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ASTRO Pushes Return to Direct Supervision in RT: Needed or ‘Babysitting’?
Although serious errors during virtual supervision are rare, ASTRO said radiation treatments (RT) should be done with a radiation oncologist on site to ensure high-quality care. But some radiation oncologists do not agree with the proposal to move back to direct in-person supervision only.
Changes to Direct Supervision
Most radiation oncology treatments are delivered in an outpatient setting under a physician’s direction and control.
During the COVID-19 pandemic when social distancing mandates were in place, CMS temporarily changed the definition of “direct supervision” to include telehealth, specifying that a physician must be immediately available to assist and direct a procedure virtually using real-time audio and video. In other words, a physician did not need to be physically present in the room when the treatment was being performed.
CMS has extended this rule until the end of 2024 and is considering making it a permanent change. In the Calendar Year (CY) 2024 Medicare Physician Fee Schedule (PFS) Final Rule, CMS asked for comments on whether to extend the rule.
“We received input from interested parties on potential patient safety or quality concerns when direct supervision occurs virtually, which we will consider for future rulemaking,” a CMS spokesperson told this news organization. “CMS is currently considering the best approach that will protect patient access and safety as well as quality of care and program integrity concerns following CY 2024.”
CMS also noted its concerns that an abrupt transition back to requiring a physician’s physical presence could interrupt care from practitioners who have established new patterns of practice with telehealth.
What Are ASTRO’s Concerns?
Late last month, ASTRO sent CMS a letter, asking the agency to change the rules back to direct in-person supervision for all radiation services, citing that virtual supervision jeopardizes patient safety and quality of care.
Jeff Michalski, MD, MBA, chair of the ASTRO Board of Directors, said in an interview that radiation oncologists should be physically present to supervise the treatments.
“ASTRO is concerned that blanket policies of general or virtual supervision could lead to patients not having direct, in-person access to their doctors’ care,” he said. “While serious errors are rare, real-world experiences of radiation oncologists across practice settings demonstrate how an in-person radiation oncology physician is best suited to ensure high-quality care.”
What Do Radiation Oncologists Think?
According to ASTRO, most radiation oncologists would agree that in-person supervision is best for patients.
But that might not be the case.
Radiation oncologists took to X (formerly Twitter) to voice their opinions about ASTRO’s letter.
Jason Beckta, MD, PhD, of Rutland Regional’s Foley Cancer Center, Vermont, said “the February 26th ASTRO letter reads like an Onion article.”
“I’m struggling to understand the Luddite-level myopia around this topic,” he said in another tweet. “Virtual direct/outpatient general supervision has done nothing but boost my productivity and in particular, face-to-face patient contact.”
Join Y. Luh, MD, with the Providence Medical Network in Eureka, California, said he understands the challenges faced by clinicians working in more isolated rural settings. “For them, it’s either having virtual supervision or closing the center,” Dr. Luh said.
“Virtual care is definitely at my clinic and is not only an option but is critical to my patients who are 2+ snowy, mountainous hours away,” Dr. Luh wrote. “But I’m still in the clinic directly supervising treatments.”
Sidney Roberts, MD, with the CHI St. Luke’s Health-Memorial, Texas, tweeted that supervision does require some face-to-face care but contended that “babysitting trained therapists for every routine treatment is a farce.”
Another issue Dr. Luh brought up is reimbursement for virtual supervision, noting that “the elephant in the room is whether that level of service should be reimbursed at the same rate. Reimbursement has not changed — but will it stay that way?”
ASTRO has acknowledged that radiation oncologists will have varying opinions and says it is working to balance these challenges.
CMS has not reached a decision on whether the change will be implemented permanently. The organization will assess concern, patient safety, and quality of care at the end of the year.
A version of this article first appeared on Medscape.com
Although serious errors during virtual supervision are rare, ASTRO said radiation treatments (RT) should be done with a radiation oncologist on site to ensure high-quality care. But some radiation oncologists do not agree with the proposal to move back to direct in-person supervision only.
Changes to Direct Supervision
Most radiation oncology treatments are delivered in an outpatient setting under a physician’s direction and control.
During the COVID-19 pandemic when social distancing mandates were in place, CMS temporarily changed the definition of “direct supervision” to include telehealth, specifying that a physician must be immediately available to assist and direct a procedure virtually using real-time audio and video. In other words, a physician did not need to be physically present in the room when the treatment was being performed.
CMS has extended this rule until the end of 2024 and is considering making it a permanent change. In the Calendar Year (CY) 2024 Medicare Physician Fee Schedule (PFS) Final Rule, CMS asked for comments on whether to extend the rule.
“We received input from interested parties on potential patient safety or quality concerns when direct supervision occurs virtually, which we will consider for future rulemaking,” a CMS spokesperson told this news organization. “CMS is currently considering the best approach that will protect patient access and safety as well as quality of care and program integrity concerns following CY 2024.”
CMS also noted its concerns that an abrupt transition back to requiring a physician’s physical presence could interrupt care from practitioners who have established new patterns of practice with telehealth.
What Are ASTRO’s Concerns?
Late last month, ASTRO sent CMS a letter, asking the agency to change the rules back to direct in-person supervision for all radiation services, citing that virtual supervision jeopardizes patient safety and quality of care.
Jeff Michalski, MD, MBA, chair of the ASTRO Board of Directors, said in an interview that radiation oncologists should be physically present to supervise the treatments.
“ASTRO is concerned that blanket policies of general or virtual supervision could lead to patients not having direct, in-person access to their doctors’ care,” he said. “While serious errors are rare, real-world experiences of radiation oncologists across practice settings demonstrate how an in-person radiation oncology physician is best suited to ensure high-quality care.”
What Do Radiation Oncologists Think?
According to ASTRO, most radiation oncologists would agree that in-person supervision is best for patients.
But that might not be the case.
Radiation oncologists took to X (formerly Twitter) to voice their opinions about ASTRO’s letter.
Jason Beckta, MD, PhD, of Rutland Regional’s Foley Cancer Center, Vermont, said “the February 26th ASTRO letter reads like an Onion article.”
“I’m struggling to understand the Luddite-level myopia around this topic,” he said in another tweet. “Virtual direct/outpatient general supervision has done nothing but boost my productivity and in particular, face-to-face patient contact.”
Join Y. Luh, MD, with the Providence Medical Network in Eureka, California, said he understands the challenges faced by clinicians working in more isolated rural settings. “For them, it’s either having virtual supervision or closing the center,” Dr. Luh said.
“Virtual care is definitely at my clinic and is not only an option but is critical to my patients who are 2+ snowy, mountainous hours away,” Dr. Luh wrote. “But I’m still in the clinic directly supervising treatments.”
Sidney Roberts, MD, with the CHI St. Luke’s Health-Memorial, Texas, tweeted that supervision does require some face-to-face care but contended that “babysitting trained therapists for every routine treatment is a farce.”
Another issue Dr. Luh brought up is reimbursement for virtual supervision, noting that “the elephant in the room is whether that level of service should be reimbursed at the same rate. Reimbursement has not changed — but will it stay that way?”
ASTRO has acknowledged that radiation oncologists will have varying opinions and says it is working to balance these challenges.
CMS has not reached a decision on whether the change will be implemented permanently. The organization will assess concern, patient safety, and quality of care at the end of the year.
A version of this article first appeared on Medscape.com
Although serious errors during virtual supervision are rare, ASTRO said radiation treatments (RT) should be done with a radiation oncologist on site to ensure high-quality care. But some radiation oncologists do not agree with the proposal to move back to direct in-person supervision only.
Changes to Direct Supervision
Most radiation oncology treatments are delivered in an outpatient setting under a physician’s direction and control.
During the COVID-19 pandemic when social distancing mandates were in place, CMS temporarily changed the definition of “direct supervision” to include telehealth, specifying that a physician must be immediately available to assist and direct a procedure virtually using real-time audio and video. In other words, a physician did not need to be physically present in the room when the treatment was being performed.
CMS has extended this rule until the end of 2024 and is considering making it a permanent change. In the Calendar Year (CY) 2024 Medicare Physician Fee Schedule (PFS) Final Rule, CMS asked for comments on whether to extend the rule.
“We received input from interested parties on potential patient safety or quality concerns when direct supervision occurs virtually, which we will consider for future rulemaking,” a CMS spokesperson told this news organization. “CMS is currently considering the best approach that will protect patient access and safety as well as quality of care and program integrity concerns following CY 2024.”
CMS also noted its concerns that an abrupt transition back to requiring a physician’s physical presence could interrupt care from practitioners who have established new patterns of practice with telehealth.
What Are ASTRO’s Concerns?
Late last month, ASTRO sent CMS a letter, asking the agency to change the rules back to direct in-person supervision for all radiation services, citing that virtual supervision jeopardizes patient safety and quality of care.
Jeff Michalski, MD, MBA, chair of the ASTRO Board of Directors, said in an interview that radiation oncologists should be physically present to supervise the treatments.
“ASTRO is concerned that blanket policies of general or virtual supervision could lead to patients not having direct, in-person access to their doctors’ care,” he said. “While serious errors are rare, real-world experiences of radiation oncologists across practice settings demonstrate how an in-person radiation oncology physician is best suited to ensure high-quality care.”
What Do Radiation Oncologists Think?
According to ASTRO, most radiation oncologists would agree that in-person supervision is best for patients.
But that might not be the case.
Radiation oncologists took to X (formerly Twitter) to voice their opinions about ASTRO’s letter.
Jason Beckta, MD, PhD, of Rutland Regional’s Foley Cancer Center, Vermont, said “the February 26th ASTRO letter reads like an Onion article.”
“I’m struggling to understand the Luddite-level myopia around this topic,” he said in another tweet. “Virtual direct/outpatient general supervision has done nothing but boost my productivity and in particular, face-to-face patient contact.”
Join Y. Luh, MD, with the Providence Medical Network in Eureka, California, said he understands the challenges faced by clinicians working in more isolated rural settings. “For them, it’s either having virtual supervision or closing the center,” Dr. Luh said.
“Virtual care is definitely at my clinic and is not only an option but is critical to my patients who are 2+ snowy, mountainous hours away,” Dr. Luh wrote. “But I’m still in the clinic directly supervising treatments.”
Sidney Roberts, MD, with the CHI St. Luke’s Health-Memorial, Texas, tweeted that supervision does require some face-to-face care but contended that “babysitting trained therapists for every routine treatment is a farce.”
Another issue Dr. Luh brought up is reimbursement for virtual supervision, noting that “the elephant in the room is whether that level of service should be reimbursed at the same rate. Reimbursement has not changed — but will it stay that way?”
ASTRO has acknowledged that radiation oncologists will have varying opinions and says it is working to balance these challenges.
CMS has not reached a decision on whether the change will be implemented permanently. The organization will assess concern, patient safety, and quality of care at the end of the year.
A version of this article first appeared on Medscape.com
Pfizer Antibody-Drug Conjugate Picks Up Pediatric ALL Indication
The CD22-directed antibody and cytotoxic drug conjugate was previously approved only for adults with the condition.
Pediatric approval was based on a single-arm study of 53 children, of whom 12 were treated with an initial dose of 1.4 mg/m2 per cycle and the rest with an initial dose of 1.8 mg/m2 per cycle for a median of two cycles and a range of one to four cycles.
Premedications included methylprednisolone plus an antipyretic and antihistamine.
Overall, 22 children (42%) had a complete remission, defined as < 5% blasts in the bone marrow, no leukemia blasts in peripheral blood, full recovery of peripheral blood counts, and resolution of extramedullary disease. The median duration of complete remission was 8.2 months.
All but one child who went into complete remission (95.5%) had no minimal residual disease (MRD) by flow cytometry, and 19 (86.4%) were MRD negative by real-time quantitative polymerase chain reaction.
Adverse events in ≥ 20% of participants included thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.
The antibody-drug conjugate carries a black box warning of hepatotoxicity, including hepatic veno-occlusive and post-hematopoietic stem cell transplant mortality.
The initial recommended dose is 1.8 mg/m2 per cycle, divided into 0.8 mg/m2 on day 1, followed by 0.5 mg/m2 on day 9 and 0.5 mg/m2 on day 15. The initial 3-week cycle can be extended to 4 weeks for patients who have a complete remission or a complete remission with incomplete hematologic recovery and/or to recover from toxicities.
According to drugs.com, 0.9 mg costs $23,423.47.
A version of this article appeared on Medscape.com.
The CD22-directed antibody and cytotoxic drug conjugate was previously approved only for adults with the condition.
Pediatric approval was based on a single-arm study of 53 children, of whom 12 were treated with an initial dose of 1.4 mg/m2 per cycle and the rest with an initial dose of 1.8 mg/m2 per cycle for a median of two cycles and a range of one to four cycles.
Premedications included methylprednisolone plus an antipyretic and antihistamine.
Overall, 22 children (42%) had a complete remission, defined as < 5% blasts in the bone marrow, no leukemia blasts in peripheral blood, full recovery of peripheral blood counts, and resolution of extramedullary disease. The median duration of complete remission was 8.2 months.
All but one child who went into complete remission (95.5%) had no minimal residual disease (MRD) by flow cytometry, and 19 (86.4%) were MRD negative by real-time quantitative polymerase chain reaction.
Adverse events in ≥ 20% of participants included thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.
The antibody-drug conjugate carries a black box warning of hepatotoxicity, including hepatic veno-occlusive and post-hematopoietic stem cell transplant mortality.
The initial recommended dose is 1.8 mg/m2 per cycle, divided into 0.8 mg/m2 on day 1, followed by 0.5 mg/m2 on day 9 and 0.5 mg/m2 on day 15. The initial 3-week cycle can be extended to 4 weeks for patients who have a complete remission or a complete remission with incomplete hematologic recovery and/or to recover from toxicities.
According to drugs.com, 0.9 mg costs $23,423.47.
A version of this article appeared on Medscape.com.
The CD22-directed antibody and cytotoxic drug conjugate was previously approved only for adults with the condition.
Pediatric approval was based on a single-arm study of 53 children, of whom 12 were treated with an initial dose of 1.4 mg/m2 per cycle and the rest with an initial dose of 1.8 mg/m2 per cycle for a median of two cycles and a range of one to four cycles.
Premedications included methylprednisolone plus an antipyretic and antihistamine.
Overall, 22 children (42%) had a complete remission, defined as < 5% blasts in the bone marrow, no leukemia blasts in peripheral blood, full recovery of peripheral blood counts, and resolution of extramedullary disease. The median duration of complete remission was 8.2 months.
All but one child who went into complete remission (95.5%) had no minimal residual disease (MRD) by flow cytometry, and 19 (86.4%) were MRD negative by real-time quantitative polymerase chain reaction.
Adverse events in ≥ 20% of participants included thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.
The antibody-drug conjugate carries a black box warning of hepatotoxicity, including hepatic veno-occlusive and post-hematopoietic stem cell transplant mortality.
The initial recommended dose is 1.8 mg/m2 per cycle, divided into 0.8 mg/m2 on day 1, followed by 0.5 mg/m2 on day 9 and 0.5 mg/m2 on day 15. The initial 3-week cycle can be extended to 4 weeks for patients who have a complete remission or a complete remission with incomplete hematologic recovery and/or to recover from toxicities.
According to drugs.com, 0.9 mg costs $23,423.47.
A version of this article appeared on Medscape.com.
FDA Removes Harmful Chemicals From Food Packaging
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
B-ALL: CAR-T Outperforms Novel Therapies
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
FROM THE 6TH EUROPEAN CAR T-CELL MEETING
New Trials in Leukemia and Lymphoma: Could Your Patient Benefit?
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
AML: Genetic Testing Unlocks Hope
For adult patients, “we’ve seen a series of remarkable and well-overdue advances in a space that had not changed much over the prior decades,” hematologist/oncologist Thomas William LeBlanc, MD, associate professor of medicine at Duke University School of Medicine, Durham, North Carolina, said in an interview.
According to the National Cancer Institute, AML will be newly diagnosed in 20,800 patients in 2024, at a median age of 69, and will cause 11,220 deaths. As many as 70% of adult patients will reach complete remission, and 45% of those will live for more than 3 years and potentially be cured. As for children, the Leukemia & Lymphoma Society says the 5-year survival rate from 2012-2018 was 69% for those under 15 years old.
As the American Cancer Society notes, the goal of AML treatment “is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way.”
Chemotherapy Strategies Shift Over Time
In terms of the treatment of adults with AML, “targeted therapies, in addition to the expanding role of venetoclax, has really altered our approach to AML from diagnosis, including after relapse, and later in the disease,” hematologist/oncologist Andrew M. Brunner, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, said in an interview. “The ability to explore these options as monotherapy and in novel combinations has dramatically expanded our treatment options.”
Much depends on the underlying genetic profile of the disease, he said. “There certainly have been gains in patient survival in AML, but those improvements remain fairly heterogeneous and dependent on the underlying genetic profile of the disease. For instance, advances in FLT3- and IDH1/2-mutated AML are a direct result of the improvements in targeted therapies directed at these mutations. Similarly, some molecular and cytogenetic subtypes of AML are particularly responsive to venetoclax-based regimens, and these regimens have been expanded to previously undertreated populations, particularly those over age 60.”
Specifically, Dr. LeBlanc said, the Food and Drug Administration has approved “3 different FLT3 inhibitors, 2 IDH1 inhibitors, 1 IDH2 inhibitor, a BCL-2 inhibitor, a smoothened/hedgehog pathway inhibitor, an oral maintenance chemotherapy/hypomethylating agent (CC-486/oral azacitidine), a CD33-targeting antibody-drug conjugate, and even a novel formulation of two older chemotherapies that improves efficacy in a poor prognosis subgroup (CPX-351/liposomal daunorubicin and cytarabine).”
There’s also been a shift in treatment protocols for patients who were not fit for intensive chemotherapy. In the past, he said, it was standard “to give single-agent hypomethylating chemotherapy with azacitidine or decitabine, or in some contexts, low-dose chemotherapy with cytarabine. Today, many patients who are older and/or more frail are receiving novel therapies either alone or in combination, with greater efficacy and longer duration of response than previously seen with chemotherapy alone.”
Outcomes Improve but Remain Grim in High-Risk Cases
As a result, Dr. LeBlanc said, “we’re definitely seeing much better outcomes in AML overall. It takes some time to prove this via outcomes data assessments in a large population, but I expect that registries will show significant improvements in overall survival in the coming years, owing to the many new FDA approvals in AML”
Dr. LeBlanc highlighted national data from 2013-2019 showing that the 5-year relative survival rate from AML is 31.7%. That’s up from 26% just a few years ago, and the numbers “always lag several years behind the current year of practice,” he said. However, “the major area where we still have relatively poor outcomes and significant unmet needs remains the ‘adverse risk’ group of patients, particularly those who are older and/or not candidates for hematopoietic stem cell transplantation, which generally is the only potentially curative option for adverse-risk AML.”
He went on to say that “this risk grouping includes those with TP53 mutations, most of which confer a particularly poor prognosis. Exciting therapies that many of us were hoping would prove effective in this subgroup have unfortunately failed in recent clinical trials. We still have a lot of work to do in adverse-risk AML particularly, and also for those whose leukemia has relapsed.”
Mikkael Sekeres, MD, MS, chief of the Division of Hematology at the University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, agreed that more progress is needed, since survival rates are low even as lifespans improve. One key will be “better identifying subtypes of acute myeloid leukemia, and identifying the therapies that will benefit those people most,” he said in an interview. On the other side, it’s important to identify “when aggressive therapies aren’t going to work in somebody and maybe turn toward less-aggressive approaches so we can maximize that person’s quality of life.”
What advice do AML experts have for their colleagues? Dr. LeBlanc said “older patients are not often enough considered for allogeneic stem cell transplantation, which could potentially cure their AML when given as a consolidation treatment for those in remission. I have several patients who are healthy and in their 70s who have enormously benefited from transplants and are now being several years out from transplant with adverse risk AML and without relapse. They’ve had no significant impairments of their quality of life, including no significant graft vs. host disease.”
Dr. Sekeres highlighted the American Society of Hematology’s guidelines for treating older adults with AML, which are currently being updated. It’s crucial to order genetic testing “up front,” he said. “I’m often pleasantly surprised when genetic testing returns and reveals that I have other treatment options.”
However, it’s crucial to understand a patient’s priorities. “I’ve had patients who are 75 who say to me, ‘Do everything under the sun to get rid of my leukemia, I want to live as long as possible.’ And I’ve had patients who say, ‘I want to see as little of doctors and nurses as I can. I want you to maximize my quality of life and keep me out of the hospital.’ ”
Dr. Sekeres also noted that insurers may not cover some pill-based AML treatments such as venetoclax. “We work with our patients and assistance programs. For the most part, we’re pretty successful at getting these drugs for our patients,” he said.
In Pediatrics, Clinical Trials Are Crucial
AML in children is less well-known than in adults, since the number of cases is so small. The disease is diagnosed in about 500 children a year in the United States, according to St. Jude Children’s Research Hospital, adding, however, that AML is “the most common second cancer among children treated for other cancers.”
AML in children gained attention earlier this year when the 2-year-old daughter of a Boston Herald NFL reporter died of the disease following a bone marrow transplant and chemotherapy. Despite the agonies of her treatment, reporter Doug Kyed told a reporter that his daughter Hallie “was still able to find joy every day.”
In an interview, hematologist/oncologist Sarah K. Tasian, MD, of Children’s Hospital of Philadelphia, said researchers are discovering that pediatric AML is significantly different on from a biological perspective from adult AML. “We’ve come to understand a lot more about who these patients are, what makes these leukemias tick, and what their Achilles’ heels are. Then we can align that with the clinical trials outcome data that we have.”
About 80%-90% of pediatric patients with AML nationwide are enrolled in clinical trials, Dr. Tasian said, and an international consortium called the Children’s Oncology Group gathers data about genetics. About 60%-70% of patients will be cured, she added.
However, “we’ve kind of been stuck for about the last 20 years,” she said. “A lot of improving the survival of patients has not been because we’ve been better at chemotherapy or using new chemo, but because we’ve gotten better at supportive care, at treating infections that can be fatal.”
There haven’t been major conflicts with insurers over coverage, she said, although drug shortages are a problem, especially in relapsed AML.
As for advice to colleagues, Dr. Tasian counseled them to understand the importance of genetic testing and the expanding role of stem cell transplants. “We are now transplanting somewhere between 30% and 50% of children with AML, which is a higher rate than we used to do,” she said. The number is up thanks to genetic testing that reveals which patients are most likely to benefit.
Also, she noted, “the chemotherapy that we get to these patients is really strong, and patients have a lot of complications. Really pay attention to supportive care.”
Dr. LeBlanc reported ties with AbbVie, Agios/Servier, Astellas, BMS/Celgene, Genentech, Pfizer, Incyte, Rige, Deverra, GSK, Jazz, and Seattle Genetics. Dr. Sekeres discloses relationships with BMS and Kurome. Dr. Tasian serves as the Leukemia & Lymphoma Society Pediatric Acute Leukemia consortium clinical trials leader and works with pharmaceutical companies on clinical trials under confidentiality agreements. Dr. Brunner has no disclosures.
For adult patients, “we’ve seen a series of remarkable and well-overdue advances in a space that had not changed much over the prior decades,” hematologist/oncologist Thomas William LeBlanc, MD, associate professor of medicine at Duke University School of Medicine, Durham, North Carolina, said in an interview.
According to the National Cancer Institute, AML will be newly diagnosed in 20,800 patients in 2024, at a median age of 69, and will cause 11,220 deaths. As many as 70% of adult patients will reach complete remission, and 45% of those will live for more than 3 years and potentially be cured. As for children, the Leukemia & Lymphoma Society says the 5-year survival rate from 2012-2018 was 69% for those under 15 years old.
As the American Cancer Society notes, the goal of AML treatment “is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way.”
Chemotherapy Strategies Shift Over Time
In terms of the treatment of adults with AML, “targeted therapies, in addition to the expanding role of venetoclax, has really altered our approach to AML from diagnosis, including after relapse, and later in the disease,” hematologist/oncologist Andrew M. Brunner, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, said in an interview. “The ability to explore these options as monotherapy and in novel combinations has dramatically expanded our treatment options.”
Much depends on the underlying genetic profile of the disease, he said. “There certainly have been gains in patient survival in AML, but those improvements remain fairly heterogeneous and dependent on the underlying genetic profile of the disease. For instance, advances in FLT3- and IDH1/2-mutated AML are a direct result of the improvements in targeted therapies directed at these mutations. Similarly, some molecular and cytogenetic subtypes of AML are particularly responsive to venetoclax-based regimens, and these regimens have been expanded to previously undertreated populations, particularly those over age 60.”
Specifically, Dr. LeBlanc said, the Food and Drug Administration has approved “3 different FLT3 inhibitors, 2 IDH1 inhibitors, 1 IDH2 inhibitor, a BCL-2 inhibitor, a smoothened/hedgehog pathway inhibitor, an oral maintenance chemotherapy/hypomethylating agent (CC-486/oral azacitidine), a CD33-targeting antibody-drug conjugate, and even a novel formulation of two older chemotherapies that improves efficacy in a poor prognosis subgroup (CPX-351/liposomal daunorubicin and cytarabine).”
There’s also been a shift in treatment protocols for patients who were not fit for intensive chemotherapy. In the past, he said, it was standard “to give single-agent hypomethylating chemotherapy with azacitidine or decitabine, or in some contexts, low-dose chemotherapy with cytarabine. Today, many patients who are older and/or more frail are receiving novel therapies either alone or in combination, with greater efficacy and longer duration of response than previously seen with chemotherapy alone.”
Outcomes Improve but Remain Grim in High-Risk Cases
As a result, Dr. LeBlanc said, “we’re definitely seeing much better outcomes in AML overall. It takes some time to prove this via outcomes data assessments in a large population, but I expect that registries will show significant improvements in overall survival in the coming years, owing to the many new FDA approvals in AML”
Dr. LeBlanc highlighted national data from 2013-2019 showing that the 5-year relative survival rate from AML is 31.7%. That’s up from 26% just a few years ago, and the numbers “always lag several years behind the current year of practice,” he said. However, “the major area where we still have relatively poor outcomes and significant unmet needs remains the ‘adverse risk’ group of patients, particularly those who are older and/or not candidates for hematopoietic stem cell transplantation, which generally is the only potentially curative option for adverse-risk AML.”
He went on to say that “this risk grouping includes those with TP53 mutations, most of which confer a particularly poor prognosis. Exciting therapies that many of us were hoping would prove effective in this subgroup have unfortunately failed in recent clinical trials. We still have a lot of work to do in adverse-risk AML particularly, and also for those whose leukemia has relapsed.”
Mikkael Sekeres, MD, MS, chief of the Division of Hematology at the University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, agreed that more progress is needed, since survival rates are low even as lifespans improve. One key will be “better identifying subtypes of acute myeloid leukemia, and identifying the therapies that will benefit those people most,” he said in an interview. On the other side, it’s important to identify “when aggressive therapies aren’t going to work in somebody and maybe turn toward less-aggressive approaches so we can maximize that person’s quality of life.”
What advice do AML experts have for their colleagues? Dr. LeBlanc said “older patients are not often enough considered for allogeneic stem cell transplantation, which could potentially cure their AML when given as a consolidation treatment for those in remission. I have several patients who are healthy and in their 70s who have enormously benefited from transplants and are now being several years out from transplant with adverse risk AML and without relapse. They’ve had no significant impairments of their quality of life, including no significant graft vs. host disease.”
Dr. Sekeres highlighted the American Society of Hematology’s guidelines for treating older adults with AML, which are currently being updated. It’s crucial to order genetic testing “up front,” he said. “I’m often pleasantly surprised when genetic testing returns and reveals that I have other treatment options.”
However, it’s crucial to understand a patient’s priorities. “I’ve had patients who are 75 who say to me, ‘Do everything under the sun to get rid of my leukemia, I want to live as long as possible.’ And I’ve had patients who say, ‘I want to see as little of doctors and nurses as I can. I want you to maximize my quality of life and keep me out of the hospital.’ ”
Dr. Sekeres also noted that insurers may not cover some pill-based AML treatments such as venetoclax. “We work with our patients and assistance programs. For the most part, we’re pretty successful at getting these drugs for our patients,” he said.
In Pediatrics, Clinical Trials Are Crucial
AML in children is less well-known than in adults, since the number of cases is so small. The disease is diagnosed in about 500 children a year in the United States, according to St. Jude Children’s Research Hospital, adding, however, that AML is “the most common second cancer among children treated for other cancers.”
AML in children gained attention earlier this year when the 2-year-old daughter of a Boston Herald NFL reporter died of the disease following a bone marrow transplant and chemotherapy. Despite the agonies of her treatment, reporter Doug Kyed told a reporter that his daughter Hallie “was still able to find joy every day.”
In an interview, hematologist/oncologist Sarah K. Tasian, MD, of Children’s Hospital of Philadelphia, said researchers are discovering that pediatric AML is significantly different on from a biological perspective from adult AML. “We’ve come to understand a lot more about who these patients are, what makes these leukemias tick, and what their Achilles’ heels are. Then we can align that with the clinical trials outcome data that we have.”
About 80%-90% of pediatric patients with AML nationwide are enrolled in clinical trials, Dr. Tasian said, and an international consortium called the Children’s Oncology Group gathers data about genetics. About 60%-70% of patients will be cured, she added.
However, “we’ve kind of been stuck for about the last 20 years,” she said. “A lot of improving the survival of patients has not been because we’ve been better at chemotherapy or using new chemo, but because we’ve gotten better at supportive care, at treating infections that can be fatal.”
There haven’t been major conflicts with insurers over coverage, she said, although drug shortages are a problem, especially in relapsed AML.
As for advice to colleagues, Dr. Tasian counseled them to understand the importance of genetic testing and the expanding role of stem cell transplants. “We are now transplanting somewhere between 30% and 50% of children with AML, which is a higher rate than we used to do,” she said. The number is up thanks to genetic testing that reveals which patients are most likely to benefit.
Also, she noted, “the chemotherapy that we get to these patients is really strong, and patients have a lot of complications. Really pay attention to supportive care.”
Dr. LeBlanc reported ties with AbbVie, Agios/Servier, Astellas, BMS/Celgene, Genentech, Pfizer, Incyte, Rige, Deverra, GSK, Jazz, and Seattle Genetics. Dr. Sekeres discloses relationships with BMS and Kurome. Dr. Tasian serves as the Leukemia & Lymphoma Society Pediatric Acute Leukemia consortium clinical trials leader and works with pharmaceutical companies on clinical trials under confidentiality agreements. Dr. Brunner has no disclosures.
For adult patients, “we’ve seen a series of remarkable and well-overdue advances in a space that had not changed much over the prior decades,” hematologist/oncologist Thomas William LeBlanc, MD, associate professor of medicine at Duke University School of Medicine, Durham, North Carolina, said in an interview.
According to the National Cancer Institute, AML will be newly diagnosed in 20,800 patients in 2024, at a median age of 69, and will cause 11,220 deaths. As many as 70% of adult patients will reach complete remission, and 45% of those will live for more than 3 years and potentially be cured. As for children, the Leukemia & Lymphoma Society says the 5-year survival rate from 2012-2018 was 69% for those under 15 years old.
As the American Cancer Society notes, the goal of AML treatment “is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way.”
Chemotherapy Strategies Shift Over Time
In terms of the treatment of adults with AML, “targeted therapies, in addition to the expanding role of venetoclax, has really altered our approach to AML from diagnosis, including after relapse, and later in the disease,” hematologist/oncologist Andrew M. Brunner, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, said in an interview. “The ability to explore these options as monotherapy and in novel combinations has dramatically expanded our treatment options.”
Much depends on the underlying genetic profile of the disease, he said. “There certainly have been gains in patient survival in AML, but those improvements remain fairly heterogeneous and dependent on the underlying genetic profile of the disease. For instance, advances in FLT3- and IDH1/2-mutated AML are a direct result of the improvements in targeted therapies directed at these mutations. Similarly, some molecular and cytogenetic subtypes of AML are particularly responsive to venetoclax-based regimens, and these regimens have been expanded to previously undertreated populations, particularly those over age 60.”
Specifically, Dr. LeBlanc said, the Food and Drug Administration has approved “3 different FLT3 inhibitors, 2 IDH1 inhibitors, 1 IDH2 inhibitor, a BCL-2 inhibitor, a smoothened/hedgehog pathway inhibitor, an oral maintenance chemotherapy/hypomethylating agent (CC-486/oral azacitidine), a CD33-targeting antibody-drug conjugate, and even a novel formulation of two older chemotherapies that improves efficacy in a poor prognosis subgroup (CPX-351/liposomal daunorubicin and cytarabine).”
There’s also been a shift in treatment protocols for patients who were not fit for intensive chemotherapy. In the past, he said, it was standard “to give single-agent hypomethylating chemotherapy with azacitidine or decitabine, or in some contexts, low-dose chemotherapy with cytarabine. Today, many patients who are older and/or more frail are receiving novel therapies either alone or in combination, with greater efficacy and longer duration of response than previously seen with chemotherapy alone.”
Outcomes Improve but Remain Grim in High-Risk Cases
As a result, Dr. LeBlanc said, “we’re definitely seeing much better outcomes in AML overall. It takes some time to prove this via outcomes data assessments in a large population, but I expect that registries will show significant improvements in overall survival in the coming years, owing to the many new FDA approvals in AML”
Dr. LeBlanc highlighted national data from 2013-2019 showing that the 5-year relative survival rate from AML is 31.7%. That’s up from 26% just a few years ago, and the numbers “always lag several years behind the current year of practice,” he said. However, “the major area where we still have relatively poor outcomes and significant unmet needs remains the ‘adverse risk’ group of patients, particularly those who are older and/or not candidates for hematopoietic stem cell transplantation, which generally is the only potentially curative option for adverse-risk AML.”
He went on to say that “this risk grouping includes those with TP53 mutations, most of which confer a particularly poor prognosis. Exciting therapies that many of us were hoping would prove effective in this subgroup have unfortunately failed in recent clinical trials. We still have a lot of work to do in adverse-risk AML particularly, and also for those whose leukemia has relapsed.”
Mikkael Sekeres, MD, MS, chief of the Division of Hematology at the University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, agreed that more progress is needed, since survival rates are low even as lifespans improve. One key will be “better identifying subtypes of acute myeloid leukemia, and identifying the therapies that will benefit those people most,” he said in an interview. On the other side, it’s important to identify “when aggressive therapies aren’t going to work in somebody and maybe turn toward less-aggressive approaches so we can maximize that person’s quality of life.”
What advice do AML experts have for their colleagues? Dr. LeBlanc said “older patients are not often enough considered for allogeneic stem cell transplantation, which could potentially cure their AML when given as a consolidation treatment for those in remission. I have several patients who are healthy and in their 70s who have enormously benefited from transplants and are now being several years out from transplant with adverse risk AML and without relapse. They’ve had no significant impairments of their quality of life, including no significant graft vs. host disease.”
Dr. Sekeres highlighted the American Society of Hematology’s guidelines for treating older adults with AML, which are currently being updated. It’s crucial to order genetic testing “up front,” he said. “I’m often pleasantly surprised when genetic testing returns and reveals that I have other treatment options.”
However, it’s crucial to understand a patient’s priorities. “I’ve had patients who are 75 who say to me, ‘Do everything under the sun to get rid of my leukemia, I want to live as long as possible.’ And I’ve had patients who say, ‘I want to see as little of doctors and nurses as I can. I want you to maximize my quality of life and keep me out of the hospital.’ ”
Dr. Sekeres also noted that insurers may not cover some pill-based AML treatments such as venetoclax. “We work with our patients and assistance programs. For the most part, we’re pretty successful at getting these drugs for our patients,” he said.
In Pediatrics, Clinical Trials Are Crucial
AML in children is less well-known than in adults, since the number of cases is so small. The disease is diagnosed in about 500 children a year in the United States, according to St. Jude Children’s Research Hospital, adding, however, that AML is “the most common second cancer among children treated for other cancers.”
AML in children gained attention earlier this year when the 2-year-old daughter of a Boston Herald NFL reporter died of the disease following a bone marrow transplant and chemotherapy. Despite the agonies of her treatment, reporter Doug Kyed told a reporter that his daughter Hallie “was still able to find joy every day.”
In an interview, hematologist/oncologist Sarah K. Tasian, MD, of Children’s Hospital of Philadelphia, said researchers are discovering that pediatric AML is significantly different on from a biological perspective from adult AML. “We’ve come to understand a lot more about who these patients are, what makes these leukemias tick, and what their Achilles’ heels are. Then we can align that with the clinical trials outcome data that we have.”
About 80%-90% of pediatric patients with AML nationwide are enrolled in clinical trials, Dr. Tasian said, and an international consortium called the Children’s Oncology Group gathers data about genetics. About 60%-70% of patients will be cured, she added.
However, “we’ve kind of been stuck for about the last 20 years,” she said. “A lot of improving the survival of patients has not been because we’ve been better at chemotherapy or using new chemo, but because we’ve gotten better at supportive care, at treating infections that can be fatal.”
There haven’t been major conflicts with insurers over coverage, she said, although drug shortages are a problem, especially in relapsed AML.
As for advice to colleagues, Dr. Tasian counseled them to understand the importance of genetic testing and the expanding role of stem cell transplants. “We are now transplanting somewhere between 30% and 50% of children with AML, which is a higher rate than we used to do,” she said. The number is up thanks to genetic testing that reveals which patients are most likely to benefit.
Also, she noted, “the chemotherapy that we get to these patients is really strong, and patients have a lot of complications. Really pay attention to supportive care.”
Dr. LeBlanc reported ties with AbbVie, Agios/Servier, Astellas, BMS/Celgene, Genentech, Pfizer, Incyte, Rige, Deverra, GSK, Jazz, and Seattle Genetics. Dr. Sekeres discloses relationships with BMS and Kurome. Dr. Tasian serves as the Leukemia & Lymphoma Society Pediatric Acute Leukemia consortium clinical trials leader and works with pharmaceutical companies on clinical trials under confidentiality agreements. Dr. Brunner has no disclosures.
Are Food Emulsifiers Associated With Increased Cancer Risk?
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Democratic Lawmakers Press Pfizer on Chemotherapy Drug Shortages
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
Asparaginase in ALL: Innovative Ways to Manage Toxicity
The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.
According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.
The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.
“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.
Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”
The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”
The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.
Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”
All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.
When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”
It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.
According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.
There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.
As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”
As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.
“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”
Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”
Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.
Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”
Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.
Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”
Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.
With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”
What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”
There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”
In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”
Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).
The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.
According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.
The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.
“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.
Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”
The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”
The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.
Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”
All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.
When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”
It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.
According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.
There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.
As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”
As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.
“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”
Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”
Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.
Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”
Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.
Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”
Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.
With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”
What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”
There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”
In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”
Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).
The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.
According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.
The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.
“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.
Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”
The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”
The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.
Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”
All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.
When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”
It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.
According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.
There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.
As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”
As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.
“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”
Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”
Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.
Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”
Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.
Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”
Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.
With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”
What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”
There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”
In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”
Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).
Unleashing Our Immune Response to Quash Cancer
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.