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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.
Dana-Farber Moves to Retract, Correct Dozens of Cancer Papers Amid Allegations
News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.
Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.
In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.”
“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.
Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.”
Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors.
The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts.
A version of this article appeared on Medscape.com.
News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.
Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.
In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.”
“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.
Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.”
Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors.
The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts.
A version of this article appeared on Medscape.com.
News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.
Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.
In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.”
“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.
Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.”
Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors.
The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts.
A version of this article appeared on Medscape.com.
FDA’s Project Optimus aims to transform early cancer research
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
AT SITC 2023
Does Gemcitabine Have a Curative Role in Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia?
INTRODUCTION
Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.
CASE REPORT
A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.
DISCUSSION
Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.
CONCLUSIONS
Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.
INTRODUCTION
Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.
CASE REPORT
A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.
DISCUSSION
Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.
CONCLUSIONS
Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.
INTRODUCTION
Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.
CASE REPORT
A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.
DISCUSSION
Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.
CONCLUSIONS
Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.
Asciminib Chronic Phase Chronic Myeloid Leukemia: A Real-World Single Institution Case Series
INTRODUCTION
The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.
CASE PRESENTATIONS
(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.
DISCUSSION
In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.
CONCLUSIONS
For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.
INTRODUCTION
The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.
CASE PRESENTATIONS
(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.
DISCUSSION
In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.
CONCLUSIONS
For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.
INTRODUCTION
The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.
CASE PRESENTATIONS
(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.
DISCUSSION
In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.
CONCLUSIONS
For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.
Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
Pathophysiology
HCL develops from activated, mature memory B-cells that, in most cases, have the acquired mutation in BRAF V600E, which is present in 80% to 90% of patients with classic HCL.1,3,5 BRAF is an integral part of the RAS-BRAF-MEK-ERK cellular pathway that transmits growth factor signals from the cell surface to the nucleus to regulate cell growth and proliferation.6 Mutated BRAF V600E continuously activates BRAF kinase and downstream signaling, resulting in enhanced HCL cell survival and unchecked proliferation.3
Variant HCL (HCLv) is a separate, more virulent disease that lacks BRAF V600E mutation and CD25 expression on flow cytometry.1,7-9 Patients with HCLv have a worse prognosis and poor responses to front-line purine analogs, and a higher proportion of these patients carry the unmutated immunoglobulin heavy chain variable (IGHV) gene (54% vs 17% in HCL).1,10,11 About 30% to 50% have wild-type BRAF and activating mutations in MAP2K1, which encodes aberrant MEK downstream of BRAF.10,12
Most patients with HCL have somatic mutations in the IGHV gene.3,13,14 Patients with unmutated IGHV4-34 and wildtype BRAF have an aggressive form of the disease, even if the HCL cells express CD25 as in classic HCL.1,15 HCL in patients with unmutated IGHV is often refractory to purine analogs and these patients have poor prognosis and rapid progression.16 Other identified mutations include CDKN1B in HCL and MAP2K1 and CCNC3 in HCLv.2
Signs and Symptoms
In many cases, HCL is asymptomatic, and diagnosed when pancytopenia, monocytopenia, and leukopenia are discovered on unrelated blood work.2,3,11 Monocytopenia is a specific presentation of HCL, but not HCLv.11 Typical systemic symptoms include unexplained weight loss and extreme fatigue (80%).1,3 Other symptoms can include fever, recurrent infections, night sweats, splenomegaly and related pain or abdominal fullness, hepatomegaly, and bleeding or bruising due to thrombocytopenia.1,3 Splenomegaly is associated with advanced disease.11
Up to 30% of patients may present with autoimmune disorders such as vasculitis or psoriasis. Although skin involvement is rare with HCL, 10% to 12% of patients will have dermatologic symptoms either due to recurrent infection or autoimmune reactions.1,2 Skin reactions include localized or generalized maculopapular rash, pyoderma gangrenosum (which may be severe), and recurrent bacterial or viral skin infections.17
Diagnosis
After complete history and physical examination, a diagnosis of HCL is usually made based on flow cytometry for immunophenotyping and molecular testing for BRAF V600E (Table 1).2,17
Disease-related fibrosis may impede bone marrow aspiration, and trephine biopsy should be done to make the diagnosis.11 On morphologic examination, HCL cells are small- to medium-sized, with round, oval, or indented, well-defined nuclei. Cytoplasm is pale blue, and cells have small cytoplasmic projections (Figure 1).2,18
On flow cytometry, HCL is positive for B-cell antigens (CD19, CD20, CD22), as well as antigens specific to the disease (CD11c, CD25, CD103, CD123), and by immunohistochemistry (IHC) for cyclin D1 and annexin-A1. CD20, CD123, and CD200 are bright in HCL. The presence of T-cell marker CD103 on B-cells indicates HCL.1-3 HCLv, in contrast, is positive for CD11c and CD103, but usually negative for CD25, CD123, and annexin-A1.2,19
BRAF V600E mutation can be identified using droplet digital polymerase chain reaction (PCR), next-generation molecular sequencing, or IHC with a VE1 stain.3,11 IHC for CD20, annexin-1, and VE1 establish the diagnosis, but also are useful in determining the extent to which leukemic cells have infiltrated bone marrow.11
Differential diagnosis of HCL includes HCL variants, splenic marginal zone lymphoma, and splenic diffuse red pulp small B-cell lymphoma.7,11
Indications for Treatment and Criteria for Response
Over time, about 90% of patients with HCL will require treatment. However, not all such patients will require urgent or immediate treatment, and some can be managed with observation and close monitoring.1,11 The indications for initiating treatment generally are systemic symptoms and significant pancytopenia (Table 2).2,11
The optimal response with treatment of HCL is complete response (CR) without minimal residual disease (MRD-free), which minimizes the risk for relapse.1,11 Hematologic and molecular response is assessed using peripheral blood samples; physical examination, ultrasound, computed tomography, or magnetic resonance imaging is used to determine response in lymph nodes, spleen, or liver.1 MRD-free is defined by the absence of HCL cells by the chosen method (IHC, flow cytometry, or PCR).20 Bone marrow aspirate flow cytometry is the most sensitive standard test for MRD detection.1Table 3 summarizes response criteria for HCL.2,11
Initial Treatment of HCL
The purine nucleoside analogs (PNAs) cladribine (± rituximab) and pentostatin are widely recommended for initial treatment.1,2,11 As monotherapy, cladribine and pentostatin are considered similarly effective, with CR in 70% to 90% of patients and durations of response > 10 years.1 Adding the anti-CD20 monoclonal antibody rituximab in 8 weekly doses starting the first day of front-line cladribine (CDAR) improves remission, MRD-free rates, and duration of response (94% MRD-free at 96 months), with minimal added toxicity.21 Rituximab is often added 4 weeks after cladribine, which offers more convenience, an equally high CR rate of 100%, and a 76% MRD-free rate at 3 months.11 Bone marrow biopsy should be delayed for 4 to 6 months to allow a full response to develop with cladribine.1,11
Daily (intravenous or subcutaneous) and weekly cladribine are equally safe and effective.2,11 Pentostatin is administered intravenously every 2 weeks for 3 to 6 months, allowing time for hematologic recovery between doses.1,11 Patient factors to consider when choosing treatment include baseline neutropenia, patient preference, and comorbidities.
Toxicities of PNAs include neutropenia and fever, which typically occur during the first month of treatment and are more frequent in patients with baseline severe neutropenia; T-cell recovery may take years.1 CDAR is associated with higher transient thrombocytopenia, but faster platelet and neutrophil recovery at 4 weeks than cladribine alone.21 Both therapies are immunosuppressive. Patients should be evaluated for existing infections and watched for new infections during treatment. Control of active infection prior to treatment initiation is required.11,23
Patients with confirmed BRAF V600E mutation are candidates for vemurafenib if they are unable to tolerate a PNA, have an active infection, or would like effective vaccinations.2,23-25
Treatment at Relapse
At suspected HCL relapse, patients should be evaluated to determine whether cytopenia is due to recurrent disease or lingering effects from prior treatment. Use of successive flow cytometry over time can clarify whether symptoms are related to disease and need interventional treatment, or will resolve with additional time.1
Patients who have an HCL relapse after initial therapy with cladribine or pentostatin may be candidates for re-treatment with the same or alternate PNA plus rituximab.2 Rituximab
monotherapy has been used for patients unable to tolerate PNA but yields CR rates as low as 13%.26 Repeated courses of PNA therapy yield lower rates and durations of response with each course.1,2
For patients with primary refractory disease (less than CR with initial therapy) or relapse within 2 years of initial therapy, treatment with the BRAF V600E inhibitor vemurafenib off-label, with or without rituximab, is an option.2,5 In HCL, vemurafenib for patients with relapsed or refractory disease achieved CR in 35% and 42% in 2 small trials (N = 54). Relapse-free survival among people with CR was 19 months in 1 of the trials.27 Vemurafenib plus rituximab achieved CR in 87% of patients with relapsed or refractory HCL, and an MRD-free CR rate of 57%. Among patients with CR, 85% were relapse-free at a median follow-up of 34 months.5 Treatment with vemurafenib is not myelotoxic—an advantage for HCL patients. Adverse effects with vemurafenib are often manageable with dose reductions, if needed. A specific concern with vemurafenib is the potential development of secondary skin cancers.5,27,28
Novel Targeted Options and Recommended Use
Promising alternatives for patients with relapsed or refractory HCL include combined BRAF and MEK inhibitors and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. The concept of BRAF/MEK inhibition was validated in studies with BRAF-mutated melanoma, in which dabrafenib plus trametinib (the MEK inhibitor) improved overall survival (OS) with less toxicity and better quality of life than vemurafenib.1,29 In a phase 2 trial in HCL, dabrafenib monotherapy demonstrated an overall response rate (ORR) of 80%, including 30% CR.30 In a subsequent phase 2 trial, dabrafenib combined with trametinib was evaluated in refractory or late relapsed HCL. Among 55 enrolled patients, objective response rate was 89%, including 65.5% CR. Nine of 36 patients with CR were MRD-free. Among responding patients, duration of response was 97.7% at 24 months.31 The most common grade ≥ 3 toxicities were hyperglycemia, pyrexia, neutropenia, and pneumonia. Secondary skin cancers were seen in about 5% of patients.31
BRAF/MEK inhibitor combinations in HCL offer effective therapy with less myelosuppression than PNAs, making them useful for patients with or at risk for infection.23 Their use in HCL is off-label, as they currently are approved for treatment of BRAF-mutated melanoma and some other tumors.32 A study of encorafenib (a BRAF inhibitor) combined with binimetinib (a MEK inhibitor) is ongoing (Table 4).32
Ibrutinib interrupts B-cell receptor signaling to stop tumor cell growth. In a phase 2 trial, patients with relapsed or refractory HCL or HCLv were treated with once-daily oral ibrutinib. Best ORR was 54% (19% CR; 3% MRD-free). Despite the low CR rate, 3-year progression-free survival with ibrutinib was 73% and OS was 85%. Treatment was well-tolerated; cytopenia (including 22% grade ≥ 3 thrombocytopenia and neutropenia) and diarrhea were frequent toxicities.33
Moxetumomab pasudotox is a novel CD22-targeted antibody fused with protein toxin that interrupts protein synthesis in tumor cells.1 As treatment, it was studied in a phase 3 trial of relapsed HCL in heavily pretreated patients, and achieved a CR rate of 41%, including 36% durable CR.34 Although FDA-approved for relapsed or refractory HCL, the drug is being discontinued due to business decisions, not safety or efficacy concerns.2 It is notable that many types of B-cell lymphoma also express CD22.35
Enrollment in a clinical trial to study possible treatment advances is recommended by the National Comprehensive Cancer Network (NCCN) at first and subsequent relapses of HCL for appropriate patients.2 Figure 2 summarizes an approach to treatment choice and sequencing for patients with HCL.
Supportive Care
Patients being treated for HCL should have supportive care to manage adverse effects of their disease. Such care includes prophylaxis against herpes virus if CD4+ T cells < 200 cells/μL and other prophylactic vaccinations to hepatitis B virus, COVID-19 and Influenza. Patients with neutropeni may require broad-spectrum antibacterial prophylaxis or neutrophil growth factors if neutropenic fever develops. Blood product support is recommended if needed.2 Assessment of anti-COVID-19 antibodies is recommended to optimize immunity, particularly prior to beginning anti-CD20 antibody therapy like rituximab.23
Unmet Needs
Despite improvements in response and survival with newer therapies, not all patients with HCL benefit from these advances. Unmet needs are finding optimal treatment for patients with HCLv, despite some success with MEK inhibitors, and for patients with BRAF mutations other than V600E, who have few options beyond PNAs and rituximab.
- Kreitman RJ, Arons E. Diagnosis and treatment of hairy cell leukemia as the COVID-19 pandemic continues. Blood Rev. 2022;51:100888. doi:10.1016/j.blre.2021.100888
- National Comprehensive Cancer Network. NCCN clinical practice guideline in oncology: hairy cell leukemia. Version 1.2023. Published August 30, 2022. Accessed March 16, 2023. https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf
- Janus A, Robak T. Hairy cell leukemia. In: Li W, ed. Leukemia [Internet]. Brisbane: Exon Publications; 2022:chap3. Accessed February 16, 2023. doi:10.36255/exon-publications-leukemia-hairy-cell-leukemia
- Tadmor T, Polliack A. Epidemiology and environmental risk in hairy cell leukemia. Best Pract Res Clin Haematol. 2015;28(4):175-179. doi:10.1016/j.beha.2015.10.014
- Tiacci E, De Carolis L, Simonetti E, et al. Vemurafenib plus rituximab in refractory or relapsed hairy-cell leukemia. N Engl J Med. 2021;384(19):1810-1823. doi:10.1056/NEJMoa20312986
- Falini B, Martelli MP, Tiacci E. BRAF V600E mutation in hairy cell leukemia: from bench to bedside. Blood. 2016;128(15):1918-1927. doi:10.1182/blood-2016-07-418434
- Matutes E. Diagnostic and therapeutic challenges in hairy cell leukemia-variant: where are we in 2021? Expert Rev Hematol. 2021;14(4):355-363. doi:10.1080/17474086.2021.1908121
- Cawley JC, Burns GF, Hayhoe FG. A chronic lymphoproliferative disorder with distinctive features: a distinct variant of hairy-cell leukaemia. Leuk Res. 1980;4(6):547-559. doi:10.1016/0145-2126(80)90066-1
- Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012;119(14):3330-3332. doi:10.1182/blood-2011-09-379339
- Durham BH, Getta B, Dietrich S, et al. Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations. Blood. 2017;130(14):1644-1648. doi:10.1182/blood-2017-01-76510711
- Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with hairy cell leukemia. Blood. 2017;129(5):553-560. doi:10.1182/blood-2016-01-689422
- Waterfall JJ, Arons E, Walker RL, et al. High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias. Nat Genet. 2014;46(1):8-10. doi:10.1038/ng.2828
- Arons E, Sunshine J, Suntum T, Kreitman RJ. Somatic hypermutation and VH gene usage in hairy cell leukaemia. Br J Haematol. 2006;133(5):504-512. doi:10.1111/j.1365-2141.2006.06066.x
- Arons E, Roth L, Sapolsky J, Suntum T, Stetler-Stevenson M, Kreitman RJ. Evidence of canonical somatic hypermutation in hairy cell leukemia. Blood. 2011;117(18):4844-4851. doi:10.1182/blood-2010-11-316737
- Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood. 2009;114(21):4687-4695. doi:10.1182/blood-2009-01-201731
- Forconi F, Sozzi E, Cencini E, et al. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood. 2009;114(21):4696-4702. doi:10.1182/blood-2009-03-212449
- Robak E, Jesionek-Kupnicka D, Robak T. Skin changes in hairy cell leukemia. Ann Hematol. 2021;100(3):615-625. doi:10.1007/s00277-020-04349-z
- Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14(suppl 1):1-12. https://pubmed.ncbi.nlm.nih.gov/7820038/
- Falini B, Tiacci E, Liso A, et al. Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection of annexin A1 (ANXA1). Lancet. 2004;363(9424): 1869-1870. doi:10.1016/S0140-6736(04)16356-3
- Robak T, Robak P. Measurable residual disease in hairy cell leukemia: technical considerations and clinical significance. Front Oncol. 2022;12:976374. doi:10.3389/fonc.2022.976374
- Chihara D, Arons E, Stetler-Stevenson M, et al. Randomized phase II study of first-line cladribine with concurrent or delayed rituximab in patients with hairy cell leukemia. J Clin Oncol. 2020;38(14):1527-1538. doi:10.1200/JCO.19.02250
- Chihara D, Kantarjian H, O’Brien S, et al. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016;174(5):760-766. doi:10.1111/bjh.14129
- Grever M, Andritsos L, Banerji V, et al. Hairy cell leukemia and COVID-19 adaptation of treatment guidelines. Leukemia. 2021;35(7):1864-1872. doi:10.1038/s41375-021-01257-7
- Konrat J, Rösler W, Roiss M, et al. BRAF inhibitor treatment of classical hairy cell leukemia allows successful vaccination against SARS-CoV-2. Ann Hematol. 2023;102(2):403-406. doi:10.1007/s00277-022-05026-z
- Park JH, Shukla M, Salcedo JM, et al. First-line chemo-free therapy with the BRAF inhibitor vemurafenib combined with obinutuzumab is effective in patients with HCL. Blood. 2019;134(suppl 1):Abstract 3998. https://doi.org/10.1182/blood-2019-124478
- Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood. 2003;102(3):810-813. doi:10.1182/blood-2003-01-0014
- Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373(18):1733-1747. doi:10.1056/NEJMoa1506583
- Maitre E, Paillassa J, Troussard X. Novel targeted treatments in hairy cell leukemia and other hairy cell-like disorders. Front Oncol. 2022;12:1068981. doi:10.3389/fonc.2022.1068981
- Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16(13):1389-1398. doi:10.1016/S1470-2045(15)00087-X
- Tiacci E, De Carolis L, Simonetti E, et al. Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial. Leukemia. 2021;35(11):3314-3318. doi:10.1038/s41375-021-01210-8
- Kreitman RJ, Moreau P, Ravandi F, et al. Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. Blood. 2023;141(9):996-1006. doi:10.1182/blood.2021013658
- Adashek JJ, Menta AK, Reddy NK, Desai AP, Roszik J, Subbiah V. Tissue agnostic activity of BRAF plus MEK inhibitor in BRAF V600E-mutated tumors. Mol Cancer Ther. 2022;21(6):871-878. doi:10.1158/1535-7163.MCT-21-0950
- Rogers KA, Andritsos LA, Wei L, et al. Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood. 2021;137(25):3473-3483. doi:10.1182/blood.2020009688
- Kreitman RJ, Dearden C, Zinzani PL, et al; Study 1053 investigators. Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial. J Hematol Oncol. 2021;14(1):35. doi:10.1186/s13045-020-01004-y
- Leonard JP, Goldenberg DM. Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies. Oncogene. 2007;26(25):3704-3713. doi:10.1038/sj.onc.1210370
Pathophysiology
HCL develops from activated, mature memory B-cells that, in most cases, have the acquired mutation in BRAF V600E, which is present in 80% to 90% of patients with classic HCL.1,3,5 BRAF is an integral part of the RAS-BRAF-MEK-ERK cellular pathway that transmits growth factor signals from the cell surface to the nucleus to regulate cell growth and proliferation.6 Mutated BRAF V600E continuously activates BRAF kinase and downstream signaling, resulting in enhanced HCL cell survival and unchecked proliferation.3
Variant HCL (HCLv) is a separate, more virulent disease that lacks BRAF V600E mutation and CD25 expression on flow cytometry.1,7-9 Patients with HCLv have a worse prognosis and poor responses to front-line purine analogs, and a higher proportion of these patients carry the unmutated immunoglobulin heavy chain variable (IGHV) gene (54% vs 17% in HCL).1,10,11 About 30% to 50% have wild-type BRAF and activating mutations in MAP2K1, which encodes aberrant MEK downstream of BRAF.10,12
Most patients with HCL have somatic mutations in the IGHV gene.3,13,14 Patients with unmutated IGHV4-34 and wildtype BRAF have an aggressive form of the disease, even if the HCL cells express CD25 as in classic HCL.1,15 HCL in patients with unmutated IGHV is often refractory to purine analogs and these patients have poor prognosis and rapid progression.16 Other identified mutations include CDKN1B in HCL and MAP2K1 and CCNC3 in HCLv.2
Signs and Symptoms
In many cases, HCL is asymptomatic, and diagnosed when pancytopenia, monocytopenia, and leukopenia are discovered on unrelated blood work.2,3,11 Monocytopenia is a specific presentation of HCL, but not HCLv.11 Typical systemic symptoms include unexplained weight loss and extreme fatigue (80%).1,3 Other symptoms can include fever, recurrent infections, night sweats, splenomegaly and related pain or abdominal fullness, hepatomegaly, and bleeding or bruising due to thrombocytopenia.1,3 Splenomegaly is associated with advanced disease.11
Up to 30% of patients may present with autoimmune disorders such as vasculitis or psoriasis. Although skin involvement is rare with HCL, 10% to 12% of patients will have dermatologic symptoms either due to recurrent infection or autoimmune reactions.1,2 Skin reactions include localized or generalized maculopapular rash, pyoderma gangrenosum (which may be severe), and recurrent bacterial or viral skin infections.17
Diagnosis
After complete history and physical examination, a diagnosis of HCL is usually made based on flow cytometry for immunophenotyping and molecular testing for BRAF V600E (Table 1).2,17
Disease-related fibrosis may impede bone marrow aspiration, and trephine biopsy should be done to make the diagnosis.11 On morphologic examination, HCL cells are small- to medium-sized, with round, oval, or indented, well-defined nuclei. Cytoplasm is pale blue, and cells have small cytoplasmic projections (Figure 1).2,18
On flow cytometry, HCL is positive for B-cell antigens (CD19, CD20, CD22), as well as antigens specific to the disease (CD11c, CD25, CD103, CD123), and by immunohistochemistry (IHC) for cyclin D1 and annexin-A1. CD20, CD123, and CD200 are bright in HCL. The presence of T-cell marker CD103 on B-cells indicates HCL.1-3 HCLv, in contrast, is positive for CD11c and CD103, but usually negative for CD25, CD123, and annexin-A1.2,19
BRAF V600E mutation can be identified using droplet digital polymerase chain reaction (PCR), next-generation molecular sequencing, or IHC with a VE1 stain.3,11 IHC for CD20, annexin-1, and VE1 establish the diagnosis, but also are useful in determining the extent to which leukemic cells have infiltrated bone marrow.11
Differential diagnosis of HCL includes HCL variants, splenic marginal zone lymphoma, and splenic diffuse red pulp small B-cell lymphoma.7,11
Indications for Treatment and Criteria for Response
Over time, about 90% of patients with HCL will require treatment. However, not all such patients will require urgent or immediate treatment, and some can be managed with observation and close monitoring.1,11 The indications for initiating treatment generally are systemic symptoms and significant pancytopenia (Table 2).2,11
The optimal response with treatment of HCL is complete response (CR) without minimal residual disease (MRD-free), which minimizes the risk for relapse.1,11 Hematologic and molecular response is assessed using peripheral blood samples; physical examination, ultrasound, computed tomography, or magnetic resonance imaging is used to determine response in lymph nodes, spleen, or liver.1 MRD-free is defined by the absence of HCL cells by the chosen method (IHC, flow cytometry, or PCR).20 Bone marrow aspirate flow cytometry is the most sensitive standard test for MRD detection.1Table 3 summarizes response criteria for HCL.2,11
Initial Treatment of HCL
The purine nucleoside analogs (PNAs) cladribine (± rituximab) and pentostatin are widely recommended for initial treatment.1,2,11 As monotherapy, cladribine and pentostatin are considered similarly effective, with CR in 70% to 90% of patients and durations of response > 10 years.1 Adding the anti-CD20 monoclonal antibody rituximab in 8 weekly doses starting the first day of front-line cladribine (CDAR) improves remission, MRD-free rates, and duration of response (94% MRD-free at 96 months), with minimal added toxicity.21 Rituximab is often added 4 weeks after cladribine, which offers more convenience, an equally high CR rate of 100%, and a 76% MRD-free rate at 3 months.11 Bone marrow biopsy should be delayed for 4 to 6 months to allow a full response to develop with cladribine.1,11
Daily (intravenous or subcutaneous) and weekly cladribine are equally safe and effective.2,11 Pentostatin is administered intravenously every 2 weeks for 3 to 6 months, allowing time for hematologic recovery between doses.1,11 Patient factors to consider when choosing treatment include baseline neutropenia, patient preference, and comorbidities.
Toxicities of PNAs include neutropenia and fever, which typically occur during the first month of treatment and are more frequent in patients with baseline severe neutropenia; T-cell recovery may take years.1 CDAR is associated with higher transient thrombocytopenia, but faster platelet and neutrophil recovery at 4 weeks than cladribine alone.21 Both therapies are immunosuppressive. Patients should be evaluated for existing infections and watched for new infections during treatment. Control of active infection prior to treatment initiation is required.11,23
Patients with confirmed BRAF V600E mutation are candidates for vemurafenib if they are unable to tolerate a PNA, have an active infection, or would like effective vaccinations.2,23-25
Treatment at Relapse
At suspected HCL relapse, patients should be evaluated to determine whether cytopenia is due to recurrent disease or lingering effects from prior treatment. Use of successive flow cytometry over time can clarify whether symptoms are related to disease and need interventional treatment, or will resolve with additional time.1
Patients who have an HCL relapse after initial therapy with cladribine or pentostatin may be candidates for re-treatment with the same or alternate PNA plus rituximab.2 Rituximab
monotherapy has been used for patients unable to tolerate PNA but yields CR rates as low as 13%.26 Repeated courses of PNA therapy yield lower rates and durations of response with each course.1,2
For patients with primary refractory disease (less than CR with initial therapy) or relapse within 2 years of initial therapy, treatment with the BRAF V600E inhibitor vemurafenib off-label, with or without rituximab, is an option.2,5 In HCL, vemurafenib for patients with relapsed or refractory disease achieved CR in 35% and 42% in 2 small trials (N = 54). Relapse-free survival among people with CR was 19 months in 1 of the trials.27 Vemurafenib plus rituximab achieved CR in 87% of patients with relapsed or refractory HCL, and an MRD-free CR rate of 57%. Among patients with CR, 85% were relapse-free at a median follow-up of 34 months.5 Treatment with vemurafenib is not myelotoxic—an advantage for HCL patients. Adverse effects with vemurafenib are often manageable with dose reductions, if needed. A specific concern with vemurafenib is the potential development of secondary skin cancers.5,27,28
Novel Targeted Options and Recommended Use
Promising alternatives for patients with relapsed or refractory HCL include combined BRAF and MEK inhibitors and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. The concept of BRAF/MEK inhibition was validated in studies with BRAF-mutated melanoma, in which dabrafenib plus trametinib (the MEK inhibitor) improved overall survival (OS) with less toxicity and better quality of life than vemurafenib.1,29 In a phase 2 trial in HCL, dabrafenib monotherapy demonstrated an overall response rate (ORR) of 80%, including 30% CR.30 In a subsequent phase 2 trial, dabrafenib combined with trametinib was evaluated in refractory or late relapsed HCL. Among 55 enrolled patients, objective response rate was 89%, including 65.5% CR. Nine of 36 patients with CR were MRD-free. Among responding patients, duration of response was 97.7% at 24 months.31 The most common grade ≥ 3 toxicities were hyperglycemia, pyrexia, neutropenia, and pneumonia. Secondary skin cancers were seen in about 5% of patients.31
BRAF/MEK inhibitor combinations in HCL offer effective therapy with less myelosuppression than PNAs, making them useful for patients with or at risk for infection.23 Their use in HCL is off-label, as they currently are approved for treatment of BRAF-mutated melanoma and some other tumors.32 A study of encorafenib (a BRAF inhibitor) combined with binimetinib (a MEK inhibitor) is ongoing (Table 4).32
Ibrutinib interrupts B-cell receptor signaling to stop tumor cell growth. In a phase 2 trial, patients with relapsed or refractory HCL or HCLv were treated with once-daily oral ibrutinib. Best ORR was 54% (19% CR; 3% MRD-free). Despite the low CR rate, 3-year progression-free survival with ibrutinib was 73% and OS was 85%. Treatment was well-tolerated; cytopenia (including 22% grade ≥ 3 thrombocytopenia and neutropenia) and diarrhea were frequent toxicities.33
Moxetumomab pasudotox is a novel CD22-targeted antibody fused with protein toxin that interrupts protein synthesis in tumor cells.1 As treatment, it was studied in a phase 3 trial of relapsed HCL in heavily pretreated patients, and achieved a CR rate of 41%, including 36% durable CR.34 Although FDA-approved for relapsed or refractory HCL, the drug is being discontinued due to business decisions, not safety or efficacy concerns.2 It is notable that many types of B-cell lymphoma also express CD22.35
Enrollment in a clinical trial to study possible treatment advances is recommended by the National Comprehensive Cancer Network (NCCN) at first and subsequent relapses of HCL for appropriate patients.2 Figure 2 summarizes an approach to treatment choice and sequencing for patients with HCL.
Supportive Care
Patients being treated for HCL should have supportive care to manage adverse effects of their disease. Such care includes prophylaxis against herpes virus if CD4+ T cells < 200 cells/μL and other prophylactic vaccinations to hepatitis B virus, COVID-19 and Influenza. Patients with neutropeni may require broad-spectrum antibacterial prophylaxis or neutrophil growth factors if neutropenic fever develops. Blood product support is recommended if needed.2 Assessment of anti-COVID-19 antibodies is recommended to optimize immunity, particularly prior to beginning anti-CD20 antibody therapy like rituximab.23
Unmet Needs
Despite improvements in response and survival with newer therapies, not all patients with HCL benefit from these advances. Unmet needs are finding optimal treatment for patients with HCLv, despite some success with MEK inhibitors, and for patients with BRAF mutations other than V600E, who have few options beyond PNAs and rituximab.
Pathophysiology
HCL develops from activated, mature memory B-cells that, in most cases, have the acquired mutation in BRAF V600E, which is present in 80% to 90% of patients with classic HCL.1,3,5 BRAF is an integral part of the RAS-BRAF-MEK-ERK cellular pathway that transmits growth factor signals from the cell surface to the nucleus to regulate cell growth and proliferation.6 Mutated BRAF V600E continuously activates BRAF kinase and downstream signaling, resulting in enhanced HCL cell survival and unchecked proliferation.3
Variant HCL (HCLv) is a separate, more virulent disease that lacks BRAF V600E mutation and CD25 expression on flow cytometry.1,7-9 Patients with HCLv have a worse prognosis and poor responses to front-line purine analogs, and a higher proportion of these patients carry the unmutated immunoglobulin heavy chain variable (IGHV) gene (54% vs 17% in HCL).1,10,11 About 30% to 50% have wild-type BRAF and activating mutations in MAP2K1, which encodes aberrant MEK downstream of BRAF.10,12
Most patients with HCL have somatic mutations in the IGHV gene.3,13,14 Patients with unmutated IGHV4-34 and wildtype BRAF have an aggressive form of the disease, even if the HCL cells express CD25 as in classic HCL.1,15 HCL in patients with unmutated IGHV is often refractory to purine analogs and these patients have poor prognosis and rapid progression.16 Other identified mutations include CDKN1B in HCL and MAP2K1 and CCNC3 in HCLv.2
Signs and Symptoms
In many cases, HCL is asymptomatic, and diagnosed when pancytopenia, monocytopenia, and leukopenia are discovered on unrelated blood work.2,3,11 Monocytopenia is a specific presentation of HCL, but not HCLv.11 Typical systemic symptoms include unexplained weight loss and extreme fatigue (80%).1,3 Other symptoms can include fever, recurrent infections, night sweats, splenomegaly and related pain or abdominal fullness, hepatomegaly, and bleeding or bruising due to thrombocytopenia.1,3 Splenomegaly is associated with advanced disease.11
Up to 30% of patients may present with autoimmune disorders such as vasculitis or psoriasis. Although skin involvement is rare with HCL, 10% to 12% of patients will have dermatologic symptoms either due to recurrent infection or autoimmune reactions.1,2 Skin reactions include localized or generalized maculopapular rash, pyoderma gangrenosum (which may be severe), and recurrent bacterial or viral skin infections.17
Diagnosis
After complete history and physical examination, a diagnosis of HCL is usually made based on flow cytometry for immunophenotyping and molecular testing for BRAF V600E (Table 1).2,17
Disease-related fibrosis may impede bone marrow aspiration, and trephine biopsy should be done to make the diagnosis.11 On morphologic examination, HCL cells are small- to medium-sized, with round, oval, or indented, well-defined nuclei. Cytoplasm is pale blue, and cells have small cytoplasmic projections (Figure 1).2,18
On flow cytometry, HCL is positive for B-cell antigens (CD19, CD20, CD22), as well as antigens specific to the disease (CD11c, CD25, CD103, CD123), and by immunohistochemistry (IHC) for cyclin D1 and annexin-A1. CD20, CD123, and CD200 are bright in HCL. The presence of T-cell marker CD103 on B-cells indicates HCL.1-3 HCLv, in contrast, is positive for CD11c and CD103, but usually negative for CD25, CD123, and annexin-A1.2,19
BRAF V600E mutation can be identified using droplet digital polymerase chain reaction (PCR), next-generation molecular sequencing, or IHC with a VE1 stain.3,11 IHC for CD20, annexin-1, and VE1 establish the diagnosis, but also are useful in determining the extent to which leukemic cells have infiltrated bone marrow.11
Differential diagnosis of HCL includes HCL variants, splenic marginal zone lymphoma, and splenic diffuse red pulp small B-cell lymphoma.7,11
Indications for Treatment and Criteria for Response
Over time, about 90% of patients with HCL will require treatment. However, not all such patients will require urgent or immediate treatment, and some can be managed with observation and close monitoring.1,11 The indications for initiating treatment generally are systemic symptoms and significant pancytopenia (Table 2).2,11
The optimal response with treatment of HCL is complete response (CR) without minimal residual disease (MRD-free), which minimizes the risk for relapse.1,11 Hematologic and molecular response is assessed using peripheral blood samples; physical examination, ultrasound, computed tomography, or magnetic resonance imaging is used to determine response in lymph nodes, spleen, or liver.1 MRD-free is defined by the absence of HCL cells by the chosen method (IHC, flow cytometry, or PCR).20 Bone marrow aspirate flow cytometry is the most sensitive standard test for MRD detection.1Table 3 summarizes response criteria for HCL.2,11
Initial Treatment of HCL
The purine nucleoside analogs (PNAs) cladribine (± rituximab) and pentostatin are widely recommended for initial treatment.1,2,11 As monotherapy, cladribine and pentostatin are considered similarly effective, with CR in 70% to 90% of patients and durations of response > 10 years.1 Adding the anti-CD20 monoclonal antibody rituximab in 8 weekly doses starting the first day of front-line cladribine (CDAR) improves remission, MRD-free rates, and duration of response (94% MRD-free at 96 months), with minimal added toxicity.21 Rituximab is often added 4 weeks after cladribine, which offers more convenience, an equally high CR rate of 100%, and a 76% MRD-free rate at 3 months.11 Bone marrow biopsy should be delayed for 4 to 6 months to allow a full response to develop with cladribine.1,11
Daily (intravenous or subcutaneous) and weekly cladribine are equally safe and effective.2,11 Pentostatin is administered intravenously every 2 weeks for 3 to 6 months, allowing time for hematologic recovery between doses.1,11 Patient factors to consider when choosing treatment include baseline neutropenia, patient preference, and comorbidities.
Toxicities of PNAs include neutropenia and fever, which typically occur during the first month of treatment and are more frequent in patients with baseline severe neutropenia; T-cell recovery may take years.1 CDAR is associated with higher transient thrombocytopenia, but faster platelet and neutrophil recovery at 4 weeks than cladribine alone.21 Both therapies are immunosuppressive. Patients should be evaluated for existing infections and watched for new infections during treatment. Control of active infection prior to treatment initiation is required.11,23
Patients with confirmed BRAF V600E mutation are candidates for vemurafenib if they are unable to tolerate a PNA, have an active infection, or would like effective vaccinations.2,23-25
Treatment at Relapse
At suspected HCL relapse, patients should be evaluated to determine whether cytopenia is due to recurrent disease or lingering effects from prior treatment. Use of successive flow cytometry over time can clarify whether symptoms are related to disease and need interventional treatment, or will resolve with additional time.1
Patients who have an HCL relapse after initial therapy with cladribine or pentostatin may be candidates for re-treatment with the same or alternate PNA plus rituximab.2 Rituximab
monotherapy has been used for patients unable to tolerate PNA but yields CR rates as low as 13%.26 Repeated courses of PNA therapy yield lower rates and durations of response with each course.1,2
For patients with primary refractory disease (less than CR with initial therapy) or relapse within 2 years of initial therapy, treatment with the BRAF V600E inhibitor vemurafenib off-label, with or without rituximab, is an option.2,5 In HCL, vemurafenib for patients with relapsed or refractory disease achieved CR in 35% and 42% in 2 small trials (N = 54). Relapse-free survival among people with CR was 19 months in 1 of the trials.27 Vemurafenib plus rituximab achieved CR in 87% of patients with relapsed or refractory HCL, and an MRD-free CR rate of 57%. Among patients with CR, 85% were relapse-free at a median follow-up of 34 months.5 Treatment with vemurafenib is not myelotoxic—an advantage for HCL patients. Adverse effects with vemurafenib are often manageable with dose reductions, if needed. A specific concern with vemurafenib is the potential development of secondary skin cancers.5,27,28
Novel Targeted Options and Recommended Use
Promising alternatives for patients with relapsed or refractory HCL include combined BRAF and MEK inhibitors and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. The concept of BRAF/MEK inhibition was validated in studies with BRAF-mutated melanoma, in which dabrafenib plus trametinib (the MEK inhibitor) improved overall survival (OS) with less toxicity and better quality of life than vemurafenib.1,29 In a phase 2 trial in HCL, dabrafenib monotherapy demonstrated an overall response rate (ORR) of 80%, including 30% CR.30 In a subsequent phase 2 trial, dabrafenib combined with trametinib was evaluated in refractory or late relapsed HCL. Among 55 enrolled patients, objective response rate was 89%, including 65.5% CR. Nine of 36 patients with CR were MRD-free. Among responding patients, duration of response was 97.7% at 24 months.31 The most common grade ≥ 3 toxicities were hyperglycemia, pyrexia, neutropenia, and pneumonia. Secondary skin cancers were seen in about 5% of patients.31
BRAF/MEK inhibitor combinations in HCL offer effective therapy with less myelosuppression than PNAs, making them useful for patients with or at risk for infection.23 Their use in HCL is off-label, as they currently are approved for treatment of BRAF-mutated melanoma and some other tumors.32 A study of encorafenib (a BRAF inhibitor) combined with binimetinib (a MEK inhibitor) is ongoing (Table 4).32
Ibrutinib interrupts B-cell receptor signaling to stop tumor cell growth. In a phase 2 trial, patients with relapsed or refractory HCL or HCLv were treated with once-daily oral ibrutinib. Best ORR was 54% (19% CR; 3% MRD-free). Despite the low CR rate, 3-year progression-free survival with ibrutinib was 73% and OS was 85%. Treatment was well-tolerated; cytopenia (including 22% grade ≥ 3 thrombocytopenia and neutropenia) and diarrhea were frequent toxicities.33
Moxetumomab pasudotox is a novel CD22-targeted antibody fused with protein toxin that interrupts protein synthesis in tumor cells.1 As treatment, it was studied in a phase 3 trial of relapsed HCL in heavily pretreated patients, and achieved a CR rate of 41%, including 36% durable CR.34 Although FDA-approved for relapsed or refractory HCL, the drug is being discontinued due to business decisions, not safety or efficacy concerns.2 It is notable that many types of B-cell lymphoma also express CD22.35
Enrollment in a clinical trial to study possible treatment advances is recommended by the National Comprehensive Cancer Network (NCCN) at first and subsequent relapses of HCL for appropriate patients.2 Figure 2 summarizes an approach to treatment choice and sequencing for patients with HCL.
Supportive Care
Patients being treated for HCL should have supportive care to manage adverse effects of their disease. Such care includes prophylaxis against herpes virus if CD4+ T cells < 200 cells/μL and other prophylactic vaccinations to hepatitis B virus, COVID-19 and Influenza. Patients with neutropeni may require broad-spectrum antibacterial prophylaxis or neutrophil growth factors if neutropenic fever develops. Blood product support is recommended if needed.2 Assessment of anti-COVID-19 antibodies is recommended to optimize immunity, particularly prior to beginning anti-CD20 antibody therapy like rituximab.23
Unmet Needs
Despite improvements in response and survival with newer therapies, not all patients with HCL benefit from these advances. Unmet needs are finding optimal treatment for patients with HCLv, despite some success with MEK inhibitors, and for patients with BRAF mutations other than V600E, who have few options beyond PNAs and rituximab.
- Kreitman RJ, Arons E. Diagnosis and treatment of hairy cell leukemia as the COVID-19 pandemic continues. Blood Rev. 2022;51:100888. doi:10.1016/j.blre.2021.100888
- National Comprehensive Cancer Network. NCCN clinical practice guideline in oncology: hairy cell leukemia. Version 1.2023. Published August 30, 2022. Accessed March 16, 2023. https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf
- Janus A, Robak T. Hairy cell leukemia. In: Li W, ed. Leukemia [Internet]. Brisbane: Exon Publications; 2022:chap3. Accessed February 16, 2023. doi:10.36255/exon-publications-leukemia-hairy-cell-leukemia
- Tadmor T, Polliack A. Epidemiology and environmental risk in hairy cell leukemia. Best Pract Res Clin Haematol. 2015;28(4):175-179. doi:10.1016/j.beha.2015.10.014
- Tiacci E, De Carolis L, Simonetti E, et al. Vemurafenib plus rituximab in refractory or relapsed hairy-cell leukemia. N Engl J Med. 2021;384(19):1810-1823. doi:10.1056/NEJMoa20312986
- Falini B, Martelli MP, Tiacci E. BRAF V600E mutation in hairy cell leukemia: from bench to bedside. Blood. 2016;128(15):1918-1927. doi:10.1182/blood-2016-07-418434
- Matutes E. Diagnostic and therapeutic challenges in hairy cell leukemia-variant: where are we in 2021? Expert Rev Hematol. 2021;14(4):355-363. doi:10.1080/17474086.2021.1908121
- Cawley JC, Burns GF, Hayhoe FG. A chronic lymphoproliferative disorder with distinctive features: a distinct variant of hairy-cell leukaemia. Leuk Res. 1980;4(6):547-559. doi:10.1016/0145-2126(80)90066-1
- Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012;119(14):3330-3332. doi:10.1182/blood-2011-09-379339
- Durham BH, Getta B, Dietrich S, et al. Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations. Blood. 2017;130(14):1644-1648. doi:10.1182/blood-2017-01-76510711
- Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with hairy cell leukemia. Blood. 2017;129(5):553-560. doi:10.1182/blood-2016-01-689422
- Waterfall JJ, Arons E, Walker RL, et al. High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias. Nat Genet. 2014;46(1):8-10. doi:10.1038/ng.2828
- Arons E, Sunshine J, Suntum T, Kreitman RJ. Somatic hypermutation and VH gene usage in hairy cell leukaemia. Br J Haematol. 2006;133(5):504-512. doi:10.1111/j.1365-2141.2006.06066.x
- Arons E, Roth L, Sapolsky J, Suntum T, Stetler-Stevenson M, Kreitman RJ. Evidence of canonical somatic hypermutation in hairy cell leukemia. Blood. 2011;117(18):4844-4851. doi:10.1182/blood-2010-11-316737
- Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood. 2009;114(21):4687-4695. doi:10.1182/blood-2009-01-201731
- Forconi F, Sozzi E, Cencini E, et al. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood. 2009;114(21):4696-4702. doi:10.1182/blood-2009-03-212449
- Robak E, Jesionek-Kupnicka D, Robak T. Skin changes in hairy cell leukemia. Ann Hematol. 2021;100(3):615-625. doi:10.1007/s00277-020-04349-z
- Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14(suppl 1):1-12. https://pubmed.ncbi.nlm.nih.gov/7820038/
- Falini B, Tiacci E, Liso A, et al. Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection of annexin A1 (ANXA1). Lancet. 2004;363(9424): 1869-1870. doi:10.1016/S0140-6736(04)16356-3
- Robak T, Robak P. Measurable residual disease in hairy cell leukemia: technical considerations and clinical significance. Front Oncol. 2022;12:976374. doi:10.3389/fonc.2022.976374
- Chihara D, Arons E, Stetler-Stevenson M, et al. Randomized phase II study of first-line cladribine with concurrent or delayed rituximab in patients with hairy cell leukemia. J Clin Oncol. 2020;38(14):1527-1538. doi:10.1200/JCO.19.02250
- Chihara D, Kantarjian H, O’Brien S, et al. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016;174(5):760-766. doi:10.1111/bjh.14129
- Grever M, Andritsos L, Banerji V, et al. Hairy cell leukemia and COVID-19 adaptation of treatment guidelines. Leukemia. 2021;35(7):1864-1872. doi:10.1038/s41375-021-01257-7
- Konrat J, Rösler W, Roiss M, et al. BRAF inhibitor treatment of classical hairy cell leukemia allows successful vaccination against SARS-CoV-2. Ann Hematol. 2023;102(2):403-406. doi:10.1007/s00277-022-05026-z
- Park JH, Shukla M, Salcedo JM, et al. First-line chemo-free therapy with the BRAF inhibitor vemurafenib combined with obinutuzumab is effective in patients with HCL. Blood. 2019;134(suppl 1):Abstract 3998. https://doi.org/10.1182/blood-2019-124478
- Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood. 2003;102(3):810-813. doi:10.1182/blood-2003-01-0014
- Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373(18):1733-1747. doi:10.1056/NEJMoa1506583
- Maitre E, Paillassa J, Troussard X. Novel targeted treatments in hairy cell leukemia and other hairy cell-like disorders. Front Oncol. 2022;12:1068981. doi:10.3389/fonc.2022.1068981
- Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16(13):1389-1398. doi:10.1016/S1470-2045(15)00087-X
- Tiacci E, De Carolis L, Simonetti E, et al. Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial. Leukemia. 2021;35(11):3314-3318. doi:10.1038/s41375-021-01210-8
- Kreitman RJ, Moreau P, Ravandi F, et al. Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. Blood. 2023;141(9):996-1006. doi:10.1182/blood.2021013658
- Adashek JJ, Menta AK, Reddy NK, Desai AP, Roszik J, Subbiah V. Tissue agnostic activity of BRAF plus MEK inhibitor in BRAF V600E-mutated tumors. Mol Cancer Ther. 2022;21(6):871-878. doi:10.1158/1535-7163.MCT-21-0950
- Rogers KA, Andritsos LA, Wei L, et al. Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood. 2021;137(25):3473-3483. doi:10.1182/blood.2020009688
- Kreitman RJ, Dearden C, Zinzani PL, et al; Study 1053 investigators. Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial. J Hematol Oncol. 2021;14(1):35. doi:10.1186/s13045-020-01004-y
- Leonard JP, Goldenberg DM. Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies. Oncogene. 2007;26(25):3704-3713. doi:10.1038/sj.onc.1210370
- Kreitman RJ, Arons E. Diagnosis and treatment of hairy cell leukemia as the COVID-19 pandemic continues. Blood Rev. 2022;51:100888. doi:10.1016/j.blre.2021.100888
- National Comprehensive Cancer Network. NCCN clinical practice guideline in oncology: hairy cell leukemia. Version 1.2023. Published August 30, 2022. Accessed March 16, 2023. https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf
- Janus A, Robak T. Hairy cell leukemia. In: Li W, ed. Leukemia [Internet]. Brisbane: Exon Publications; 2022:chap3. Accessed February 16, 2023. doi:10.36255/exon-publications-leukemia-hairy-cell-leukemia
- Tadmor T, Polliack A. Epidemiology and environmental risk in hairy cell leukemia. Best Pract Res Clin Haematol. 2015;28(4):175-179. doi:10.1016/j.beha.2015.10.014
- Tiacci E, De Carolis L, Simonetti E, et al. Vemurafenib plus rituximab in refractory or relapsed hairy-cell leukemia. N Engl J Med. 2021;384(19):1810-1823. doi:10.1056/NEJMoa20312986
- Falini B, Martelli MP, Tiacci E. BRAF V600E mutation in hairy cell leukemia: from bench to bedside. Blood. 2016;128(15):1918-1927. doi:10.1182/blood-2016-07-418434
- Matutes E. Diagnostic and therapeutic challenges in hairy cell leukemia-variant: where are we in 2021? Expert Rev Hematol. 2021;14(4):355-363. doi:10.1080/17474086.2021.1908121
- Cawley JC, Burns GF, Hayhoe FG. A chronic lymphoproliferative disorder with distinctive features: a distinct variant of hairy-cell leukaemia. Leuk Res. 1980;4(6):547-559. doi:10.1016/0145-2126(80)90066-1
- Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012;119(14):3330-3332. doi:10.1182/blood-2011-09-379339
- Durham BH, Getta B, Dietrich S, et al. Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations. Blood. 2017;130(14):1644-1648. doi:10.1182/blood-2017-01-76510711
- Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with hairy cell leukemia. Blood. 2017;129(5):553-560. doi:10.1182/blood-2016-01-689422
- Waterfall JJ, Arons E, Walker RL, et al. High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias. Nat Genet. 2014;46(1):8-10. doi:10.1038/ng.2828
- Arons E, Sunshine J, Suntum T, Kreitman RJ. Somatic hypermutation and VH gene usage in hairy cell leukaemia. Br J Haematol. 2006;133(5):504-512. doi:10.1111/j.1365-2141.2006.06066.x
- Arons E, Roth L, Sapolsky J, Suntum T, Stetler-Stevenson M, Kreitman RJ. Evidence of canonical somatic hypermutation in hairy cell leukemia. Blood. 2011;117(18):4844-4851. doi:10.1182/blood-2010-11-316737
- Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood. 2009;114(21):4687-4695. doi:10.1182/blood-2009-01-201731
- Forconi F, Sozzi E, Cencini E, et al. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood. 2009;114(21):4696-4702. doi:10.1182/blood-2009-03-212449
- Robak E, Jesionek-Kupnicka D, Robak T. Skin changes in hairy cell leukemia. Ann Hematol. 2021;100(3):615-625. doi:10.1007/s00277-020-04349-z
- Bouroncle BA. Thirty-five years in the progress of hairy cell leukemia. Leuk Lymphoma. 1994;14(suppl 1):1-12. https://pubmed.ncbi.nlm.nih.gov/7820038/
- Falini B, Tiacci E, Liso A, et al. Simple diagnostic assay for hairy cell leukaemia by immunocytochemical detection of annexin A1 (ANXA1). Lancet. 2004;363(9424): 1869-1870. doi:10.1016/S0140-6736(04)16356-3
- Robak T, Robak P. Measurable residual disease in hairy cell leukemia: technical considerations and clinical significance. Front Oncol. 2022;12:976374. doi:10.3389/fonc.2022.976374
- Chihara D, Arons E, Stetler-Stevenson M, et al. Randomized phase II study of first-line cladribine with concurrent or delayed rituximab in patients with hairy cell leukemia. J Clin Oncol. 2020;38(14):1527-1538. doi:10.1200/JCO.19.02250
- Chihara D, Kantarjian H, O’Brien S, et al. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016;174(5):760-766. doi:10.1111/bjh.14129
- Grever M, Andritsos L, Banerji V, et al. Hairy cell leukemia and COVID-19 adaptation of treatment guidelines. Leukemia. 2021;35(7):1864-1872. doi:10.1038/s41375-021-01257-7
- Konrat J, Rösler W, Roiss M, et al. BRAF inhibitor treatment of classical hairy cell leukemia allows successful vaccination against SARS-CoV-2. Ann Hematol. 2023;102(2):403-406. doi:10.1007/s00277-022-05026-z
- Park JH, Shukla M, Salcedo JM, et al. First-line chemo-free therapy with the BRAF inhibitor vemurafenib combined with obinutuzumab is effective in patients with HCL. Blood. 2019;134(suppl 1):Abstract 3998. https://doi.org/10.1182/blood-2019-124478
- Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood. 2003;102(3):810-813. doi:10.1182/blood-2003-01-0014
- Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373(18):1733-1747. doi:10.1056/NEJMoa1506583
- Maitre E, Paillassa J, Troussard X. Novel targeted treatments in hairy cell leukemia and other hairy cell-like disorders. Front Oncol. 2022;12:1068981. doi:10.3389/fonc.2022.1068981
- Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16(13):1389-1398. doi:10.1016/S1470-2045(15)00087-X
- Tiacci E, De Carolis L, Simonetti E, et al. Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial. Leukemia. 2021;35(11):3314-3318. doi:10.1038/s41375-021-01210-8
- Kreitman RJ, Moreau P, Ravandi F, et al. Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. Blood. 2023;141(9):996-1006. doi:10.1182/blood.2021013658
- Adashek JJ, Menta AK, Reddy NK, Desai AP, Roszik J, Subbiah V. Tissue agnostic activity of BRAF plus MEK inhibitor in BRAF V600E-mutated tumors. Mol Cancer Ther. 2022;21(6):871-878. doi:10.1158/1535-7163.MCT-21-0950
- Rogers KA, Andritsos LA, Wei L, et al. Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood. 2021;137(25):3473-3483. doi:10.1182/blood.2020009688
- Kreitman RJ, Dearden C, Zinzani PL, et al; Study 1053 investigators. Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial. J Hematol Oncol. 2021;14(1):35. doi:10.1186/s13045-020-01004-y
- Leonard JP, Goldenberg DM. Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies. Oncogene. 2007;26(25):3704-3713. doi:10.1038/sj.onc.1210370
Multiprong strategy makes clinical trials less White
CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.
For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.
When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.
There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.
a period that included a pandemic-induced hiatus in clinical trials in general.
Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.
During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.
Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.
“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.
The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
Program to increase underrepresented patient accrual
The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.
“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.
“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
What works?
The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”
“I’m going to violate the rules of your question,” Dr. Paskett replied.
“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.
She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.
Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:
- Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
- Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
- Translation of informational materials for patients.
- Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
- Real-time monitoring of accrual demographics by the Alliance and at the trial site.
- Closing protocol enrollment to majority populations.
- Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.
The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.
For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.
When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.
There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.
a period that included a pandemic-induced hiatus in clinical trials in general.
Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.
During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.
Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.
“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.
The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
Program to increase underrepresented patient accrual
The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.
“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.
“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
What works?
The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”
“I’m going to violate the rules of your question,” Dr. Paskett replied.
“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.
She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.
Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:
- Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
- Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
- Translation of informational materials for patients.
- Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
- Real-time monitoring of accrual demographics by the Alliance and at the trial site.
- Closing protocol enrollment to majority populations.
- Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.
The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.
For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.
When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.
There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.
a period that included a pandemic-induced hiatus in clinical trials in general.
Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.
During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.
Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.
“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.
The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
Program to increase underrepresented patient accrual
The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.
“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.
“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
What works?
The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”
“I’m going to violate the rules of your question,” Dr. Paskett replied.
“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.
She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.
Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:
- Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
- Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
- Translation of informational materials for patients.
- Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
- Real-time monitoring of accrual demographics by the Alliance and at the trial site.
- Closing protocol enrollment to majority populations.
- Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.
The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
AT ASCO 2023
CBSM phone app eases anxiety, depression in cancer patients
CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.
Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.
A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.
In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).
However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.
The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.
“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.
“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
Impressive and elegant
“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.
“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.
CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.
To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.
Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.
They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
High-quality control
Ms. Ramiller said that the control app set “a high bar.”
“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.
A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.
The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).
CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)
An extension study of the durability of the effects at 3 and 6 months is underway.
The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.
“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”
The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
A version of this article originally appeared on Medscape.com.
CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.
Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.
A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.
In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).
However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.
The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.
“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.
“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
Impressive and elegant
“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.
“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.
CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.
To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.
Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.
They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
High-quality control
Ms. Ramiller said that the control app set “a high bar.”
“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.
A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.
The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).
CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)
An extension study of the durability of the effects at 3 and 6 months is underway.
The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.
“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”
The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
A version of this article originally appeared on Medscape.com.
CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.
Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.
A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.
In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).
However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.
The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.
“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.
“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
Impressive and elegant
“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.
“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.
CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.
To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.
Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.
They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
High-quality control
Ms. Ramiller said that the control app set “a high bar.”
“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.
A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.
The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).
CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)
An extension study of the durability of the effects at 3 and 6 months is underway.
The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.
“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”
The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
A version of this article originally appeared on Medscape.com.
AT ASCO 2023
Huge underuse of germline testing for cancer patients
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
AT ASCO 2023