs 91.9%; P = .031) and had better quality of life (138.6 vs 125.5; P = .010).
Question: What’s next for your research in this area?
Dr. El-Jawahri: We are doing a large-scale randomized, comparative effectiveness trial of specialty palliative care vs primary palliative care in 11,150 patients with acute myeloid leukemia across 20 institutions in the United States. We expect results in 2028.
Question: What are you hoping to understand?
Dr. El-Jawahri: We will never have enough specialty palliative care clinicians to take care of all patients with serious illness. As a result, we have to learn how palliative care works: How does it improve outcomes? How do we potentially take what palliative care clinicians do and try to integrate it into regular oncology practice? A lot of the work that I’m excited about now regards what we call primary palliative care. How do we train oncology clinicians to incorporate palliative care skills in their practices so we’re able to better meet the needs of our patients and their families? What we’d love to understand from future research is which patient populations need specialty palliative care and which patients can do just fine with an oncology clinician who has a lot of good palliative care skills integrated into their practice.
Dr. El-Jawahri disclosed consulting for Incyte and Novartis.
A version of this article first appeared on Medscape.com.
Today, she practices hematology at Massachusetts General Hospital, Boston, and is a leading advocate for palliative care in oncology.
In an interview, Dr. El-Jawahri spoke about her journey from Baghdad to Boston and the future of palliative medicine in hematology.
Question: Where did you grow up?
Dr. El-Jawahri: My family is from Baghdad, Iraq, and I was born there. We moved to the States when I was 14. I came to Michigan not speaking a word of English. My parents — my father is a mechanical engineer, and my mom is a computer engineer — chose to live in a very white neighborhood in Farmington Hills, in the suburbs of Detroit. The neighborhood did not have any immigrants or Arab Americans. There are a lot of Arab Americans in Michigan, but they chose for me not to hang out with them early on so that I could learn the language. It was a really good choice.
Question: What happened to your college friend?
Dr. El-Jawahri: She had a brain tumor and ended up receiving intensive care at the end of life. We had a lot of conversations about her wishes and desires, but none of those were honored. Her ending was not something that she wanted, nor did it honor her memory.
Question: What do you think went wrong?
Dr. El-Jawahri: She was getting treatment for her family’s sake. The idea of losing her was too hard for them. I remember vividly the conversations where she would say, “I just hope I don’t end up in the hospital at the end of life.” We had that conversation explicitly. But because we were young, her family was very involved in her care. A lot of the decision-making was very complicated.
Question: How did this experience change your career path?
Dr. El-Jawahri: I went into medicine specifically to become an oncologist and cure cancer. The naive 20-year-old in me said, “Nobody should die this miserable death. I’m going to go in, and I’m going to cure it.”
Question: How did palliative medicine become your major focus?
Dr. El-Jawahri: During my first year at Harvard Medical School, I took a course that’s called “Living With Life-Threatening Illness.” It allows medical students to spend their entire first year getting to know a patient living with a serious illness. We’d spend weekly coffee or lunch breaks with them, where we’d hear about their experiences. After every weekly meeting with a patient, we also had a group meeting with several students and group facilitators to talk about — and process — the interactions we had with patients. I was assigned a woman who was living with metastatic breast cancer. I was also introduced to the field of palliative care and how it helps patients manage complex symptoms and process and cope with a difficult diagnosis. It also cultivates the understanding to make informed decisions about their care. That’s when I knew what I wanted to do for the rest of my life — figure out ways to integrate these palliative and supportive care concepts and improve the lived experience of patients and families within the oncology setting.
Question: What happened next?
Dr. El-Jawahri: When I was a first-year intern, I went to residency at Massachusetts General Hospital. I was on an oncology service and admitted a young college student who was diagnosed with acute myeloid leukemia. She was an athlete, and every time she went up the stairs to her dorm, she was getting very short of breath. She went to a walk-in clinic because when you’re 20 and you’re healthy, you don’t think you need anything. They did some blood work, and 2 hours later, they called her and said, “You probably have leukemia. You need to go to the emergency department immediately.” There she saw an emergency doctor who said, “You will be admitted to the hospital. You have leukemia. I’m calling an oncologist, and you’ll probably have to start chemotherapy within the next day or two.”
Question: What was that experience like for the patient?
Dr. El-Jawahri: I’ve never seen someone so scared. The first question she asked me was about her family, who were from North Carolina. She said, “It feels like everybody thinks that I’m dying. Do you think my family will have time to get here?” They were in a car driving over. This is not a unique story in this population. Unfortunately, these patients experience the most traumatic way of being diagnosed and probably the most traumatic experience in oncology. They’re being abducted into a hospital environment, losing all control and starting immediate therapy. Then, for the first 4-6 weeks, they experience immense toxicity, side effects like nausea, vomiting, diarrhea, and mucositis, where they have painful mouth and throat sores that require intravenous pain medications. This causes real posttraumatic stress. After seeing that woman, I made the decision to work in leukemia and transplants to try to make things a little bit better for these patients.
Question: How did the patient fare?
Dr. El-Jawahri: She actually did great and was cured of her disease. Many of our patients with leukemia, especially younger ones, do well in terms of survival. But they struggle with the trauma of their diagnosis and the distress of the acute treatment period. Even in the curative setting, helping patients to cope with a traumatic diagnosis can have a big impact on their quality of life, how they feel, and their long-term outcomes in terms of psychological stress, depression, anxiety, and posttraumatic stress. But so often, our patients with leukemia are not offered palliative care and supportive care because they’re going to be cured.
Question: What is an important lesson from your research into palliative care in hematology?
Dr. El-Jawahri: We can make things better for patients and families by integrating palliative care clinicians into the care of patients. Patients receiving palliative care are more likely to document their end-of-life preferences and discuss them with their clinicians, and they’re less likely to be hospitalized at the end of life. When you ask patients with cancer where do they want to die, many of patients say, “I want to die at home. I don’t want to be in a hospital.” A lot of the work I’m doing now is focused on creating digital apps with components of palliative care and supportive care interventions. Patients can administer these interventions to themselves and learn how to effectively cope and deal with their illness. Some patients may do well with a digital app, but others may actually need the in-person touch. Some may need a hybrid approach. One of the other future directions for us is thinking about how we optimize supportive care interventions. Which ones do we give to which patient?
Question: Considering all that you’ve learned since college, how do you think your sick friend should have been treated?
Dr. El-Jawahri: She was neither introduced to the term palliative care nor to palliative care specialists. Now the standard of care — especially in patients with advanced cancer — is to integrate palliative care clinicians early in the course of illness. We would have loved for her to have a palliative care clinician who didn’t replace the oncologist but rather helped the patient, family, and oncologist communicate more effectively with one another. We hear all the time from patients who say different things to their oncologist than to their palliative care clinician. It’s not like my friend wasn’t able to communicate with her oncologist. But maybe part of it was that she wanted to not disappoint her oncologist [by ending treatment].
Question: Could you tell me about the research you presented at ASCO 2024 regarding 115 adult patients with acute myeloid leukemia and high-risk myelodysplastic syndrome who were receiving non-intensive chemotherapy?
Dr. El-Jawahri: These patients receive therapy that requires frequent clinic visits and often substantially impairs their quality of life. We know this population often does not engage in any timely discussion with their clinicians about their end-of-life care preferences. This multisite randomized clinical trial assigned patients to receive usual oncology care [with palliative care consultations only upon request] vs to see palliative care clinicians monthly in the outpatient setting and twice weekly every time they were hospitalized. The intervention focused on how to help patients manage their symptoms and end-of-life communication in particular. The primary outcome of the study was time from the documentation of end-of-life care preferences to death.
Question: What did you learn?
Dr. El-Jawahri: This is one of the first studies to highlight the impact of palliative care integration on end-of-life care preferences and discussions and documentation in this population. Patients receiving the palliative care intervention were much more likely to discuss their end-of-life care preferences (96.5% vs 68.4%; P < .001). More importantly, those receiving the intervention had a much longer time from documentation of end-of-life care preferences to death. On average, patients in the palliative care intervention group vs the usual care group had a mean of 41 vs 1.5 days from documentation of their preferences to death (P < .001). In the intervention group, these conversations were happening early enough for patients to plan, talk to their families, and discuss their wishes. In the usual care group, they were happening acutely while these patients were dying. We also learned that patients receiving palliative care intervention were less likely to be hospitalized at the end of life (70.6% vs 91.9%; P = .031) and had better quality of life (138.6 vs 125.5; P = .010).
Question: What’s next for your research in this area?
Dr. El-Jawahri: We are doing a large-scale randomized, comparative effectiveness trial of specialty palliative care vs primary palliative care in 11,150 patients with acute myeloid leukemia across 20 institutions in the United States. We expect results in 2028.
Question: What are you hoping to understand?
Dr. El-Jawahri: We will never have enough specialty palliative care clinicians to take care of all patients with serious illness. As a result, we have to learn how palliative care works: How does it improve outcomes? How do we potentially take what palliative care clinicians do and try to integrate it into regular oncology practice? A lot of the work that I’m excited about now regards what we call primary palliative care. How do we train oncology clinicians to incorporate palliative care skills in their practices so we’re able to better meet the needs of our patients and their families? What we’d love to understand from future research is which patient populations need specialty palliative care and which patients can do just fine with an oncology clinician who has a lot of good palliative care skills integrated into their practice.
Dr. El-Jawahri disclosed consulting for Incyte and Novartis.
A version of this article first appeared on Medscape.com.
Immunotherapy May Be Overused in Dying Patients With Cancer
Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.
Immunotherapy, however, has been taking its place.
This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.
What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
The N-of-1 Patient
With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.
He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.
The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.
Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”
At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”
This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
Back to Earth
The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.
Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.
Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.
She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.
Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.
Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.
And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.
In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
Prescribing Decisions
Recent research highlights the growing use of immunotherapy at the end of life.
Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.
Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.
Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.
Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.
Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.
More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.
The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.
Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.
To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”
While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.
As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.
Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.
“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.
“Just because something can be done doesn’t always mean it should be done,” he said.
At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.
Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”
Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.
“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”
Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.
Immunotherapy, however, has been taking its place.
This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.
What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
The N-of-1 Patient
With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.
He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.
The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.
Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”
At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”
This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
Back to Earth
The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.
Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.
Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.
She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.
Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.
Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.
And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.
In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
Prescribing Decisions
Recent research highlights the growing use of immunotherapy at the end of life.
Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.
Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.
Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.
Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.
Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.
More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.
The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.
Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.
To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”
While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.
As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.
Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.
“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.
“Just because something can be done doesn’t always mean it should be done,” he said.
At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.
Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”
Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.
“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”
Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.
Immunotherapy, however, has been taking its place.
This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.
What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
The N-of-1 Patient
With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.
He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.
The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.
Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”
At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”
This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
Back to Earth
The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.
Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.
Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.
She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.
Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.
Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.
And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.
In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
Prescribing Decisions
Recent research highlights the growing use of immunotherapy at the end of life.
Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.
Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.
Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.
Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.
Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.
More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.
The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.
Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.
To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”
While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.
As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.
Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.
“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.
“Just because something can be done doesn’t always mean it should be done,” he said.
At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.
Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”
Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.
“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”
Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Ancient Viruses in Our DNA Hold Clues to Cancer Treatment
according to a fascinating new study in Science Advances. Targeting these viral remnants still lingering in our DNA could lead to more effective cancer treatment with fewer side effects, the researchers said.
The study “gives a better understanding of how gene regulation can be impacted by these ancient retroviral sequences,” said Dixie Mager, PhD, scientist emeritus at the Terry Fox Laboratory at the British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada. (Mager was not involved in the study.)
Long thought to be “junk” DNA with no biologic function, “endogenous retroviruses,” which have mutated over time and lost their ability to create the virus, are now known to regulate genes — allowing some genes to turn on and off. Research in recent years suggests they may play a role in diseases like cancer.
But scientists weren’t exactly sure what that role was, said senior study author Edward Chuong, PhD, a genome biologist at the University of Colorado Boulder.
Most studies have looked at whether endogenous retroviruses code for proteins that influence cancer. But these ancient viral strands usually don’t code for proteins at all.
Dr. Chuong took a different approach. Inspired by scientists who’ve studied how viral remnants regulate positive processes (immunity, brain development, or placenta development), he and his team explored whether some might regulate genes that, once activated, help cancer thrive.
Borrowing from epigenomic analysis data (data on molecules that alter gene expression) for 21 cancers mapped by the Cancer Genome Atlas, the researchers identified 19 virus-derived DNA sequences that bind to regulatory proteins more in cancer cells than in healthy cells. All of these could potentially act as gene regulators that promote cancer.
The researchers homed in on one sequence, called LTR10, because it showed especially high activity in several cancers, including lung and colorectal cancer. This DNA segment comes from a virus that entered our ancestors’ genome 30 million years ago, and it’s activated in a third of colorectal cancers.
Using the gene editing technology clustered regularly interspaced short palindromic repeats (CRISPR), Dr. Chuong’s team silenced LTR10 in colorectal cancer cells, altering the gene sequence so it couldn’t bind to regulatory proteins. Doing so dampened the activity of nearby cancer-promoting genes.
“They still behaved like cancer cells,” Dr. Chuong said. But “it made the cancer cells more susceptible to radiation. That would imply that the presence of that viral ‘switch’ actually helped those cancer cells survive radiation therapy.”
Previously, two studies had found that viral regulators play a role in promoting two types of cancer: Leukemia and prostate cancer. The new study shows these two cases weren’t flukes. All 21 cancers they looked at had at least one of those 19 viral elements, presumably working as cancer enhancers.
The study also identified what activates LTR10 to make it promote cancer. The culprit is a regulator protein called mitogen-activated protein (MAP) kinase, which is overactivated in about 40% of all human cancers.
Some cancer drugs — MAP kinase inhibitors — already target MAP kinase, and they’re often the first ones prescribed when a patient is diagnosed with cancer, Dr. Chuong said. As with many cancer treatments, doctors don’t know why they work, just that they do.
“By understanding the mechanisms in the cell, we might be able to make them work better or further optimize their treatment,” he said.
“MAP kinase inhibitors are really like a sledgehammer to the cell,” Dr. Chuong said — meaning they affect many cellular processes, not just those related to cancer.
“If we’re able to say that these viral switches are what’s important, then that could potentially help us develop a more targeted therapy that uses something like CRISPR to silence these viral elements,” he said. Or it could help providers choose a MAP kinase inhibitor from among the dozens available best suited to treat an individual patient and avoid side effects.
Still, whether the findings translate to real cancer patients remains to be seen. “It’s very, very hard to go the final step of showing in a patient that these actually make a difference in the cancer,” Dr. Mager said.
More lab research, human trials, and at least a few years will be needed before this discovery could help treat cancer. “Directly targeting these elements as a therapy would be at least 5 years out,” Dr. Chuong said, “partly because that application would rely on CRISPR epigenome editing technology that is still being developed for clinical use.”
A version of this article first appeared on Medscape.com.
according to a fascinating new study in Science Advances. Targeting these viral remnants still lingering in our DNA could lead to more effective cancer treatment with fewer side effects, the researchers said.
The study “gives a better understanding of how gene regulation can be impacted by these ancient retroviral sequences,” said Dixie Mager, PhD, scientist emeritus at the Terry Fox Laboratory at the British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada. (Mager was not involved in the study.)
Long thought to be “junk” DNA with no biologic function, “endogenous retroviruses,” which have mutated over time and lost their ability to create the virus, are now known to regulate genes — allowing some genes to turn on and off. Research in recent years suggests they may play a role in diseases like cancer.
But scientists weren’t exactly sure what that role was, said senior study author Edward Chuong, PhD, a genome biologist at the University of Colorado Boulder.
Most studies have looked at whether endogenous retroviruses code for proteins that influence cancer. But these ancient viral strands usually don’t code for proteins at all.
Dr. Chuong took a different approach. Inspired by scientists who’ve studied how viral remnants regulate positive processes (immunity, brain development, or placenta development), he and his team explored whether some might regulate genes that, once activated, help cancer thrive.
Borrowing from epigenomic analysis data (data on molecules that alter gene expression) for 21 cancers mapped by the Cancer Genome Atlas, the researchers identified 19 virus-derived DNA sequences that bind to regulatory proteins more in cancer cells than in healthy cells. All of these could potentially act as gene regulators that promote cancer.
The researchers homed in on one sequence, called LTR10, because it showed especially high activity in several cancers, including lung and colorectal cancer. This DNA segment comes from a virus that entered our ancestors’ genome 30 million years ago, and it’s activated in a third of colorectal cancers.
Using the gene editing technology clustered regularly interspaced short palindromic repeats (CRISPR), Dr. Chuong’s team silenced LTR10 in colorectal cancer cells, altering the gene sequence so it couldn’t bind to regulatory proteins. Doing so dampened the activity of nearby cancer-promoting genes.
“They still behaved like cancer cells,” Dr. Chuong said. But “it made the cancer cells more susceptible to radiation. That would imply that the presence of that viral ‘switch’ actually helped those cancer cells survive radiation therapy.”
Previously, two studies had found that viral regulators play a role in promoting two types of cancer: Leukemia and prostate cancer. The new study shows these two cases weren’t flukes. All 21 cancers they looked at had at least one of those 19 viral elements, presumably working as cancer enhancers.
The study also identified what activates LTR10 to make it promote cancer. The culprit is a regulator protein called mitogen-activated protein (MAP) kinase, which is overactivated in about 40% of all human cancers.
Some cancer drugs — MAP kinase inhibitors — already target MAP kinase, and they’re often the first ones prescribed when a patient is diagnosed with cancer, Dr. Chuong said. As with many cancer treatments, doctors don’t know why they work, just that they do.
“By understanding the mechanisms in the cell, we might be able to make them work better or further optimize their treatment,” he said.
“MAP kinase inhibitors are really like a sledgehammer to the cell,” Dr. Chuong said — meaning they affect many cellular processes, not just those related to cancer.
“If we’re able to say that these viral switches are what’s important, then that could potentially help us develop a more targeted therapy that uses something like CRISPR to silence these viral elements,” he said. Or it could help providers choose a MAP kinase inhibitor from among the dozens available best suited to treat an individual patient and avoid side effects.
Still, whether the findings translate to real cancer patients remains to be seen. “It’s very, very hard to go the final step of showing in a patient that these actually make a difference in the cancer,” Dr. Mager said.
More lab research, human trials, and at least a few years will be needed before this discovery could help treat cancer. “Directly targeting these elements as a therapy would be at least 5 years out,” Dr. Chuong said, “partly because that application would rely on CRISPR epigenome editing technology that is still being developed for clinical use.”
A version of this article first appeared on Medscape.com.
according to a fascinating new study in Science Advances. Targeting these viral remnants still lingering in our DNA could lead to more effective cancer treatment with fewer side effects, the researchers said.
The study “gives a better understanding of how gene regulation can be impacted by these ancient retroviral sequences,” said Dixie Mager, PhD, scientist emeritus at the Terry Fox Laboratory at the British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada. (Mager was not involved in the study.)
Long thought to be “junk” DNA with no biologic function, “endogenous retroviruses,” which have mutated over time and lost their ability to create the virus, are now known to regulate genes — allowing some genes to turn on and off. Research in recent years suggests they may play a role in diseases like cancer.
But scientists weren’t exactly sure what that role was, said senior study author Edward Chuong, PhD, a genome biologist at the University of Colorado Boulder.
Most studies have looked at whether endogenous retroviruses code for proteins that influence cancer. But these ancient viral strands usually don’t code for proteins at all.
Dr. Chuong took a different approach. Inspired by scientists who’ve studied how viral remnants regulate positive processes (immunity, brain development, or placenta development), he and his team explored whether some might regulate genes that, once activated, help cancer thrive.
Borrowing from epigenomic analysis data (data on molecules that alter gene expression) for 21 cancers mapped by the Cancer Genome Atlas, the researchers identified 19 virus-derived DNA sequences that bind to regulatory proteins more in cancer cells than in healthy cells. All of these could potentially act as gene regulators that promote cancer.
The researchers homed in on one sequence, called LTR10, because it showed especially high activity in several cancers, including lung and colorectal cancer. This DNA segment comes from a virus that entered our ancestors’ genome 30 million years ago, and it’s activated in a third of colorectal cancers.
Using the gene editing technology clustered regularly interspaced short palindromic repeats (CRISPR), Dr. Chuong’s team silenced LTR10 in colorectal cancer cells, altering the gene sequence so it couldn’t bind to regulatory proteins. Doing so dampened the activity of nearby cancer-promoting genes.
“They still behaved like cancer cells,” Dr. Chuong said. But “it made the cancer cells more susceptible to radiation. That would imply that the presence of that viral ‘switch’ actually helped those cancer cells survive radiation therapy.”
Previously, two studies had found that viral regulators play a role in promoting two types of cancer: Leukemia and prostate cancer. The new study shows these two cases weren’t flukes. All 21 cancers they looked at had at least one of those 19 viral elements, presumably working as cancer enhancers.
The study also identified what activates LTR10 to make it promote cancer. The culprit is a regulator protein called mitogen-activated protein (MAP) kinase, which is overactivated in about 40% of all human cancers.
Some cancer drugs — MAP kinase inhibitors — already target MAP kinase, and they’re often the first ones prescribed when a patient is diagnosed with cancer, Dr. Chuong said. As with many cancer treatments, doctors don’t know why they work, just that they do.
“By understanding the mechanisms in the cell, we might be able to make them work better or further optimize their treatment,” he said.
“MAP kinase inhibitors are really like a sledgehammer to the cell,” Dr. Chuong said — meaning they affect many cellular processes, not just those related to cancer.
“If we’re able to say that these viral switches are what’s important, then that could potentially help us develop a more targeted therapy that uses something like CRISPR to silence these viral elements,” he said. Or it could help providers choose a MAP kinase inhibitor from among the dozens available best suited to treat an individual patient and avoid side effects.
Still, whether the findings translate to real cancer patients remains to be seen. “It’s very, very hard to go the final step of showing in a patient that these actually make a difference in the cancer,” Dr. Mager said.
More lab research, human trials, and at least a few years will be needed before this discovery could help treat cancer. “Directly targeting these elements as a therapy would be at least 5 years out,” Dr. Chuong said, “partly because that application would rely on CRISPR epigenome editing technology that is still being developed for clinical use.”
A version of this article first appeared on Medscape.com.
FROM SCIENCE ADVANCES
Cancer Drug Shortages Continue in the US, Survey Finds
Nearly 90% of the 28 NCCN member centers who responded to the survey, conducted between May 28 and June 11, said they were experiencing a shortage of at least one drug.
“Many drugs that are currently in shortage form the backbones of effective multiagent regimens across both curative and palliative treatment settings,” NCCN’s CEO Crystal S. Denlinger, MD, said in an interview.
The good news is that carboplatin and cisplatin shortages have fallen dramatically since 2023. At the peak of the shortage in 2023, 93% of centers surveyed reported experiencing a shortage of carboplatin and 70% were experiencing a shortage of cisplatin, whereas in 2024, only 11% reported a carboplatin shortage and 7% reported a cisplatin shortage.
“Thankfully, the shortages for carboplatin and cisplatin are mostly resolved at this time,” Dr. Denlinger said.
However, all three NCCN surveys conducted in the past year, including the most recent one, have found shortages of various chemotherapies and supportive care medications, which suggests this is an ongoing issue affecting a significant spectrum of generic drugs.
“The acute crisis associated with the shortage of carboplatin and cisplatin was a singular event that brought the issue into the national spotlight,” but it’s “important to note that the current broad drug shortages found on this survey are not new,” said Dr. Denlinger.
In the latest survey, 89% of NCCN centers continue to report shortages of one or more drugs, and 75% said they are experiencing shortages of two or more drugs.
Overall, 57% of centers are short on vinblastine, 46% are short on etoposide, and 43% are short on topotecan. Other common chemotherapy and supportive care agents in short supply include dacarbazine (18% of centers) as well as 5-fluorouracil (5-FU) and methotrexate (14% of centers).
In 2023, however, shortages of methotrexate and 5-FU were worse, with 67% of centers reporting shortages of methotrexate and 26% of 5-FU.
In the current survey, 75% of NCCN centers also noted they were aware of drug shortages within community practices in their area, and more than one in four centers reported treatment delays requiring additional prior authorization.
Cancer drug shortages impact not only routine treatments but also clinical trials. The recent survey found that 43% of respondents said drug shortages disrupted clinical trials at their center. The biggest issues centers flagged included greater administrative burdens, lower patient enrollment, and fewer open trials.
How are centers dealing with ongoing supply issues?
Top mitigation strategies include reducing waste, limiting use of current stock, and adjusting the timing and dosage within evidence-based ranges.
“The current situation underscores the need for sustainable, long-term solutions that ensure a stable supply of high-quality cancer medications,” Alyssa Schatz, MSW, NCCN senior director of policy and advocacy, said in a news release.
Three-quarters (75%) of survey respondents said they would like to see economic incentives put in place to encourage the high-quality manufacturing of medications, especially generic versions that are often in short supply. Nearly two-thirds (64%) cited a need for a broader buffer stock payment, and the same percentage would like to see more information on user experiences with various generic suppliers to help hospitals contract with those engaging in high-quality practices.
The NCCN also continues to work with federal regulators, agencies, and lawmakers to implement long-term solutions to cancer drug shortages.
“The federal government has a key role to play in addressing this issue,” Ms. Schatz said. “Establishing economic incentives, such as tax breaks or manufacturing grants for generic drugmakers, will help support a robust and resilient supply chain — ultimately safeguarding care for people with cancer across the country.”
A version of this article appeared on Medscape.com.
Nearly 90% of the 28 NCCN member centers who responded to the survey, conducted between May 28 and June 11, said they were experiencing a shortage of at least one drug.
“Many drugs that are currently in shortage form the backbones of effective multiagent regimens across both curative and palliative treatment settings,” NCCN’s CEO Crystal S. Denlinger, MD, said in an interview.
The good news is that carboplatin and cisplatin shortages have fallen dramatically since 2023. At the peak of the shortage in 2023, 93% of centers surveyed reported experiencing a shortage of carboplatin and 70% were experiencing a shortage of cisplatin, whereas in 2024, only 11% reported a carboplatin shortage and 7% reported a cisplatin shortage.
“Thankfully, the shortages for carboplatin and cisplatin are mostly resolved at this time,” Dr. Denlinger said.
However, all three NCCN surveys conducted in the past year, including the most recent one, have found shortages of various chemotherapies and supportive care medications, which suggests this is an ongoing issue affecting a significant spectrum of generic drugs.
“The acute crisis associated with the shortage of carboplatin and cisplatin was a singular event that brought the issue into the national spotlight,” but it’s “important to note that the current broad drug shortages found on this survey are not new,” said Dr. Denlinger.
In the latest survey, 89% of NCCN centers continue to report shortages of one or more drugs, and 75% said they are experiencing shortages of two or more drugs.
Overall, 57% of centers are short on vinblastine, 46% are short on etoposide, and 43% are short on topotecan. Other common chemotherapy and supportive care agents in short supply include dacarbazine (18% of centers) as well as 5-fluorouracil (5-FU) and methotrexate (14% of centers).
In 2023, however, shortages of methotrexate and 5-FU were worse, with 67% of centers reporting shortages of methotrexate and 26% of 5-FU.
In the current survey, 75% of NCCN centers also noted they were aware of drug shortages within community practices in their area, and more than one in four centers reported treatment delays requiring additional prior authorization.
Cancer drug shortages impact not only routine treatments but also clinical trials. The recent survey found that 43% of respondents said drug shortages disrupted clinical trials at their center. The biggest issues centers flagged included greater administrative burdens, lower patient enrollment, and fewer open trials.
How are centers dealing with ongoing supply issues?
Top mitigation strategies include reducing waste, limiting use of current stock, and adjusting the timing and dosage within evidence-based ranges.
“The current situation underscores the need for sustainable, long-term solutions that ensure a stable supply of high-quality cancer medications,” Alyssa Schatz, MSW, NCCN senior director of policy and advocacy, said in a news release.
Three-quarters (75%) of survey respondents said they would like to see economic incentives put in place to encourage the high-quality manufacturing of medications, especially generic versions that are often in short supply. Nearly two-thirds (64%) cited a need for a broader buffer stock payment, and the same percentage would like to see more information on user experiences with various generic suppliers to help hospitals contract with those engaging in high-quality practices.
The NCCN also continues to work with federal regulators, agencies, and lawmakers to implement long-term solutions to cancer drug shortages.
“The federal government has a key role to play in addressing this issue,” Ms. Schatz said. “Establishing economic incentives, such as tax breaks or manufacturing grants for generic drugmakers, will help support a robust and resilient supply chain — ultimately safeguarding care for people with cancer across the country.”
A version of this article appeared on Medscape.com.
Nearly 90% of the 28 NCCN member centers who responded to the survey, conducted between May 28 and June 11, said they were experiencing a shortage of at least one drug.
“Many drugs that are currently in shortage form the backbones of effective multiagent regimens across both curative and palliative treatment settings,” NCCN’s CEO Crystal S. Denlinger, MD, said in an interview.
The good news is that carboplatin and cisplatin shortages have fallen dramatically since 2023. At the peak of the shortage in 2023, 93% of centers surveyed reported experiencing a shortage of carboplatin and 70% were experiencing a shortage of cisplatin, whereas in 2024, only 11% reported a carboplatin shortage and 7% reported a cisplatin shortage.
“Thankfully, the shortages for carboplatin and cisplatin are mostly resolved at this time,” Dr. Denlinger said.
However, all three NCCN surveys conducted in the past year, including the most recent one, have found shortages of various chemotherapies and supportive care medications, which suggests this is an ongoing issue affecting a significant spectrum of generic drugs.
“The acute crisis associated with the shortage of carboplatin and cisplatin was a singular event that brought the issue into the national spotlight,” but it’s “important to note that the current broad drug shortages found on this survey are not new,” said Dr. Denlinger.
In the latest survey, 89% of NCCN centers continue to report shortages of one or more drugs, and 75% said they are experiencing shortages of two or more drugs.
Overall, 57% of centers are short on vinblastine, 46% are short on etoposide, and 43% are short on topotecan. Other common chemotherapy and supportive care agents in short supply include dacarbazine (18% of centers) as well as 5-fluorouracil (5-FU) and methotrexate (14% of centers).
In 2023, however, shortages of methotrexate and 5-FU were worse, with 67% of centers reporting shortages of methotrexate and 26% of 5-FU.
In the current survey, 75% of NCCN centers also noted they were aware of drug shortages within community practices in their area, and more than one in four centers reported treatment delays requiring additional prior authorization.
Cancer drug shortages impact not only routine treatments but also clinical trials. The recent survey found that 43% of respondents said drug shortages disrupted clinical trials at their center. The biggest issues centers flagged included greater administrative burdens, lower patient enrollment, and fewer open trials.
How are centers dealing with ongoing supply issues?
Top mitigation strategies include reducing waste, limiting use of current stock, and adjusting the timing and dosage within evidence-based ranges.
“The current situation underscores the need for sustainable, long-term solutions that ensure a stable supply of high-quality cancer medications,” Alyssa Schatz, MSW, NCCN senior director of policy and advocacy, said in a news release.
Three-quarters (75%) of survey respondents said they would like to see economic incentives put in place to encourage the high-quality manufacturing of medications, especially generic versions that are often in short supply. Nearly two-thirds (64%) cited a need for a broader buffer stock payment, and the same percentage would like to see more information on user experiences with various generic suppliers to help hospitals contract with those engaging in high-quality practices.
The NCCN also continues to work with federal regulators, agencies, and lawmakers to implement long-term solutions to cancer drug shortages.
“The federal government has a key role to play in addressing this issue,” Ms. Schatz said. “Establishing economic incentives, such as tax breaks or manufacturing grants for generic drugmakers, will help support a robust and resilient supply chain — ultimately safeguarding care for people with cancer across the country.”
A version of this article appeared on Medscape.com.
FDA Approves First-in-Class Drug for Lower-Risk Myelodysplastic Syndromes
The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).
Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.
“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.
Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.
Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.
Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.
The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.
An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.
Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.
The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information.
“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).
Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.
“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.
Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.
Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.
Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.
The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.
An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.
Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.
The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information.
“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).
Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.
“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.
Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.
Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.
Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.
The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.
An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.
Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.
The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information.
“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
A version of this article appeared on Medscape.com.