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AML: Genetic Testing Unlocks Hope
For adult patients, “we’ve seen a series of remarkable and well-overdue advances in a space that had not changed much over the prior decades,” hematologist/oncologist Thomas William LeBlanc, MD, associate professor of medicine at Duke University School of Medicine, Durham, North Carolina, said in an interview.
According to the National Cancer Institute, AML will be newly diagnosed in 20,800 patients in 2024, at a median age of 69, and will cause 11,220 deaths. As many as 70% of adult patients will reach complete remission, and 45% of those will live for more than 3 years and potentially be cured. As for children, the Leukemia & Lymphoma Society says the 5-year survival rate from 2012-2018 was 69% for those under 15 years old.
As the American Cancer Society notes, the goal of AML treatment “is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way.”
Chemotherapy Strategies Shift Over Time
In terms of the treatment of adults with AML, “targeted therapies, in addition to the expanding role of venetoclax, has really altered our approach to AML from diagnosis, including after relapse, and later in the disease,” hematologist/oncologist Andrew M. Brunner, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, said in an interview. “The ability to explore these options as monotherapy and in novel combinations has dramatically expanded our treatment options.”
Much depends on the underlying genetic profile of the disease, he said. “There certainly have been gains in patient survival in AML, but those improvements remain fairly heterogeneous and dependent on the underlying genetic profile of the disease. For instance, advances in FLT3- and IDH1/2-mutated AML are a direct result of the improvements in targeted therapies directed at these mutations. Similarly, some molecular and cytogenetic subtypes of AML are particularly responsive to venetoclax-based regimens, and these regimens have been expanded to previously undertreated populations, particularly those over age 60.”
Specifically, Dr. LeBlanc said, the Food and Drug Administration has approved “3 different FLT3 inhibitors, 2 IDH1 inhibitors, 1 IDH2 inhibitor, a BCL-2 inhibitor, a smoothened/hedgehog pathway inhibitor, an oral maintenance chemotherapy/hypomethylating agent (CC-486/oral azacitidine), a CD33-targeting antibody-drug conjugate, and even a novel formulation of two older chemotherapies that improves efficacy in a poor prognosis subgroup (CPX-351/liposomal daunorubicin and cytarabine).”
There’s also been a shift in treatment protocols for patients who were not fit for intensive chemotherapy. In the past, he said, it was standard “to give single-agent hypomethylating chemotherapy with azacitidine or decitabine, or in some contexts, low-dose chemotherapy with cytarabine. Today, many patients who are older and/or more frail are receiving novel therapies either alone or in combination, with greater efficacy and longer duration of response than previously seen with chemotherapy alone.”
Outcomes Improve but Remain Grim in High-Risk Cases
As a result, Dr. LeBlanc said, “we’re definitely seeing much better outcomes in AML overall. It takes some time to prove this via outcomes data assessments in a large population, but I expect that registries will show significant improvements in overall survival in the coming years, owing to the many new FDA approvals in AML”
Dr. LeBlanc highlighted national data from 2013-2019 showing that the 5-year relative survival rate from AML is 31.7%. That’s up from 26% just a few years ago, and the numbers “always lag several years behind the current year of practice,” he said. However, “the major area where we still have relatively poor outcomes and significant unmet needs remains the ‘adverse risk’ group of patients, particularly those who are older and/or not candidates for hematopoietic stem cell transplantation, which generally is the only potentially curative option for adverse-risk AML.”
He went on to say that “this risk grouping includes those with TP53 mutations, most of which confer a particularly poor prognosis. Exciting therapies that many of us were hoping would prove effective in this subgroup have unfortunately failed in recent clinical trials. We still have a lot of work to do in adverse-risk AML particularly, and also for those whose leukemia has relapsed.”
Mikkael Sekeres, MD, MS, chief of the Division of Hematology at the University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, agreed that more progress is needed, since survival rates are low even as lifespans improve. One key will be “better identifying subtypes of acute myeloid leukemia, and identifying the therapies that will benefit those people most,” he said in an interview. On the other side, it’s important to identify “when aggressive therapies aren’t going to work in somebody and maybe turn toward less-aggressive approaches so we can maximize that person’s quality of life.”
What advice do AML experts have for their colleagues? Dr. LeBlanc said “older patients are not often enough considered for allogeneic stem cell transplantation, which could potentially cure their AML when given as a consolidation treatment for those in remission. I have several patients who are healthy and in their 70s who have enormously benefited from transplants and are now being several years out from transplant with adverse risk AML and without relapse. They’ve had no significant impairments of their quality of life, including no significant graft vs. host disease.”
Dr. Sekeres highlighted the American Society of Hematology’s guidelines for treating older adults with AML, which are currently being updated. It’s crucial to order genetic testing “up front,” he said. “I’m often pleasantly surprised when genetic testing returns and reveals that I have other treatment options.”
However, it’s crucial to understand a patient’s priorities. “I’ve had patients who are 75 who say to me, ‘Do everything under the sun to get rid of my leukemia, I want to live as long as possible.’ And I’ve had patients who say, ‘I want to see as little of doctors and nurses as I can. I want you to maximize my quality of life and keep me out of the hospital.’ ”
Dr. Sekeres also noted that insurers may not cover some pill-based AML treatments such as venetoclax. “We work with our patients and assistance programs. For the most part, we’re pretty successful at getting these drugs for our patients,” he said.
In Pediatrics, Clinical Trials Are Crucial
AML in children is less well-known than in adults, since the number of cases is so small. The disease is diagnosed in about 500 children a year in the United States, according to St. Jude Children’s Research Hospital, adding, however, that AML is “the most common second cancer among children treated for other cancers.”
AML in children gained attention earlier this year when the 2-year-old daughter of a Boston Herald NFL reporter died of the disease following a bone marrow transplant and chemotherapy. Despite the agonies of her treatment, reporter Doug Kyed told a reporter that his daughter Hallie “was still able to find joy every day.”
In an interview, hematologist/oncologist Sarah K. Tasian, MD, of Children’s Hospital of Philadelphia, said researchers are discovering that pediatric AML is significantly different on from a biological perspective from adult AML. “We’ve come to understand a lot more about who these patients are, what makes these leukemias tick, and what their Achilles’ heels are. Then we can align that with the clinical trials outcome data that we have.”
About 80%-90% of pediatric patients with AML nationwide are enrolled in clinical trials, Dr. Tasian said, and an international consortium called the Children’s Oncology Group gathers data about genetics. About 60%-70% of patients will be cured, she added.
However, “we’ve kind of been stuck for about the last 20 years,” she said. “A lot of improving the survival of patients has not been because we’ve been better at chemotherapy or using new chemo, but because we’ve gotten better at supportive care, at treating infections that can be fatal.”
There haven’t been major conflicts with insurers over coverage, she said, although drug shortages are a problem, especially in relapsed AML.
As for advice to colleagues, Dr. Tasian counseled them to understand the importance of genetic testing and the expanding role of stem cell transplants. “We are now transplanting somewhere between 30% and 50% of children with AML, which is a higher rate than we used to do,” she said. The number is up thanks to genetic testing that reveals which patients are most likely to benefit.
Also, she noted, “the chemotherapy that we get to these patients is really strong, and patients have a lot of complications. Really pay attention to supportive care.”
Dr. LeBlanc reported ties with AbbVie, Agios/Servier, Astellas, BMS/Celgene, Genentech, Pfizer, Incyte, Rige, Deverra, GSK, Jazz, and Seattle Genetics. Dr. Sekeres discloses relationships with BMS and Kurome. Dr. Tasian serves as the Leukemia & Lymphoma Society Pediatric Acute Leukemia consortium clinical trials leader and works with pharmaceutical companies on clinical trials under confidentiality agreements. Dr. Brunner has no disclosures.
For adult patients, “we’ve seen a series of remarkable and well-overdue advances in a space that had not changed much over the prior decades,” hematologist/oncologist Thomas William LeBlanc, MD, associate professor of medicine at Duke University School of Medicine, Durham, North Carolina, said in an interview.
According to the National Cancer Institute, AML will be newly diagnosed in 20,800 patients in 2024, at a median age of 69, and will cause 11,220 deaths. As many as 70% of adult patients will reach complete remission, and 45% of those will live for more than 3 years and potentially be cured. As for children, the Leukemia & Lymphoma Society says the 5-year survival rate from 2012-2018 was 69% for those under 15 years old.
As the American Cancer Society notes, the goal of AML treatment “is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way.”
Chemotherapy Strategies Shift Over Time
In terms of the treatment of adults with AML, “targeted therapies, in addition to the expanding role of venetoclax, has really altered our approach to AML from diagnosis, including after relapse, and later in the disease,” hematologist/oncologist Andrew M. Brunner, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, said in an interview. “The ability to explore these options as monotherapy and in novel combinations has dramatically expanded our treatment options.”
Much depends on the underlying genetic profile of the disease, he said. “There certainly have been gains in patient survival in AML, but those improvements remain fairly heterogeneous and dependent on the underlying genetic profile of the disease. For instance, advances in FLT3- and IDH1/2-mutated AML are a direct result of the improvements in targeted therapies directed at these mutations. Similarly, some molecular and cytogenetic subtypes of AML are particularly responsive to venetoclax-based regimens, and these regimens have been expanded to previously undertreated populations, particularly those over age 60.”
Specifically, Dr. LeBlanc said, the Food and Drug Administration has approved “3 different FLT3 inhibitors, 2 IDH1 inhibitors, 1 IDH2 inhibitor, a BCL-2 inhibitor, a smoothened/hedgehog pathway inhibitor, an oral maintenance chemotherapy/hypomethylating agent (CC-486/oral azacitidine), a CD33-targeting antibody-drug conjugate, and even a novel formulation of two older chemotherapies that improves efficacy in a poor prognosis subgroup (CPX-351/liposomal daunorubicin and cytarabine).”
There’s also been a shift in treatment protocols for patients who were not fit for intensive chemotherapy. In the past, he said, it was standard “to give single-agent hypomethylating chemotherapy with azacitidine or decitabine, or in some contexts, low-dose chemotherapy with cytarabine. Today, many patients who are older and/or more frail are receiving novel therapies either alone or in combination, with greater efficacy and longer duration of response than previously seen with chemotherapy alone.”
Outcomes Improve but Remain Grim in High-Risk Cases
As a result, Dr. LeBlanc said, “we’re definitely seeing much better outcomes in AML overall. It takes some time to prove this via outcomes data assessments in a large population, but I expect that registries will show significant improvements in overall survival in the coming years, owing to the many new FDA approvals in AML”
Dr. LeBlanc highlighted national data from 2013-2019 showing that the 5-year relative survival rate from AML is 31.7%. That’s up from 26% just a few years ago, and the numbers “always lag several years behind the current year of practice,” he said. However, “the major area where we still have relatively poor outcomes and significant unmet needs remains the ‘adverse risk’ group of patients, particularly those who are older and/or not candidates for hematopoietic stem cell transplantation, which generally is the only potentially curative option for adverse-risk AML.”
He went on to say that “this risk grouping includes those with TP53 mutations, most of which confer a particularly poor prognosis. Exciting therapies that many of us were hoping would prove effective in this subgroup have unfortunately failed in recent clinical trials. We still have a lot of work to do in adverse-risk AML particularly, and also for those whose leukemia has relapsed.”
Mikkael Sekeres, MD, MS, chief of the Division of Hematology at the University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, agreed that more progress is needed, since survival rates are low even as lifespans improve. One key will be “better identifying subtypes of acute myeloid leukemia, and identifying the therapies that will benefit those people most,” he said in an interview. On the other side, it’s important to identify “when aggressive therapies aren’t going to work in somebody and maybe turn toward less-aggressive approaches so we can maximize that person’s quality of life.”
What advice do AML experts have for their colleagues? Dr. LeBlanc said “older patients are not often enough considered for allogeneic stem cell transplantation, which could potentially cure their AML when given as a consolidation treatment for those in remission. I have several patients who are healthy and in their 70s who have enormously benefited from transplants and are now being several years out from transplant with adverse risk AML and without relapse. They’ve had no significant impairments of their quality of life, including no significant graft vs. host disease.”
Dr. Sekeres highlighted the American Society of Hematology’s guidelines for treating older adults with AML, which are currently being updated. It’s crucial to order genetic testing “up front,” he said. “I’m often pleasantly surprised when genetic testing returns and reveals that I have other treatment options.”
However, it’s crucial to understand a patient’s priorities. “I’ve had patients who are 75 who say to me, ‘Do everything under the sun to get rid of my leukemia, I want to live as long as possible.’ And I’ve had patients who say, ‘I want to see as little of doctors and nurses as I can. I want you to maximize my quality of life and keep me out of the hospital.’ ”
Dr. Sekeres also noted that insurers may not cover some pill-based AML treatments such as venetoclax. “We work with our patients and assistance programs. For the most part, we’re pretty successful at getting these drugs for our patients,” he said.
In Pediatrics, Clinical Trials Are Crucial
AML in children is less well-known than in adults, since the number of cases is so small. The disease is diagnosed in about 500 children a year in the United States, according to St. Jude Children’s Research Hospital, adding, however, that AML is “the most common second cancer among children treated for other cancers.”
AML in children gained attention earlier this year when the 2-year-old daughter of a Boston Herald NFL reporter died of the disease following a bone marrow transplant and chemotherapy. Despite the agonies of her treatment, reporter Doug Kyed told a reporter that his daughter Hallie “was still able to find joy every day.”
In an interview, hematologist/oncologist Sarah K. Tasian, MD, of Children’s Hospital of Philadelphia, said researchers are discovering that pediatric AML is significantly different on from a biological perspective from adult AML. “We’ve come to understand a lot more about who these patients are, what makes these leukemias tick, and what their Achilles’ heels are. Then we can align that with the clinical trials outcome data that we have.”
About 80%-90% of pediatric patients with AML nationwide are enrolled in clinical trials, Dr. Tasian said, and an international consortium called the Children’s Oncology Group gathers data about genetics. About 60%-70% of patients will be cured, she added.
However, “we’ve kind of been stuck for about the last 20 years,” she said. “A lot of improving the survival of patients has not been because we’ve been better at chemotherapy or using new chemo, but because we’ve gotten better at supportive care, at treating infections that can be fatal.”
There haven’t been major conflicts with insurers over coverage, she said, although drug shortages are a problem, especially in relapsed AML.
As for advice to colleagues, Dr. Tasian counseled them to understand the importance of genetic testing and the expanding role of stem cell transplants. “We are now transplanting somewhere between 30% and 50% of children with AML, which is a higher rate than we used to do,” she said. The number is up thanks to genetic testing that reveals which patients are most likely to benefit.
Also, she noted, “the chemotherapy that we get to these patients is really strong, and patients have a lot of complications. Really pay attention to supportive care.”
Dr. LeBlanc reported ties with AbbVie, Agios/Servier, Astellas, BMS/Celgene, Genentech, Pfizer, Incyte, Rige, Deverra, GSK, Jazz, and Seattle Genetics. Dr. Sekeres discloses relationships with BMS and Kurome. Dr. Tasian serves as the Leukemia & Lymphoma Society Pediatric Acute Leukemia consortium clinical trials leader and works with pharmaceutical companies on clinical trials under confidentiality agreements. Dr. Brunner has no disclosures.
For adult patients, “we’ve seen a series of remarkable and well-overdue advances in a space that had not changed much over the prior decades,” hematologist/oncologist Thomas William LeBlanc, MD, associate professor of medicine at Duke University School of Medicine, Durham, North Carolina, said in an interview.
According to the National Cancer Institute, AML will be newly diagnosed in 20,800 patients in 2024, at a median age of 69, and will cause 11,220 deaths. As many as 70% of adult patients will reach complete remission, and 45% of those will live for more than 3 years and potentially be cured. As for children, the Leukemia & Lymphoma Society says the 5-year survival rate from 2012-2018 was 69% for those under 15 years old.
As the American Cancer Society notes, the goal of AML treatment “is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way.”
Chemotherapy Strategies Shift Over Time
In terms of the treatment of adults with AML, “targeted therapies, in addition to the expanding role of venetoclax, has really altered our approach to AML from diagnosis, including after relapse, and later in the disease,” hematologist/oncologist Andrew M. Brunner, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, said in an interview. “The ability to explore these options as monotherapy and in novel combinations has dramatically expanded our treatment options.”
Much depends on the underlying genetic profile of the disease, he said. “There certainly have been gains in patient survival in AML, but those improvements remain fairly heterogeneous and dependent on the underlying genetic profile of the disease. For instance, advances in FLT3- and IDH1/2-mutated AML are a direct result of the improvements in targeted therapies directed at these mutations. Similarly, some molecular and cytogenetic subtypes of AML are particularly responsive to venetoclax-based regimens, and these regimens have been expanded to previously undertreated populations, particularly those over age 60.”
Specifically, Dr. LeBlanc said, the Food and Drug Administration has approved “3 different FLT3 inhibitors, 2 IDH1 inhibitors, 1 IDH2 inhibitor, a BCL-2 inhibitor, a smoothened/hedgehog pathway inhibitor, an oral maintenance chemotherapy/hypomethylating agent (CC-486/oral azacitidine), a CD33-targeting antibody-drug conjugate, and even a novel formulation of two older chemotherapies that improves efficacy in a poor prognosis subgroup (CPX-351/liposomal daunorubicin and cytarabine).”
There’s also been a shift in treatment protocols for patients who were not fit for intensive chemotherapy. In the past, he said, it was standard “to give single-agent hypomethylating chemotherapy with azacitidine or decitabine, or in some contexts, low-dose chemotherapy with cytarabine. Today, many patients who are older and/or more frail are receiving novel therapies either alone or in combination, with greater efficacy and longer duration of response than previously seen with chemotherapy alone.”
Outcomes Improve but Remain Grim in High-Risk Cases
As a result, Dr. LeBlanc said, “we’re definitely seeing much better outcomes in AML overall. It takes some time to prove this via outcomes data assessments in a large population, but I expect that registries will show significant improvements in overall survival in the coming years, owing to the many new FDA approvals in AML”
Dr. LeBlanc highlighted national data from 2013-2019 showing that the 5-year relative survival rate from AML is 31.7%. That’s up from 26% just a few years ago, and the numbers “always lag several years behind the current year of practice,” he said. However, “the major area where we still have relatively poor outcomes and significant unmet needs remains the ‘adverse risk’ group of patients, particularly those who are older and/or not candidates for hematopoietic stem cell transplantation, which generally is the only potentially curative option for adverse-risk AML.”
He went on to say that “this risk grouping includes those with TP53 mutations, most of which confer a particularly poor prognosis. Exciting therapies that many of us were hoping would prove effective in this subgroup have unfortunately failed in recent clinical trials. We still have a lot of work to do in adverse-risk AML particularly, and also for those whose leukemia has relapsed.”
Mikkael Sekeres, MD, MS, chief of the Division of Hematology at the University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, agreed that more progress is needed, since survival rates are low even as lifespans improve. One key will be “better identifying subtypes of acute myeloid leukemia, and identifying the therapies that will benefit those people most,” he said in an interview. On the other side, it’s important to identify “when aggressive therapies aren’t going to work in somebody and maybe turn toward less-aggressive approaches so we can maximize that person’s quality of life.”
What advice do AML experts have for their colleagues? Dr. LeBlanc said “older patients are not often enough considered for allogeneic stem cell transplantation, which could potentially cure their AML when given as a consolidation treatment for those in remission. I have several patients who are healthy and in their 70s who have enormously benefited from transplants and are now being several years out from transplant with adverse risk AML and without relapse. They’ve had no significant impairments of their quality of life, including no significant graft vs. host disease.”
Dr. Sekeres highlighted the American Society of Hematology’s guidelines for treating older adults with AML, which are currently being updated. It’s crucial to order genetic testing “up front,” he said. “I’m often pleasantly surprised when genetic testing returns and reveals that I have other treatment options.”
However, it’s crucial to understand a patient’s priorities. “I’ve had patients who are 75 who say to me, ‘Do everything under the sun to get rid of my leukemia, I want to live as long as possible.’ And I’ve had patients who say, ‘I want to see as little of doctors and nurses as I can. I want you to maximize my quality of life and keep me out of the hospital.’ ”
Dr. Sekeres also noted that insurers may not cover some pill-based AML treatments such as venetoclax. “We work with our patients and assistance programs. For the most part, we’re pretty successful at getting these drugs for our patients,” he said.
In Pediatrics, Clinical Trials Are Crucial
AML in children is less well-known than in adults, since the number of cases is so small. The disease is diagnosed in about 500 children a year in the United States, according to St. Jude Children’s Research Hospital, adding, however, that AML is “the most common second cancer among children treated for other cancers.”
AML in children gained attention earlier this year when the 2-year-old daughter of a Boston Herald NFL reporter died of the disease following a bone marrow transplant and chemotherapy. Despite the agonies of her treatment, reporter Doug Kyed told a reporter that his daughter Hallie “was still able to find joy every day.”
In an interview, hematologist/oncologist Sarah K. Tasian, MD, of Children’s Hospital of Philadelphia, said researchers are discovering that pediatric AML is significantly different on from a biological perspective from adult AML. “We’ve come to understand a lot more about who these patients are, what makes these leukemias tick, and what their Achilles’ heels are. Then we can align that with the clinical trials outcome data that we have.”
About 80%-90% of pediatric patients with AML nationwide are enrolled in clinical trials, Dr. Tasian said, and an international consortium called the Children’s Oncology Group gathers data about genetics. About 60%-70% of patients will be cured, she added.
However, “we’ve kind of been stuck for about the last 20 years,” she said. “A lot of improving the survival of patients has not been because we’ve been better at chemotherapy or using new chemo, but because we’ve gotten better at supportive care, at treating infections that can be fatal.”
There haven’t been major conflicts with insurers over coverage, she said, although drug shortages are a problem, especially in relapsed AML.
As for advice to colleagues, Dr. Tasian counseled them to understand the importance of genetic testing and the expanding role of stem cell transplants. “We are now transplanting somewhere between 30% and 50% of children with AML, which is a higher rate than we used to do,” she said. The number is up thanks to genetic testing that reveals which patients are most likely to benefit.
Also, she noted, “the chemotherapy that we get to these patients is really strong, and patients have a lot of complications. Really pay attention to supportive care.”
Dr. LeBlanc reported ties with AbbVie, Agios/Servier, Astellas, BMS/Celgene, Genentech, Pfizer, Incyte, Rige, Deverra, GSK, Jazz, and Seattle Genetics. Dr. Sekeres discloses relationships with BMS and Kurome. Dr. Tasian serves as the Leukemia & Lymphoma Society Pediatric Acute Leukemia consortium clinical trials leader and works with pharmaceutical companies on clinical trials under confidentiality agreements. Dr. Brunner has no disclosures.
Asparaginase in ALL: Innovative Ways to Manage Toxicity
The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.
According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.
The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.
“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.
Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”
The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”
The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.
Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”
All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.
When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”
It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.
According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.
There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.
As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”
As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.
“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”
Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”
Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.
Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”
Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.
Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”
Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.
With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”
What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”
There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”
In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”
Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).
The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.
According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.
The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.
“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.
Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”
The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”
The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.
Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”
All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.
When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”
It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.
According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.
There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.
As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”
As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.
“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”
Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”
Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.
Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”
Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.
Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”
Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.
With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”
What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”
There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”
In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”
Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).
The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.
According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.
The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.
“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.
Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”
The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”
The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.
Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”
All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.
When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”
It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.
According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.
There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.
As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”
As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.
“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”
Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”
Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.
Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”
Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.
Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”
Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.
With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”
What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”
There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”
In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”
Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).
Preventing Gout Flares and Hospitalizations Means Targeting These Serum Urate Levels
Clinical efforts to get patients with a history of gout to reach specific target serum urate (SU) levels less than either 5 or 6 mg/dL could prevent the great majority of gout flares and hospitalizations for them, according to a new study that tracked patients for a mean of 8.3 years.
The findings, which appeared February 6 in JAMA, “support the value of target serum urate levels in gout flare prevention in primary care, where most gout patients are treated,” rheumatologist and study coauthor Hyon K. Choi, MD, DrPH, of Harvard Medical School and Massachusetts General Hospital, Boston, told this news organization. However, Dr. Choi noted that “the value of relying on target urate levels is not accepted in primary care practice,” and the author of an accompanying commentary said that the jury is still out about the best strategy to prevent flares.
Gout is caused by monosodium urate crystallization within the joints, which occurs when SU levels exceed the saturation point for uric acid crystallization in the body: approximately 6.8 mg/dL. “Studies have found strongly graded associations between serum urate levels above the saturation point and the risk of developing new cases of gout among individuals without gout at baseline,” Dr. Choi said. “However, associations between serum urate levels and the risk of recurrent flares among preexisting gout patients, which is relevant to clinical gout care practice, has not been established.”
Dr. Choi added that “despite the emphasis in US and European rheumatology guidelines on the use of urate-lowering therapy to treat-to-target serum urate level — eg, under 6 or 5 mg/dL — the proportions of flares associated with such target urate levels remained unknown.”
Study Shows Relationship Between SU Levels and Recurrent Flares
For the study, researchers tracked 3613 patients aged 40-69 with gout in the UK Biobank database from 2006-2010 to 2017 or 2020. The patients, 86% of whom were men, had a mean age of 60 years and about 96% were White.
Among the patients, 1773 new episodes of acute gout occurred in 27% of the patients (16% had one episode, 6% had two episodes, and 5% had at least three episodes). These were treated in primary care or required hospitalizations. The other 73% of patients had no new acute gout episodes.
Overall, 95% of flares occurred in those with baseline SU levels ≥ 6 mg/dL, and 98% occurred in those with levels ≥ 5 mg/dL.
Patients with baseline SU levels < 6.0 mg/dL had an acute gout flare rate of 10.6 per 1000 person-years. In comparison, relative risks for acute gout flares per 1000 person-years were 3.16 at baseline SU levels of 6.0-6.9 mg/dL, 6.20 for 7.0-7.9 mg/dL, 7.70 for 8.0-8.9 mg/dL, 9.80 for 9.0-9.9 mg/dL, and 11.26 for > 10 mg/dL after adjustment for various possible confounders (P < .001).
The researchers identified 64 hospitalizations with gout as the main discharge diagnosis, and 97% occurred in patients with baseline SU levels ≥ 6 mg/dL. All were in patients with baseline SU levels ≥ 5 mg/dL.
“An important feature of this study was that serum urate measurements were obtained from all gout patients at the study baseline, irrespective of clinical needs or flare status,” Dr. Choi said. “Prior studies failed to reveal the truly compelling nature of relations between serum urate levels and recurrent flares among preexisting gout patients.”
As for the cost of SU tests, Dr. Choi said they can run as low as $2. “Portable tests similar to home glucose measurement for diabetes patients are also being adopted by certain gout care practices,” he said.
The findings matter, Dr. Choi said, because SU is not tracked in the “vast majority of gout patients” in primary care. Instead, primary care doctors — as per the guidelines of the American College of Physicians — often adopt an approach that treats symptoms as needed instead of tracking and lowering SU levels, he said. In fact, “95% and 98% of gout flares can be potentially preventable at the population level if serum urate levels < 6 and < 5 mg/dL can be met, respectively, and 100% of hospitalizations for gout could be preventable with serum urate < 5 mg/dL,” he said.
As for limitations, the authors noted that participants in the UK Biobank “typically have a better socioeconomic status and are healthier than the UK general population,” and they added that “these data may underestimate the number of acute gout flares in the cohort.” Also, 55% of the total 502,490 patients in the UK Biobank were excluded owing to lack of primary care data.
Study ‘Offers the Kind of Evidence That We Need’
In an accompanying commentary, University of Alabama at Birmingham rheumatologist Angelo L. Gaffo, MD, MSPH, also noted that the study population was overwhelmingly White, had a low mean SU level (6.9 mg/dL), and had a low level of comorbidities, making the sample “poorly representative of the most commonly described gout populations.”
However, he also noted that there is “growing evidence linking serum urate levels with clinical outcomes,” with a pair of studies — one from 2021 and the other from 2022 — linking reductions in SU to < 6 md/dL to lower flare rates.
Dr. Gaffo told this news organization that although rheumatology guidelines support a treat-to-target strategy, “we haven›t generated a whole lot of important evidence to support it.”
The new study “offers the kind of evidence that we need,” he said, “but this is not going to be the ultimate answer.” That will only come from randomized clinical trials in the works that will pit the treat-to-target approach vs the primary care–favored strategy of titrating treatment until flares are controlled, he said.
Even though evidence is sparse, Dr. Gaffo said he still believes in the treat-to-target strategy: “I believe it is the best way to treat gout.”
What’s next? Researchers hope to understand how to better reach target SU goals in clinical practice, Dr. Choi said. “Involving nurses, pharmacists, or interactive online or app systems — as in other chronic treat-to-target care such as anticoagulation care, blood pressure, or lipid care — is actively being researched.”
He added that “we are trying to find the effective and safe medications and nonpharmacologic measures to reduce the urate burden, which can also simultaneously take care of gout’s frequent cardiovascular-kidney comorbidities.”
The US National Institutes of Health supported the study. Dr. Choi reports receiving grants from Horizon and serving on a board or committee for LG Chem, Shanton, and ANI Pharmaceuticals. Some other authors report an employment and stockholder relationship with Regeneron and support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Rheumatology Research Foundation. Dr. Gaffo reports personal fees from PK MED, SOBI/Selecta, Atom, and UpToDate.
A version of this article first appeared on Medscape.com.
Clinical efforts to get patients with a history of gout to reach specific target serum urate (SU) levels less than either 5 or 6 mg/dL could prevent the great majority of gout flares and hospitalizations for them, according to a new study that tracked patients for a mean of 8.3 years.
The findings, which appeared February 6 in JAMA, “support the value of target serum urate levels in gout flare prevention in primary care, where most gout patients are treated,” rheumatologist and study coauthor Hyon K. Choi, MD, DrPH, of Harvard Medical School and Massachusetts General Hospital, Boston, told this news organization. However, Dr. Choi noted that “the value of relying on target urate levels is not accepted in primary care practice,” and the author of an accompanying commentary said that the jury is still out about the best strategy to prevent flares.
Gout is caused by monosodium urate crystallization within the joints, which occurs when SU levels exceed the saturation point for uric acid crystallization in the body: approximately 6.8 mg/dL. “Studies have found strongly graded associations between serum urate levels above the saturation point and the risk of developing new cases of gout among individuals without gout at baseline,” Dr. Choi said. “However, associations between serum urate levels and the risk of recurrent flares among preexisting gout patients, which is relevant to clinical gout care practice, has not been established.”
Dr. Choi added that “despite the emphasis in US and European rheumatology guidelines on the use of urate-lowering therapy to treat-to-target serum urate level — eg, under 6 or 5 mg/dL — the proportions of flares associated with such target urate levels remained unknown.”
Study Shows Relationship Between SU Levels and Recurrent Flares
For the study, researchers tracked 3613 patients aged 40-69 with gout in the UK Biobank database from 2006-2010 to 2017 or 2020. The patients, 86% of whom were men, had a mean age of 60 years and about 96% were White.
Among the patients, 1773 new episodes of acute gout occurred in 27% of the patients (16% had one episode, 6% had two episodes, and 5% had at least three episodes). These were treated in primary care or required hospitalizations. The other 73% of patients had no new acute gout episodes.
Overall, 95% of flares occurred in those with baseline SU levels ≥ 6 mg/dL, and 98% occurred in those with levels ≥ 5 mg/dL.
Patients with baseline SU levels < 6.0 mg/dL had an acute gout flare rate of 10.6 per 1000 person-years. In comparison, relative risks for acute gout flares per 1000 person-years were 3.16 at baseline SU levels of 6.0-6.9 mg/dL, 6.20 for 7.0-7.9 mg/dL, 7.70 for 8.0-8.9 mg/dL, 9.80 for 9.0-9.9 mg/dL, and 11.26 for > 10 mg/dL after adjustment for various possible confounders (P < .001).
The researchers identified 64 hospitalizations with gout as the main discharge diagnosis, and 97% occurred in patients with baseline SU levels ≥ 6 mg/dL. All were in patients with baseline SU levels ≥ 5 mg/dL.
“An important feature of this study was that serum urate measurements were obtained from all gout patients at the study baseline, irrespective of clinical needs or flare status,” Dr. Choi said. “Prior studies failed to reveal the truly compelling nature of relations between serum urate levels and recurrent flares among preexisting gout patients.”
As for the cost of SU tests, Dr. Choi said they can run as low as $2. “Portable tests similar to home glucose measurement for diabetes patients are also being adopted by certain gout care practices,” he said.
The findings matter, Dr. Choi said, because SU is not tracked in the “vast majority of gout patients” in primary care. Instead, primary care doctors — as per the guidelines of the American College of Physicians — often adopt an approach that treats symptoms as needed instead of tracking and lowering SU levels, he said. In fact, “95% and 98% of gout flares can be potentially preventable at the population level if serum urate levels < 6 and < 5 mg/dL can be met, respectively, and 100% of hospitalizations for gout could be preventable with serum urate < 5 mg/dL,” he said.
As for limitations, the authors noted that participants in the UK Biobank “typically have a better socioeconomic status and are healthier than the UK general population,” and they added that “these data may underestimate the number of acute gout flares in the cohort.” Also, 55% of the total 502,490 patients in the UK Biobank were excluded owing to lack of primary care data.
Study ‘Offers the Kind of Evidence That We Need’
In an accompanying commentary, University of Alabama at Birmingham rheumatologist Angelo L. Gaffo, MD, MSPH, also noted that the study population was overwhelmingly White, had a low mean SU level (6.9 mg/dL), and had a low level of comorbidities, making the sample “poorly representative of the most commonly described gout populations.”
However, he also noted that there is “growing evidence linking serum urate levels with clinical outcomes,” with a pair of studies — one from 2021 and the other from 2022 — linking reductions in SU to < 6 md/dL to lower flare rates.
Dr. Gaffo told this news organization that although rheumatology guidelines support a treat-to-target strategy, “we haven›t generated a whole lot of important evidence to support it.”
The new study “offers the kind of evidence that we need,” he said, “but this is not going to be the ultimate answer.” That will only come from randomized clinical trials in the works that will pit the treat-to-target approach vs the primary care–favored strategy of titrating treatment until flares are controlled, he said.
Even though evidence is sparse, Dr. Gaffo said he still believes in the treat-to-target strategy: “I believe it is the best way to treat gout.”
What’s next? Researchers hope to understand how to better reach target SU goals in clinical practice, Dr. Choi said. “Involving nurses, pharmacists, or interactive online or app systems — as in other chronic treat-to-target care such as anticoagulation care, blood pressure, or lipid care — is actively being researched.”
He added that “we are trying to find the effective and safe medications and nonpharmacologic measures to reduce the urate burden, which can also simultaneously take care of gout’s frequent cardiovascular-kidney comorbidities.”
The US National Institutes of Health supported the study. Dr. Choi reports receiving grants from Horizon and serving on a board or committee for LG Chem, Shanton, and ANI Pharmaceuticals. Some other authors report an employment and stockholder relationship with Regeneron and support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Rheumatology Research Foundation. Dr. Gaffo reports personal fees from PK MED, SOBI/Selecta, Atom, and UpToDate.
A version of this article first appeared on Medscape.com.
Clinical efforts to get patients with a history of gout to reach specific target serum urate (SU) levels less than either 5 or 6 mg/dL could prevent the great majority of gout flares and hospitalizations for them, according to a new study that tracked patients for a mean of 8.3 years.
The findings, which appeared February 6 in JAMA, “support the value of target serum urate levels in gout flare prevention in primary care, where most gout patients are treated,” rheumatologist and study coauthor Hyon K. Choi, MD, DrPH, of Harvard Medical School and Massachusetts General Hospital, Boston, told this news organization. However, Dr. Choi noted that “the value of relying on target urate levels is not accepted in primary care practice,” and the author of an accompanying commentary said that the jury is still out about the best strategy to prevent flares.
Gout is caused by monosodium urate crystallization within the joints, which occurs when SU levels exceed the saturation point for uric acid crystallization in the body: approximately 6.8 mg/dL. “Studies have found strongly graded associations between serum urate levels above the saturation point and the risk of developing new cases of gout among individuals without gout at baseline,” Dr. Choi said. “However, associations between serum urate levels and the risk of recurrent flares among preexisting gout patients, which is relevant to clinical gout care practice, has not been established.”
Dr. Choi added that “despite the emphasis in US and European rheumatology guidelines on the use of urate-lowering therapy to treat-to-target serum urate level — eg, under 6 or 5 mg/dL — the proportions of flares associated with such target urate levels remained unknown.”
Study Shows Relationship Between SU Levels and Recurrent Flares
For the study, researchers tracked 3613 patients aged 40-69 with gout in the UK Biobank database from 2006-2010 to 2017 or 2020. The patients, 86% of whom were men, had a mean age of 60 years and about 96% were White.
Among the patients, 1773 new episodes of acute gout occurred in 27% of the patients (16% had one episode, 6% had two episodes, and 5% had at least three episodes). These were treated in primary care or required hospitalizations. The other 73% of patients had no new acute gout episodes.
Overall, 95% of flares occurred in those with baseline SU levels ≥ 6 mg/dL, and 98% occurred in those with levels ≥ 5 mg/dL.
Patients with baseline SU levels < 6.0 mg/dL had an acute gout flare rate of 10.6 per 1000 person-years. In comparison, relative risks for acute gout flares per 1000 person-years were 3.16 at baseline SU levels of 6.0-6.9 mg/dL, 6.20 for 7.0-7.9 mg/dL, 7.70 for 8.0-8.9 mg/dL, 9.80 for 9.0-9.9 mg/dL, and 11.26 for > 10 mg/dL after adjustment for various possible confounders (P < .001).
The researchers identified 64 hospitalizations with gout as the main discharge diagnosis, and 97% occurred in patients with baseline SU levels ≥ 6 mg/dL. All were in patients with baseline SU levels ≥ 5 mg/dL.
“An important feature of this study was that serum urate measurements were obtained from all gout patients at the study baseline, irrespective of clinical needs or flare status,” Dr. Choi said. “Prior studies failed to reveal the truly compelling nature of relations between serum urate levels and recurrent flares among preexisting gout patients.”
As for the cost of SU tests, Dr. Choi said they can run as low as $2. “Portable tests similar to home glucose measurement for diabetes patients are also being adopted by certain gout care practices,” he said.
The findings matter, Dr. Choi said, because SU is not tracked in the “vast majority of gout patients” in primary care. Instead, primary care doctors — as per the guidelines of the American College of Physicians — often adopt an approach that treats symptoms as needed instead of tracking and lowering SU levels, he said. In fact, “95% and 98% of gout flares can be potentially preventable at the population level if serum urate levels < 6 and < 5 mg/dL can be met, respectively, and 100% of hospitalizations for gout could be preventable with serum urate < 5 mg/dL,” he said.
As for limitations, the authors noted that participants in the UK Biobank “typically have a better socioeconomic status and are healthier than the UK general population,” and they added that “these data may underestimate the number of acute gout flares in the cohort.” Also, 55% of the total 502,490 patients in the UK Biobank were excluded owing to lack of primary care data.
Study ‘Offers the Kind of Evidence That We Need’
In an accompanying commentary, University of Alabama at Birmingham rheumatologist Angelo L. Gaffo, MD, MSPH, also noted that the study population was overwhelmingly White, had a low mean SU level (6.9 mg/dL), and had a low level of comorbidities, making the sample “poorly representative of the most commonly described gout populations.”
However, he also noted that there is “growing evidence linking serum urate levels with clinical outcomes,” with a pair of studies — one from 2021 and the other from 2022 — linking reductions in SU to < 6 md/dL to lower flare rates.
Dr. Gaffo told this news organization that although rheumatology guidelines support a treat-to-target strategy, “we haven›t generated a whole lot of important evidence to support it.”
The new study “offers the kind of evidence that we need,” he said, “but this is not going to be the ultimate answer.” That will only come from randomized clinical trials in the works that will pit the treat-to-target approach vs the primary care–favored strategy of titrating treatment until flares are controlled, he said.
Even though evidence is sparse, Dr. Gaffo said he still believes in the treat-to-target strategy: “I believe it is the best way to treat gout.”
What’s next? Researchers hope to understand how to better reach target SU goals in clinical practice, Dr. Choi said. “Involving nurses, pharmacists, or interactive online or app systems — as in other chronic treat-to-target care such as anticoagulation care, blood pressure, or lipid care — is actively being researched.”
He added that “we are trying to find the effective and safe medications and nonpharmacologic measures to reduce the urate burden, which can also simultaneously take care of gout’s frequent cardiovascular-kidney comorbidities.”
The US National Institutes of Health supported the study. Dr. Choi reports receiving grants from Horizon and serving on a board or committee for LG Chem, Shanton, and ANI Pharmaceuticals. Some other authors report an employment and stockholder relationship with Regeneron and support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Rheumatology Research Foundation. Dr. Gaffo reports personal fees from PK MED, SOBI/Selecta, Atom, and UpToDate.
A version of this article first appeared on Medscape.com.
FROM JAMA
ALL: When Should MRD Trigger Stem Cell Transplants?
Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”
Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.
A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.
However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.
As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”
As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”
Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”
He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.
As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.
In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”
If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”
How can hematologists make the best decision about HSCT?
In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”
The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.
In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”
In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”
The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.
Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”
If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”
As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”
What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”
Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.
Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”
Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.
A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.
However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.
As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”
As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”
Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”
He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.
As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.
In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”
If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”
How can hematologists make the best decision about HSCT?
In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”
The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.
In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”
In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”
The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.
Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”
If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”
As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”
What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”
Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.
Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”
Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.
A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.
However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.
As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”
As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”
Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”
He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.
As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.
In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”
If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”
How can hematologists make the best decision about HSCT?
In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”
The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.
In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”
In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”
The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.
Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”
If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”
As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”
What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”
Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.
Time Off Isn’t Really Off-Time for Most Physicians, Study Finds
About 20% of US physicians took less than 1 week of vacation in the previous year, a new study found. When doctors did go on vacation, 70% reported working on their days off to handle patient-related tasks.
, according to the cross-sectional study, which was published on January 12, 2024, in JAMA Network Open.“It’s important to provide physicians with adequate time to disconnect from work and recharge,” said study coauthor Tait Shanafelt, MD, chief wellness officer at Stanford Medicine, in an interview.
The study’s conclusion that most US physicians work on their days off “is a marker of inadequate staffing, suboptimal teamwork, and poorly designed coverage systems,” he added. “Simply allocating people a number of vacation days is not enough.”
According to Dr. Shanafelt, there’s been little research into vacation’s impact on physician well-being. However, it is clear that work overload and exhaustion are major problems among American physicians. “Inadequate time off may magnify these challenges.”
Research suggests that physicians suffer more burnout than other US workers even after adjusting for confounders, he said. Extensive evidence shows that burnout in physicians contributes to medical errors and erodes quality of care and patient satisfaction, he added.
For the new study, researchers mailed surveys to 3671 members of the American Medical Association from 2020 to 2021, and 1162 (31.7%) responded. Another 6348 (7.1%) responded to an email survey sent to 90,000 physicians. An analysis suggested the respondents were representative of all US practicing physicians.
Among 3024 respondents who responded to a subsurvey about vacations, about 40% took more than 15 days of vacation over the past year, about 40% took 6-15 days, and about 20% took 5 or fewer days.
Fewer than half of physicians said their electronic health record (EHR) inboxes were fully covered by others while they were away. About 70% said they worked while on vacation, with nearly 15% working an hour or more each day.
Emergency physicians were the least likely and anesthesiologists were the most likely to take at least 15 days of vacation per year, according to the study.
Women were more likely than men to work 30 or more minutes a day on vacation. Physicians aged 65 years and older were more likely to take 15 or more days of vacation per year than those under 35 years.
An adjusted analysis linked complete EHR inbox coverage to lower odds of taking time during vacation to work (odds ratio [OR], 0.68; 95% CI, 0.57-0.80).
“For many, difficulty finding clinical coverage, lack of EHR inbox coverage, and returning to an overwhelming backlog of EHR inbox work at were identified as barriers to taking vacation,” Dr. Shanafelt said.
Researchers linked lower rates of burnout to taking more than 3 weeks of vacation per year (OR, 0.59-0.66, depending on time spent; 95% CI, 0.40-0.98) vs none. They also linked less burnout to full EHR inbox coverage while on vacation (OR, 0.74; 95% CI, 0.63-0.88) and more burnout to spending 30 minutes or more on work while on a typical vacation day (OR, 1.58-1.97, depending on time spent; 95% CI, 1.22-2.77).
Study limitations include the low participation rate and lack of insight into causation. It’s not clear how burnout and less vacation time are related and whether one causes the other, Shanafelt said. “It is possible there are a number of interacting factors rather than a simple, linear relationship.”
In an interview, Lazar J. Greenfield, Jr., MD, PhD, professor and chairman of neurology at UConn Health, Farmington, Connecticut, said his department encourages clinicians to plan vacations well ahead of time, and “we make a real strong effort to make sure that people are fully covered and someone has their Epic inbox.”
Dr. Greenfield, who wasn’t involved in the new study, recommended that physicians plan active vacations, so they have less downtime to catch up on work matters. But he acknowledged that stepping away from emails can be difficult, especially when physicians fear pileups of work upon their return or don’t want to annoy patients with tardy responses.
“They have a hard time disengaging from their moral obligations to patients,” he said. “Another issue, particularly in my field of neurology, is that there’s a lot of subspecialties. Finding somebody with the exact subspecialty and expertise to cover a very specific patient population they treat can be really hard.”
The Stanford WellMD Center, Mayo Clinic Department of Medicine Program on Physician Well-being, and American Medical Association funded the study.
Dr. Shanafelt discloses coinventing the Well-Being Index and its derivatives with another study author; Mayo Clinic licensed the Well-Being Index and pays them royalties outside the submitted work. Dr. Shanafelt also reported support for grand rounds, lectures, and advising for healthcare organizations outside the submitted work. Other authors reported personal fees from Marvin Behavioral Health and grants from the National Institute of Nursing Research, National Science Foundation, and Med Ed Solutions.
Dr. Greenfield had no disclosures.
A version of this article appeared on Medscape.com.
About 20% of US physicians took less than 1 week of vacation in the previous year, a new study found. When doctors did go on vacation, 70% reported working on their days off to handle patient-related tasks.
, according to the cross-sectional study, which was published on January 12, 2024, in JAMA Network Open.“It’s important to provide physicians with adequate time to disconnect from work and recharge,” said study coauthor Tait Shanafelt, MD, chief wellness officer at Stanford Medicine, in an interview.
The study’s conclusion that most US physicians work on their days off “is a marker of inadequate staffing, suboptimal teamwork, and poorly designed coverage systems,” he added. “Simply allocating people a number of vacation days is not enough.”
According to Dr. Shanafelt, there’s been little research into vacation’s impact on physician well-being. However, it is clear that work overload and exhaustion are major problems among American physicians. “Inadequate time off may magnify these challenges.”
Research suggests that physicians suffer more burnout than other US workers even after adjusting for confounders, he said. Extensive evidence shows that burnout in physicians contributes to medical errors and erodes quality of care and patient satisfaction, he added.
For the new study, researchers mailed surveys to 3671 members of the American Medical Association from 2020 to 2021, and 1162 (31.7%) responded. Another 6348 (7.1%) responded to an email survey sent to 90,000 physicians. An analysis suggested the respondents were representative of all US practicing physicians.
Among 3024 respondents who responded to a subsurvey about vacations, about 40% took more than 15 days of vacation over the past year, about 40% took 6-15 days, and about 20% took 5 or fewer days.
Fewer than half of physicians said their electronic health record (EHR) inboxes were fully covered by others while they were away. About 70% said they worked while on vacation, with nearly 15% working an hour or more each day.
Emergency physicians were the least likely and anesthesiologists were the most likely to take at least 15 days of vacation per year, according to the study.
Women were more likely than men to work 30 or more minutes a day on vacation. Physicians aged 65 years and older were more likely to take 15 or more days of vacation per year than those under 35 years.
An adjusted analysis linked complete EHR inbox coverage to lower odds of taking time during vacation to work (odds ratio [OR], 0.68; 95% CI, 0.57-0.80).
“For many, difficulty finding clinical coverage, lack of EHR inbox coverage, and returning to an overwhelming backlog of EHR inbox work at were identified as barriers to taking vacation,” Dr. Shanafelt said.
Researchers linked lower rates of burnout to taking more than 3 weeks of vacation per year (OR, 0.59-0.66, depending on time spent; 95% CI, 0.40-0.98) vs none. They also linked less burnout to full EHR inbox coverage while on vacation (OR, 0.74; 95% CI, 0.63-0.88) and more burnout to spending 30 minutes or more on work while on a typical vacation day (OR, 1.58-1.97, depending on time spent; 95% CI, 1.22-2.77).
Study limitations include the low participation rate and lack of insight into causation. It’s not clear how burnout and less vacation time are related and whether one causes the other, Shanafelt said. “It is possible there are a number of interacting factors rather than a simple, linear relationship.”
In an interview, Lazar J. Greenfield, Jr., MD, PhD, professor and chairman of neurology at UConn Health, Farmington, Connecticut, said his department encourages clinicians to plan vacations well ahead of time, and “we make a real strong effort to make sure that people are fully covered and someone has their Epic inbox.”
Dr. Greenfield, who wasn’t involved in the new study, recommended that physicians plan active vacations, so they have less downtime to catch up on work matters. But he acknowledged that stepping away from emails can be difficult, especially when physicians fear pileups of work upon their return or don’t want to annoy patients with tardy responses.
“They have a hard time disengaging from their moral obligations to patients,” he said. “Another issue, particularly in my field of neurology, is that there’s a lot of subspecialties. Finding somebody with the exact subspecialty and expertise to cover a very specific patient population they treat can be really hard.”
The Stanford WellMD Center, Mayo Clinic Department of Medicine Program on Physician Well-being, and American Medical Association funded the study.
Dr. Shanafelt discloses coinventing the Well-Being Index and its derivatives with another study author; Mayo Clinic licensed the Well-Being Index and pays them royalties outside the submitted work. Dr. Shanafelt also reported support for grand rounds, lectures, and advising for healthcare organizations outside the submitted work. Other authors reported personal fees from Marvin Behavioral Health and grants from the National Institute of Nursing Research, National Science Foundation, and Med Ed Solutions.
Dr. Greenfield had no disclosures.
A version of this article appeared on Medscape.com.
About 20% of US physicians took less than 1 week of vacation in the previous year, a new study found. When doctors did go on vacation, 70% reported working on their days off to handle patient-related tasks.
, according to the cross-sectional study, which was published on January 12, 2024, in JAMA Network Open.“It’s important to provide physicians with adequate time to disconnect from work and recharge,” said study coauthor Tait Shanafelt, MD, chief wellness officer at Stanford Medicine, in an interview.
The study’s conclusion that most US physicians work on their days off “is a marker of inadequate staffing, suboptimal teamwork, and poorly designed coverage systems,” he added. “Simply allocating people a number of vacation days is not enough.”
According to Dr. Shanafelt, there’s been little research into vacation’s impact on physician well-being. However, it is clear that work overload and exhaustion are major problems among American physicians. “Inadequate time off may magnify these challenges.”
Research suggests that physicians suffer more burnout than other US workers even after adjusting for confounders, he said. Extensive evidence shows that burnout in physicians contributes to medical errors and erodes quality of care and patient satisfaction, he added.
For the new study, researchers mailed surveys to 3671 members of the American Medical Association from 2020 to 2021, and 1162 (31.7%) responded. Another 6348 (7.1%) responded to an email survey sent to 90,000 physicians. An analysis suggested the respondents were representative of all US practicing physicians.
Among 3024 respondents who responded to a subsurvey about vacations, about 40% took more than 15 days of vacation over the past year, about 40% took 6-15 days, and about 20% took 5 or fewer days.
Fewer than half of physicians said their electronic health record (EHR) inboxes were fully covered by others while they were away. About 70% said they worked while on vacation, with nearly 15% working an hour or more each day.
Emergency physicians were the least likely and anesthesiologists were the most likely to take at least 15 days of vacation per year, according to the study.
Women were more likely than men to work 30 or more minutes a day on vacation. Physicians aged 65 years and older were more likely to take 15 or more days of vacation per year than those under 35 years.
An adjusted analysis linked complete EHR inbox coverage to lower odds of taking time during vacation to work (odds ratio [OR], 0.68; 95% CI, 0.57-0.80).
“For many, difficulty finding clinical coverage, lack of EHR inbox coverage, and returning to an overwhelming backlog of EHR inbox work at were identified as barriers to taking vacation,” Dr. Shanafelt said.
Researchers linked lower rates of burnout to taking more than 3 weeks of vacation per year (OR, 0.59-0.66, depending on time spent; 95% CI, 0.40-0.98) vs none. They also linked less burnout to full EHR inbox coverage while on vacation (OR, 0.74; 95% CI, 0.63-0.88) and more burnout to spending 30 minutes or more on work while on a typical vacation day (OR, 1.58-1.97, depending on time spent; 95% CI, 1.22-2.77).
Study limitations include the low participation rate and lack of insight into causation. It’s not clear how burnout and less vacation time are related and whether one causes the other, Shanafelt said. “It is possible there are a number of interacting factors rather than a simple, linear relationship.”
In an interview, Lazar J. Greenfield, Jr., MD, PhD, professor and chairman of neurology at UConn Health, Farmington, Connecticut, said his department encourages clinicians to plan vacations well ahead of time, and “we make a real strong effort to make sure that people are fully covered and someone has their Epic inbox.”
Dr. Greenfield, who wasn’t involved in the new study, recommended that physicians plan active vacations, so they have less downtime to catch up on work matters. But he acknowledged that stepping away from emails can be difficult, especially when physicians fear pileups of work upon their return or don’t want to annoy patients with tardy responses.
“They have a hard time disengaging from their moral obligations to patients,” he said. “Another issue, particularly in my field of neurology, is that there’s a lot of subspecialties. Finding somebody with the exact subspecialty and expertise to cover a very specific patient population they treat can be really hard.”
The Stanford WellMD Center, Mayo Clinic Department of Medicine Program on Physician Well-being, and American Medical Association funded the study.
Dr. Shanafelt discloses coinventing the Well-Being Index and its derivatives with another study author; Mayo Clinic licensed the Well-Being Index and pays them royalties outside the submitted work. Dr. Shanafelt also reported support for grand rounds, lectures, and advising for healthcare organizations outside the submitted work. Other authors reported personal fees from Marvin Behavioral Health and grants from the National Institute of Nursing Research, National Science Foundation, and Med Ed Solutions.
Dr. Greenfield had no disclosures.
A version of this article appeared on Medscape.com.
FROM JAMA NETWORK OPEN
ALL: What Prompts A Post-Childhood ‘Survival Cliff’?
In a session at the annual meeting of the American Society of Hematology in December, clinicians defined the extent of the problem — which one described as a “survival cliff” — and they discussed potential strategies to turn things around.
Cleveland Clinic hematologist John Molina, MD, EdM, highlighted a 2022 study that revealed “the 5-year overall survival for younger pediatric patients is quite phenomenal at 93%. But as you start shifting even to 15-19 patients, that shifts to an overall survival of 74%.”
In the rest of the young adult population, from age 20 to 39, the overall survival rate dips down to 59%. What’s going on?
As Dr. Molina noted, a 2008 study revealed that outcomes in ALL for those aged 16-20 “historically depended on which door you walked into”: the pediatric setting or the adult setting. Patients fared better on pediatric regimens.
Currently, he explained, those who begin treatment in adult oncology clinics will start with either a pediatric-inspired treatment called CALGB 10403 or HyperCVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone plus methotrexate and cytarabine).
CALGB 10403 was developed based on a pediatric backbone of COG AALL0232, Dr. Molina said, and has higher doses of major myelosuppressive agents vs. HyperCVAD. A 2019 study determined that it was feasible to treat adolescents and young adults up to age 40 “with low treatment-related mortality and marked improvement in outcomes. OS [overall survival] at 3 years was 73%.”
However, Dr. Molina observed that only 39% of patients completed the treatment per protocol.
Which is better, CALGB 10403 or HyperCVAD? Dr. Molina said the risk of infertility and other long-term adverse effects is higher in HyperCVAD, but it has a lower risk of hepatic, pancreatic and thrombotic complications. And the CALGB 10403 regimen is more complicated to deliver, which is a potential obstacle in clinics without large numbers of patients.
As for outcomes, some research suggests they improve with pediatric-inspired regimens like CALGB 10403, he said, noting that “the debate continues.”
However, even with better regimens, Dr. Molina added, older ALL patients are still faring worse.
Also at the ASH presentation, Emory University/Children’s Healthcare of Atlanta pediatric cancer specialist Tamara Miller, MD, explored possible reasons that could explain the difference in outcomes based on age.
Cancer biology, response to chemotherapy, toxicities, psychosocial challenges, and low enrollment in clinical trials are all potential factors, she said. Specifically, aging into adulthood can lower tolerance of chemotherapy, and older patients are more prone to obesity, which is associated with worse outcomes, she said.
As for psychosocial challenges, it can be hard for older patients to manage their own medications, and they may lack insurance coverage, she said. Some patients may have worries about fertility, she added, and some may rebel against the requirements of treatment. Adherence is crucial to reducing risk of relapse, she added.
University of Cincinnati leukemia specialist Emily Curran, MD, told the ASH audience that researchers are exploring various avenues to improve outcomes.
Philadelphia chromosome-like (Ph-like) ALL, a subset of B-ALL, is associated with worse outcomes, she said, but it has multiple targetable pathways. An ongoing trial is exploring ruxolitinib (Jakafi) and chemotherapy in patients aged 18-39 with Ph-like ALL, Dr. Curran said.
Researchers are also wondering if up-front immunotherapy can help overcome disease biology, she said. Another potential therapy, she added, is CAR-T therapy for T-ALL.
Beyond cancer biology, “psychosocial factors are an even more challenging area in which we have fewer ongoing and less solutions,” Dr. Curran said.
Dr. Molina disclosed honoraria and consulting relationships with Autolus. Dr. Curran reported ties with Kite, Amgen, Incyte, Pfizer, Jazz, and Servier. Dr. Miller has no disclosures.
In a session at the annual meeting of the American Society of Hematology in December, clinicians defined the extent of the problem — which one described as a “survival cliff” — and they discussed potential strategies to turn things around.
Cleveland Clinic hematologist John Molina, MD, EdM, highlighted a 2022 study that revealed “the 5-year overall survival for younger pediatric patients is quite phenomenal at 93%. But as you start shifting even to 15-19 patients, that shifts to an overall survival of 74%.”
In the rest of the young adult population, from age 20 to 39, the overall survival rate dips down to 59%. What’s going on?
As Dr. Molina noted, a 2008 study revealed that outcomes in ALL for those aged 16-20 “historically depended on which door you walked into”: the pediatric setting or the adult setting. Patients fared better on pediatric regimens.
Currently, he explained, those who begin treatment in adult oncology clinics will start with either a pediatric-inspired treatment called CALGB 10403 or HyperCVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone plus methotrexate and cytarabine).
CALGB 10403 was developed based on a pediatric backbone of COG AALL0232, Dr. Molina said, and has higher doses of major myelosuppressive agents vs. HyperCVAD. A 2019 study determined that it was feasible to treat adolescents and young adults up to age 40 “with low treatment-related mortality and marked improvement in outcomes. OS [overall survival] at 3 years was 73%.”
However, Dr. Molina observed that only 39% of patients completed the treatment per protocol.
Which is better, CALGB 10403 or HyperCVAD? Dr. Molina said the risk of infertility and other long-term adverse effects is higher in HyperCVAD, but it has a lower risk of hepatic, pancreatic and thrombotic complications. And the CALGB 10403 regimen is more complicated to deliver, which is a potential obstacle in clinics without large numbers of patients.
As for outcomes, some research suggests they improve with pediatric-inspired regimens like CALGB 10403, he said, noting that “the debate continues.”
However, even with better regimens, Dr. Molina added, older ALL patients are still faring worse.
Also at the ASH presentation, Emory University/Children’s Healthcare of Atlanta pediatric cancer specialist Tamara Miller, MD, explored possible reasons that could explain the difference in outcomes based on age.
Cancer biology, response to chemotherapy, toxicities, psychosocial challenges, and low enrollment in clinical trials are all potential factors, she said. Specifically, aging into adulthood can lower tolerance of chemotherapy, and older patients are more prone to obesity, which is associated with worse outcomes, she said.
As for psychosocial challenges, it can be hard for older patients to manage their own medications, and they may lack insurance coverage, she said. Some patients may have worries about fertility, she added, and some may rebel against the requirements of treatment. Adherence is crucial to reducing risk of relapse, she added.
University of Cincinnati leukemia specialist Emily Curran, MD, told the ASH audience that researchers are exploring various avenues to improve outcomes.
Philadelphia chromosome-like (Ph-like) ALL, a subset of B-ALL, is associated with worse outcomes, she said, but it has multiple targetable pathways. An ongoing trial is exploring ruxolitinib (Jakafi) and chemotherapy in patients aged 18-39 with Ph-like ALL, Dr. Curran said.
Researchers are also wondering if up-front immunotherapy can help overcome disease biology, she said. Another potential therapy, she added, is CAR-T therapy for T-ALL.
Beyond cancer biology, “psychosocial factors are an even more challenging area in which we have fewer ongoing and less solutions,” Dr. Curran said.
Dr. Molina disclosed honoraria and consulting relationships with Autolus. Dr. Curran reported ties with Kite, Amgen, Incyte, Pfizer, Jazz, and Servier. Dr. Miller has no disclosures.
In a session at the annual meeting of the American Society of Hematology in December, clinicians defined the extent of the problem — which one described as a “survival cliff” — and they discussed potential strategies to turn things around.
Cleveland Clinic hematologist John Molina, MD, EdM, highlighted a 2022 study that revealed “the 5-year overall survival for younger pediatric patients is quite phenomenal at 93%. But as you start shifting even to 15-19 patients, that shifts to an overall survival of 74%.”
In the rest of the young adult population, from age 20 to 39, the overall survival rate dips down to 59%. What’s going on?
As Dr. Molina noted, a 2008 study revealed that outcomes in ALL for those aged 16-20 “historically depended on which door you walked into”: the pediatric setting or the adult setting. Patients fared better on pediatric regimens.
Currently, he explained, those who begin treatment in adult oncology clinics will start with either a pediatric-inspired treatment called CALGB 10403 or HyperCVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone plus methotrexate and cytarabine).
CALGB 10403 was developed based on a pediatric backbone of COG AALL0232, Dr. Molina said, and has higher doses of major myelosuppressive agents vs. HyperCVAD. A 2019 study determined that it was feasible to treat adolescents and young adults up to age 40 “with low treatment-related mortality and marked improvement in outcomes. OS [overall survival] at 3 years was 73%.”
However, Dr. Molina observed that only 39% of patients completed the treatment per protocol.
Which is better, CALGB 10403 or HyperCVAD? Dr. Molina said the risk of infertility and other long-term adverse effects is higher in HyperCVAD, but it has a lower risk of hepatic, pancreatic and thrombotic complications. And the CALGB 10403 regimen is more complicated to deliver, which is a potential obstacle in clinics without large numbers of patients.
As for outcomes, some research suggests they improve with pediatric-inspired regimens like CALGB 10403, he said, noting that “the debate continues.”
However, even with better regimens, Dr. Molina added, older ALL patients are still faring worse.
Also at the ASH presentation, Emory University/Children’s Healthcare of Atlanta pediatric cancer specialist Tamara Miller, MD, explored possible reasons that could explain the difference in outcomes based on age.
Cancer biology, response to chemotherapy, toxicities, psychosocial challenges, and low enrollment in clinical trials are all potential factors, she said. Specifically, aging into adulthood can lower tolerance of chemotherapy, and older patients are more prone to obesity, which is associated with worse outcomes, she said.
As for psychosocial challenges, it can be hard for older patients to manage their own medications, and they may lack insurance coverage, she said. Some patients may have worries about fertility, she added, and some may rebel against the requirements of treatment. Adherence is crucial to reducing risk of relapse, she added.
University of Cincinnati leukemia specialist Emily Curran, MD, told the ASH audience that researchers are exploring various avenues to improve outcomes.
Philadelphia chromosome-like (Ph-like) ALL, a subset of B-ALL, is associated with worse outcomes, she said, but it has multiple targetable pathways. An ongoing trial is exploring ruxolitinib (Jakafi) and chemotherapy in patients aged 18-39 with Ph-like ALL, Dr. Curran said.
Researchers are also wondering if up-front immunotherapy can help overcome disease biology, she said. Another potential therapy, she added, is CAR-T therapy for T-ALL.
Beyond cancer biology, “psychosocial factors are an even more challenging area in which we have fewer ongoing and less solutions,” Dr. Curran said.
Dr. Molina disclosed honoraria and consulting relationships with Autolus. Dr. Curran reported ties with Kite, Amgen, Incyte, Pfizer, Jazz, and Servier. Dr. Miller has no disclosures.
FROM ASH 2023
ALL: ASH Draws Up Tx Guidelines For Patients 15-39
At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.
The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.
As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”
Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”
In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.
In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.
“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”
One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.
“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”
Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?
In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?
“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.
On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.
ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.
Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.
At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.
The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.
As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”
Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”
In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.
In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.
“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”
One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.
“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”
Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?
In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?
“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.
On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.
ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.
Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.
At the crux of the matter is the unusual nature of ALL, said University of Chicago leukemia specialist Wendy Stock, MD, in a presentation at the annual meeting of the American Society of Hematology in December 2023. The disease is both rare and unique since it spans the entire lifetime from infancy to old age, she said.
The guidelines will focus on adolescents and young adults, which the National Cancer Institute defines as those aged 15-39. For these patients, “treatment is administered by the whole gamut of practitioners in the world of hematology, from pediatricians to adult hematologist/oncologists, which provides unique challenges in terms of understanding and access to care,” Dr. Stock said.
As she explained, ALL “is the bread and butter of pediatric oncology, but in the world of adult hematology-oncology, many patients are treated in small-practice settings where there have been very few uniform approaches available to the treating practitioners,” she said. “There’s not going to ever be the ability to get every — or even the majority — of adults into those big academic centers.”
Meanwhile, research from around the world has highlighted major mortality gaps between pediatric and adult care in ALL. “This has been our huge challenge: Is it the treatment approach? Is it the disease biology, the patient biology, the doctors who treat these diseases? Is it the geographic location where they’re treated? Well, we now know that, of course, it’s probably all of the above, and a lot more than that.”
In light of the need for guidance in ALL treatment, it will be crucial to disseminate data and recommendations via the guidelines, she said.
In 2021, ASH members approved the development of new clinical practice guidelines for this population. The process so far has been difficult, said pediatric oncologist Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Toronto, Ontario, at the ASH presentation.
“At one point,” Dr. Gupta recalled, “someone on our methodology team said this was the most challenging systematic review and guideline creation that they’d ever worked on, which is not what you want to hear as a co-chair.”
One major challenge for the guideline drafters is to balance ALL research findings that cover only certain ages, Dr. Gupta said. A study, for example, may only include patients up to age 21 or over age 35, making it difficult to decide how it fits into a larger evidence base for adolescents and young adults.
“We don’t always have perfect evidence. But we’re trying to take all of that and translate it into a formalized systematic review,” he said. “This is tricky for any guideline. But ALL poses a particular challenge because of how the evidence base is spread out.”
Another challenge is figuring out how to review psychosocial interventions in ALL. They are obviously crucial, he said. But should guidelines only take into account strategies that were tested in ALL? Or should they look at a wider perspective and encompass research into non–ALL-specific approaches?
In terms of guidance about frontline treatment, the guideline developers are focusing on several topics, said University of Rochester hematologist/oncologist Kristen O’Dwyer, MD, at the ASH presentation. These include: Should adolescents and young adults receive pediatric or adult regimens? Where do targeted therapy, immunotherapy, steroids, allogeneic stem cell transplants, and central nervous system (CNS) prophylaxis fit in?
“Finally, there are a series of questions that are addressing the toxicity prevention and management that go along with these intensive chemotherapy regimens,” she said.
On one front, there’s a “knowledge gap” about the value of stem cell transplant vs pediatric-inspired chemotherapy as postremission therapies, Dr. O’Dwyer said, because there are no direct comparisons. What to do? “There are retrospective comparisons that are emerging along with population-level analysis, single-arm observational studies that suggest that a pediatric-based chemotherapy approach is superior with similar relapse rates and less treatment-related mortality,” she said.
ASH expects to release a draft of its ALL guidelines for adolescents and young adults later this year and publish final recommendations in late 2024 or early 2025.
Dr. Stock, Dr. Gupta, and Dr. O’Dwyer have no disclosures.
FROM ASH 2023
Evidence Grows for SGLT2 Inhibitors in Rheumatology
Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they’re also being used to treat heart failure and chronic kidney disease. Now, there’s growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.
“I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases,” said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.
In gout, for example, “SGLT2 inhibitors hold great promise as a multipurpose treatment option,” said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr. Jorge and Dr. Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.
There’s a big caveat. For the moment, SGLT2 inhibitors aren’t cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.
But studies could pave the way toward more approved uses in rheumatology. And there’s good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, “sizable proportions of patients have comorbidities for which they are already indicated,” Dr. Yokose said.
Research Hints at Gout-Busting Potential
The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs “lower blood sugar by causing the kidneys to remove sugar from the body through urine,” reports the National Kidney Foundation, and they “help to protect the kidneys and heart in people with CKD [chronic kidney disease].”
As Dr. Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors “have really become blockbuster drugs, and they’ve now been integrated into multiple professional society guidelines and recommendations.”
These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they’re variously indicated for type 2 diabetes and obesity.
Dr. Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.
A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs. dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).
What about recurrent gout? In a 2023 study, Dr. Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).
“This finding requires further replication in other populations and compared to other drugs,” Dr. Yokose cautioned.
Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.
Lower Urate Levels and Less Inflammation Could Be Key
How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr. Yokose said, but researchers often excluded patients with gout.
For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr. Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs. 4.2% of sulfonylurea initiators.
“The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It’s believed to be between 1.5-2.0 mg/dL among patients with gout,” Dr. Yokose said. “Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification.”
Moving forward, she said, “I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout.”
In Lupus, Findings Are More Mixed
Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr. Jorge of Massachusetts General Hospital and Harvard Medical School. However, “one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE,” she said.
Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).
“Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use,” Dr. Jorge said. “We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication.”
Dr. Jorge added that “we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens.”
However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: “We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant … early experience suggested marginal benefit of SGLT2 inhibitors in SLE,” researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.
“My cohort is not showing miracles from SGLT2 inhibitors,” study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.
Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, “the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration,” Dr. Jorge added.
As for mechanism, Dr. Jorge said it’s not clear how the drugs may affect lupus. “It’s proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes.”
Side Effects and Cost: Where Do They Fit In?
According to Dr. Yokose, SGLT2 inhibitors “are generally quite well-tolerated, and very serious adverse effects are rare.” Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.
Urinary-related problems are understandable “because these drugs cause the kidneys to pass more glucose into the urine,” University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.
In Dr. Yokose’s 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding “was what we’d expect,” she said.
She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. “Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections.”
Dr. Cheung added that “doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range.”
As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1,000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.
“If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost,” Dr. Yokose said.
She added: “It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout.”
In regard to lupus, “many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs,” Dr. Jorge said. “Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment.”
As for prescribing the drugs in lupus now, Dr. Jorge said they can be an option in lupus nephritis. “There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range,” she said. “However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies.”
As for gout, Dr. Yokose isn’t ready to prescribe the drugs to patients who don’t have comorbidities that can be treated by the medications. However, she noted that those patients are rare.
“If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor.”
Dr. Yokose, Dr. Petri, and Dr. Cheung have no relevant disclosures. Dr. Jorge disclosed serving as a site investigator for SLE clinical trials funded by Bristol-Myers Squibb and Cabaletta Bio; the trials are not related to SGLT2 inhibitors.
Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they’re also being used to treat heart failure and chronic kidney disease. Now, there’s growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.
“I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases,” said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.
In gout, for example, “SGLT2 inhibitors hold great promise as a multipurpose treatment option,” said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr. Jorge and Dr. Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.
There’s a big caveat. For the moment, SGLT2 inhibitors aren’t cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.
But studies could pave the way toward more approved uses in rheumatology. And there’s good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, “sizable proportions of patients have comorbidities for which they are already indicated,” Dr. Yokose said.
Research Hints at Gout-Busting Potential
The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs “lower blood sugar by causing the kidneys to remove sugar from the body through urine,” reports the National Kidney Foundation, and they “help to protect the kidneys and heart in people with CKD [chronic kidney disease].”
As Dr. Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors “have really become blockbuster drugs, and they’ve now been integrated into multiple professional society guidelines and recommendations.”
These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they’re variously indicated for type 2 diabetes and obesity.
Dr. Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.
A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs. dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).
What about recurrent gout? In a 2023 study, Dr. Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).
“This finding requires further replication in other populations and compared to other drugs,” Dr. Yokose cautioned.
Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.
Lower Urate Levels and Less Inflammation Could Be Key
How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr. Yokose said, but researchers often excluded patients with gout.
For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr. Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs. 4.2% of sulfonylurea initiators.
“The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It’s believed to be between 1.5-2.0 mg/dL among patients with gout,” Dr. Yokose said. “Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification.”
Moving forward, she said, “I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout.”
In Lupus, Findings Are More Mixed
Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr. Jorge of Massachusetts General Hospital and Harvard Medical School. However, “one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE,” she said.
Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).
“Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use,” Dr. Jorge said. “We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication.”
Dr. Jorge added that “we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens.”
However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: “We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant … early experience suggested marginal benefit of SGLT2 inhibitors in SLE,” researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.
“My cohort is not showing miracles from SGLT2 inhibitors,” study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.
Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, “the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration,” Dr. Jorge added.
As for mechanism, Dr. Jorge said it’s not clear how the drugs may affect lupus. “It’s proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes.”
Side Effects and Cost: Where Do They Fit In?
According to Dr. Yokose, SGLT2 inhibitors “are generally quite well-tolerated, and very serious adverse effects are rare.” Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.
Urinary-related problems are understandable “because these drugs cause the kidneys to pass more glucose into the urine,” University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.
In Dr. Yokose’s 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding “was what we’d expect,” she said.
She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. “Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections.”
Dr. Cheung added that “doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range.”
As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1,000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.
“If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost,” Dr. Yokose said.
She added: “It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout.”
In regard to lupus, “many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs,” Dr. Jorge said. “Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment.”
As for prescribing the drugs in lupus now, Dr. Jorge said they can be an option in lupus nephritis. “There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range,” she said. “However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies.”
As for gout, Dr. Yokose isn’t ready to prescribe the drugs to patients who don’t have comorbidities that can be treated by the medications. However, she noted that those patients are rare.
“If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor.”
Dr. Yokose, Dr. Petri, and Dr. Cheung have no relevant disclosures. Dr. Jorge disclosed serving as a site investigator for SLE clinical trials funded by Bristol-Myers Squibb and Cabaletta Bio; the trials are not related to SGLT2 inhibitors.
Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they’re also being used to treat heart failure and chronic kidney disease. Now, there’s growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.
“I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases,” said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.
In gout, for example, “SGLT2 inhibitors hold great promise as a multipurpose treatment option,” said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr. Jorge and Dr. Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.
There’s a big caveat. For the moment, SGLT2 inhibitors aren’t cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.
But studies could pave the way toward more approved uses in rheumatology. And there’s good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, “sizable proportions of patients have comorbidities for which they are already indicated,” Dr. Yokose said.
Research Hints at Gout-Busting Potential
The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs “lower blood sugar by causing the kidneys to remove sugar from the body through urine,” reports the National Kidney Foundation, and they “help to protect the kidneys and heart in people with CKD [chronic kidney disease].”
As Dr. Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors “have really become blockbuster drugs, and they’ve now been integrated into multiple professional society guidelines and recommendations.”
These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they’re variously indicated for type 2 diabetes and obesity.
Dr. Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.
A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs. dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).
What about recurrent gout? In a 2023 study, Dr. Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).
“This finding requires further replication in other populations and compared to other drugs,” Dr. Yokose cautioned.
Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.
Lower Urate Levels and Less Inflammation Could Be Key
How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr. Yokose said, but researchers often excluded patients with gout.
For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr. Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs. 4.2% of sulfonylurea initiators.
“The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It’s believed to be between 1.5-2.0 mg/dL among patients with gout,” Dr. Yokose said. “Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification.”
Moving forward, she said, “I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout.”
In Lupus, Findings Are More Mixed
Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr. Jorge of Massachusetts General Hospital and Harvard Medical School. However, “one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE,” she said.
Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).
“Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use,” Dr. Jorge said. “We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication.”
Dr. Jorge added that “we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens.”
However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: “We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant … early experience suggested marginal benefit of SGLT2 inhibitors in SLE,” researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.
“My cohort is not showing miracles from SGLT2 inhibitors,” study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.
Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, “the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration,” Dr. Jorge added.
As for mechanism, Dr. Jorge said it’s not clear how the drugs may affect lupus. “It’s proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes.”
Side Effects and Cost: Where Do They Fit In?
According to Dr. Yokose, SGLT2 inhibitors “are generally quite well-tolerated, and very serious adverse effects are rare.” Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.
Urinary-related problems are understandable “because these drugs cause the kidneys to pass more glucose into the urine,” University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.
In Dr. Yokose’s 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding “was what we’d expect,” she said.
She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. “Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections.”
Dr. Cheung added that “doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range.”
As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1,000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.
“If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost,” Dr. Yokose said.
She added: “It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout.”
In regard to lupus, “many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs,” Dr. Jorge said. “Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment.”
As for prescribing the drugs in lupus now, Dr. Jorge said they can be an option in lupus nephritis. “There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range,” she said. “However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies.”
As for gout, Dr. Yokose isn’t ready to prescribe the drugs to patients who don’t have comorbidities that can be treated by the medications. However, she noted that those patients are rare.
“If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor.”
Dr. Yokose, Dr. Petri, and Dr. Cheung have no relevant disclosures. Dr. Jorge disclosed serving as a site investigator for SLE clinical trials funded by Bristol-Myers Squibb and Cabaletta Bio; the trials are not related to SGLT2 inhibitors.
ALL mortality gains bypass older adults
From 1999 to 2020, age-adjusted mortality rates for patients with ALL aged 55 and up didn’t change, oncologist-hematologist Jamie L. Koprivnikar, MD, of New Jersey’s Hackensack University Medical Center, reported at the annual meeting of the American Society of Hematology. The rates were 10.8 per 1 million in 1999 and 10.6 per 1 million in 2020.
By contrast, the mortality rates for children aged 0-15 improved from 3.5 per 1 million in 1999 to 2.2 per 1 million in 2020.
“The findings were particularly surprising and disappointing to me,” Dr. Koprivnikar said in an interview. “My overall sense is that we’ve really improved our outcomes of treating patients with ALL and are making great strides forward, moving away from so much chemotherapy and toward more kinds of immunotherapies and targeted therapies. So we need to understand what’s driving this.”
According to Dr. Koprivnikar, ALL is more common in children than adults. However, “even though the majority of cases tend to occur in children, we know that the majority of deaths are actually in the adult patient population,” she said.
One challenge for treatment is that therapies that work well in the pediatric population aren’t as effective in adults, she said. ALL is biologically different in adults in some ways, she added, and older patients may have more comorbidities. “It ends up being a really complicated story with all of these different factors playing into the complexity.”
For the new study, Dr. Koprivnikar and colleagues analyzed death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research database. They found that 17,238 people died from ALL between 1999 and 2020. There were no significant differences in terms of gender, race, and region.
The study authors noted that mortality rates didn’t change despite medical advances in ALL such as blinatumomab, inotuzumab, and targeted tyrosine kinase inhibitor-based therapy. It’s unclear if the treatments have made it to the older-adult setting yet, Dr. Koprivnikar said.
There may be problems with access due to socioeconomic factors as well, she said. “ALL is actually more common among those of Hispanic heritage, and we don’t completely understand that.”
Marlise R. Luskin, MD, a leukemia specialist at Dana-Farber Cancer Institute, Boston, said in an interview that the study “is a reminder that clinical trial outcomes are limited — specifically trial results that often emphasize early results and report on a select population of older patients who generally are socially resourced and physically and mentally more fit.”
Dr. Luskin added that the study reports on outcomes through 2020, including years when newer regimens were not broadly disseminated outside of clinical trials.
Moving forward, she said, “this report suggests we need to continue to develop novel approaches and understand long-term outcomes as well as ‘real world’ outcomes. A similar study should be repeated again in 3-5 years as novel regimens become standard. We hope to see improvements.”
No study funding was reported. Dr. Koprivnikar disclosed consulting relationships with Alexion, GSK, Novartis, and Apellis. Other authors reported no disclosures. Dr. Luskin disclosed ties with Pfizer, Novartis, Jazz, Kite, and AbbVie.
From 1999 to 2020, age-adjusted mortality rates for patients with ALL aged 55 and up didn’t change, oncologist-hematologist Jamie L. Koprivnikar, MD, of New Jersey’s Hackensack University Medical Center, reported at the annual meeting of the American Society of Hematology. The rates were 10.8 per 1 million in 1999 and 10.6 per 1 million in 2020.
By contrast, the mortality rates for children aged 0-15 improved from 3.5 per 1 million in 1999 to 2.2 per 1 million in 2020.
“The findings were particularly surprising and disappointing to me,” Dr. Koprivnikar said in an interview. “My overall sense is that we’ve really improved our outcomes of treating patients with ALL and are making great strides forward, moving away from so much chemotherapy and toward more kinds of immunotherapies and targeted therapies. So we need to understand what’s driving this.”
According to Dr. Koprivnikar, ALL is more common in children than adults. However, “even though the majority of cases tend to occur in children, we know that the majority of deaths are actually in the adult patient population,” she said.
One challenge for treatment is that therapies that work well in the pediatric population aren’t as effective in adults, she said. ALL is biologically different in adults in some ways, she added, and older patients may have more comorbidities. “It ends up being a really complicated story with all of these different factors playing into the complexity.”
For the new study, Dr. Koprivnikar and colleagues analyzed death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research database. They found that 17,238 people died from ALL between 1999 and 2020. There were no significant differences in terms of gender, race, and region.
The study authors noted that mortality rates didn’t change despite medical advances in ALL such as blinatumomab, inotuzumab, and targeted tyrosine kinase inhibitor-based therapy. It’s unclear if the treatments have made it to the older-adult setting yet, Dr. Koprivnikar said.
There may be problems with access due to socioeconomic factors as well, she said. “ALL is actually more common among those of Hispanic heritage, and we don’t completely understand that.”
Marlise R. Luskin, MD, a leukemia specialist at Dana-Farber Cancer Institute, Boston, said in an interview that the study “is a reminder that clinical trial outcomes are limited — specifically trial results that often emphasize early results and report on a select population of older patients who generally are socially resourced and physically and mentally more fit.”
Dr. Luskin added that the study reports on outcomes through 2020, including years when newer regimens were not broadly disseminated outside of clinical trials.
Moving forward, she said, “this report suggests we need to continue to develop novel approaches and understand long-term outcomes as well as ‘real world’ outcomes. A similar study should be repeated again in 3-5 years as novel regimens become standard. We hope to see improvements.”
No study funding was reported. Dr. Koprivnikar disclosed consulting relationships with Alexion, GSK, Novartis, and Apellis. Other authors reported no disclosures. Dr. Luskin disclosed ties with Pfizer, Novartis, Jazz, Kite, and AbbVie.
From 1999 to 2020, age-adjusted mortality rates for patients with ALL aged 55 and up didn’t change, oncologist-hematologist Jamie L. Koprivnikar, MD, of New Jersey’s Hackensack University Medical Center, reported at the annual meeting of the American Society of Hematology. The rates were 10.8 per 1 million in 1999 and 10.6 per 1 million in 2020.
By contrast, the mortality rates for children aged 0-15 improved from 3.5 per 1 million in 1999 to 2.2 per 1 million in 2020.
“The findings were particularly surprising and disappointing to me,” Dr. Koprivnikar said in an interview. “My overall sense is that we’ve really improved our outcomes of treating patients with ALL and are making great strides forward, moving away from so much chemotherapy and toward more kinds of immunotherapies and targeted therapies. So we need to understand what’s driving this.”
According to Dr. Koprivnikar, ALL is more common in children than adults. However, “even though the majority of cases tend to occur in children, we know that the majority of deaths are actually in the adult patient population,” she said.
One challenge for treatment is that therapies that work well in the pediatric population aren’t as effective in adults, she said. ALL is biologically different in adults in some ways, she added, and older patients may have more comorbidities. “It ends up being a really complicated story with all of these different factors playing into the complexity.”
For the new study, Dr. Koprivnikar and colleagues analyzed death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research database. They found that 17,238 people died from ALL between 1999 and 2020. There were no significant differences in terms of gender, race, and region.
The study authors noted that mortality rates didn’t change despite medical advances in ALL such as blinatumomab, inotuzumab, and targeted tyrosine kinase inhibitor-based therapy. It’s unclear if the treatments have made it to the older-adult setting yet, Dr. Koprivnikar said.
There may be problems with access due to socioeconomic factors as well, she said. “ALL is actually more common among those of Hispanic heritage, and we don’t completely understand that.”
Marlise R. Luskin, MD, a leukemia specialist at Dana-Farber Cancer Institute, Boston, said in an interview that the study “is a reminder that clinical trial outcomes are limited — specifically trial results that often emphasize early results and report on a select population of older patients who generally are socially resourced and physically and mentally more fit.”
Dr. Luskin added that the study reports on outcomes through 2020, including years when newer regimens were not broadly disseminated outside of clinical trials.
Moving forward, she said, “this report suggests we need to continue to develop novel approaches and understand long-term outcomes as well as ‘real world’ outcomes. A similar study should be repeated again in 3-5 years as novel regimens become standard. We hope to see improvements.”
No study funding was reported. Dr. Koprivnikar disclosed consulting relationships with Alexion, GSK, Novartis, and Apellis. Other authors reported no disclosures. Dr. Luskin disclosed ties with Pfizer, Novartis, Jazz, Kite, and AbbVie.
FROM ASH 2023
How scientists are uncovering the mysteries of ARDS
, the devastating disorder that floods the lungs with fluid and has ushered countless millions to death after infection with pneumonia, sepsis, and COVID-19.
Two centuries after the lung damage caused by the disorder was first described in medicine, it’s now clear that ARDS is an autoimmune condition spurred by the body’s overactive defenses. There’s interest in disrupting “crosstalk” between cells, and rise of a new form of genetic analysis is allowing researchers to test their hypotheses more effectively than ever before. And, perhaps most importantly, recent findings reveal how stem cells in the epithelial lining of the lungs get stalled in an intermediate stage before regenerating into new cells. Reversing this process could trigger repair and recovery.
There’s still a ways to go before clinical trials can test therapies to turn things around at the epithelial level, acknowledged University of Michigan, Ann Arbor, professor of internal medicine Rachel L. Zemans, MD, in an interview. Still, “it’s a pretty exciting time,” said Dr Zemans, who manages a lab that explores how the lung epithelium responds to injury.
A lung disorder’s deep roots in human history
A British doctor first described the traits of ARDS in 1821, although this form of pulmonary edema had been described in “ancient writings,” according to a 2005 report by Gordon Bernard, MD, of Vanderbilt University Medical Center, Nashville, Tennessee. Sometimes called “double pneumonia,” ARDS was almost always fatal until the last few decades of the 20th century. “The advent of well-equipped ICUs, well-trained staff, and the availability of reliable positive pressure ventilators has allowed patients to be kept alive much longer and thus have the opportunity to heal the pulmonary injury and survive,” Dr Bernard wrote.
According to the Mayo Clinic, there are many causes of ARDS. Sepsis is the most common, and others include severe pneumonia, head/chest injuries, massive blood transfusions, pancreatitis, burns, and inhalation of harmful substances. Since 2020, ARDS has been a hallmark of COVID-19.
In an interview, University of Washington, Seattle, emeritus professor of medicine Thomas R. Martin MD, explained that ARDS occurs when the epithelium barrier in the lungs breaks down. Unlike the permeable endothelial barrier, the alveolar epithelium is “like a brick wall or a big dam, keeping red cells and plasma out of the airspace.”
In cases of pulmonary edema due to heart failure, fluid can back up into the lungs, said Dr Martin, who studies ARDS. However, pumps in the epithelium can clear that excess fluid pretty quickly because the epithelium remains in a normal state, he said. “Given enough time and enough medical support, people with heart failure and pulmonary edema can get better without lung injury.”
In ARDS, however, “the epithelium is damaged. Cells die in the alveolar wall, the scaffolding is exposed, and the fluid in the alveoli cannot be cleared out. You’ve got a disaster on your hands because all of the fluid and red blood cells and inflammatory products in the blood are going right into the airspace. The patient gets extremely short of breath because their oxygen level falls.”
COVID-19 virus finds a weak spot in the lungs
COVID-19 is “a classic example of an attack on the alveolar epithelium,” Dr Martin said.
By chance, the virus evolved to recognize receptors in the epithelium, allowing it to enter and propagate. “To make matters worse, defense mechanisms in the body attack those dying epithelial cells because the virus is visible on the surface cells. So lymphocytes from the immune system and macrophages attack the outer walls and cause further damage.”
Other scientists agree about this general picture of ARDS. “Studies of human lung tissue support the notion that failure of alveolar repair and regeneration mechanisms underlie the chronic lung dysfunction that can result from ARD,” wrote researchers from Cedars-Sinai Medical Center, Los Angeles, California, and Icahn School of Medicine at Mount Sinai, New York, NY, in a 2022 report.
According to Dr Martin, researchers and clinicians have discovered a pair of strategies to help vanquish COVID-19: Control viral entry through antiviral medication and dampen the body’s inflammatory response via steroids.
Still, “although we’ve learned lessons from COVID-19, we’re not good at all at promoting repair,” Dr Martin said. While new drugs have dramatically improved treatment for lung diseases such as cystic fibrosis, he said, “we don’t have good examples of new therapies that promote repair in ARDS.”
Looking for a way to turn the tide of fluid buildup
Dr Zemans and colleagues have uncovered a crucial obstacle to repair: the failure of stem cells to fully differentiate and become functional alveolar epithelial cells.
Researchers only began to understand a few years ago that the stem cells go through a transitional stage from type 2 to type 1, which make up 98% of cells in the epithelial surface, Dr Zemans said. In patients with ARDS who don’t get better quickly, “it looks like the cells get hung up in this intermediate state. They can’t finish that regeneration.”
As a 2022 study by Dr Zemans and colleagues put it, this process can lead to “ongoing barrier permeability, noncardiogenic pulmonary edema, and ventilator dependence, and mortality.” In fact, she said, “when we look at the lungs of people who died of ARDS, their cells were all in that intermediate stage.”
The discovery of the intermediate state only came about because of new technology called single-cell RNA sequencing, she said. “Now, these transitional cells are being found in other organs.”
Why do the epithelial cells get only part way through the regeneration process? It’s not entirely clear, Dr Zemans said, but researcher are intrigued by the idea that “cross-talk” between cells is playing a role.
“When the cells are in that stage, they also activate neighboring cells, including inflammatory cells, like macrophages, and fibroblasts,” she said. “And once those cells become activated, they become pathologic. What we think is that those cells then can talk back to the epithelial cells and prevent the epithelial cells from finishing that differentiation. It’s really hard to snap out of that positive feedback loop.”
This interaction probably evolved “for a good reason,” she said, “but it also became pathologic.” If the cells stay in the intermediate stage too long, she said, fibrosis develops. “They have scar tissue that never goes away. It takes a lot of work to expand the lungs when they’re so stiff when they should be stretchy like a rubber band. Scar tissue also gets in the way of the oxygen absorption, so some people have low oxygen levels.”
Future directions: Teaching cells to get “unstuck”
What’s next for research? One direction is exploring the variety of types of cells in the epithelium. Recent finding are revealing “new cell subpopulations that maintain alveolar homeostasis, communicate injury signals, and participate in normal and maladaptive repair. Emerging data illuminate the complexity of alveolar physiology and pathology to provide a more complete picture of how alveoli maintain health and respond to injurious stimuli,” write the researchers from Cedars-Sinai Medical Center and Icahn School of Medicine at Mount Sinai in their 2022 report.
Meanwhile, “we’re trying to look at the signaling pathways, the proteins or molecules, to understand the signals that tell a cell how to get unstuck,” Dr Zemans said. And researchers are exploring whether knocking out certain genes expressed by transitional cells in mice will lead to better outcomes, she said.
The 2022 study by Dr Zeman and colleagues described the potential ramifications of better understanding of the entire process: “Ultimately, investigation of the cellular and molecular mechanisms underlying ineffectual alveolar regeneration in ARDS and fibrosis may lead to novel therapies to promote physiological regeneration, thus accelerating restoration of barrier integrity, resolution of edema, liberation from the ventilator and survival in ARDS, and preventing fibrosis in fibroproliferative ARDS and [idiopathic pulmonary fibrosis].”
To put it more simply, “if you can seal the barrier, you can get the fluid out of the lungs, and you can get the patients off the ventilator, get out of the ICU, and go home,” Dr Zemans said.
Dr Zemans and Dr Martin have no disclosures.
, the devastating disorder that floods the lungs with fluid and has ushered countless millions to death after infection with pneumonia, sepsis, and COVID-19.
Two centuries after the lung damage caused by the disorder was first described in medicine, it’s now clear that ARDS is an autoimmune condition spurred by the body’s overactive defenses. There’s interest in disrupting “crosstalk” between cells, and rise of a new form of genetic analysis is allowing researchers to test their hypotheses more effectively than ever before. And, perhaps most importantly, recent findings reveal how stem cells in the epithelial lining of the lungs get stalled in an intermediate stage before regenerating into new cells. Reversing this process could trigger repair and recovery.
There’s still a ways to go before clinical trials can test therapies to turn things around at the epithelial level, acknowledged University of Michigan, Ann Arbor, professor of internal medicine Rachel L. Zemans, MD, in an interview. Still, “it’s a pretty exciting time,” said Dr Zemans, who manages a lab that explores how the lung epithelium responds to injury.
A lung disorder’s deep roots in human history
A British doctor first described the traits of ARDS in 1821, although this form of pulmonary edema had been described in “ancient writings,” according to a 2005 report by Gordon Bernard, MD, of Vanderbilt University Medical Center, Nashville, Tennessee. Sometimes called “double pneumonia,” ARDS was almost always fatal until the last few decades of the 20th century. “The advent of well-equipped ICUs, well-trained staff, and the availability of reliable positive pressure ventilators has allowed patients to be kept alive much longer and thus have the opportunity to heal the pulmonary injury and survive,” Dr Bernard wrote.
According to the Mayo Clinic, there are many causes of ARDS. Sepsis is the most common, and others include severe pneumonia, head/chest injuries, massive blood transfusions, pancreatitis, burns, and inhalation of harmful substances. Since 2020, ARDS has been a hallmark of COVID-19.
In an interview, University of Washington, Seattle, emeritus professor of medicine Thomas R. Martin MD, explained that ARDS occurs when the epithelium barrier in the lungs breaks down. Unlike the permeable endothelial barrier, the alveolar epithelium is “like a brick wall or a big dam, keeping red cells and plasma out of the airspace.”
In cases of pulmonary edema due to heart failure, fluid can back up into the lungs, said Dr Martin, who studies ARDS. However, pumps in the epithelium can clear that excess fluid pretty quickly because the epithelium remains in a normal state, he said. “Given enough time and enough medical support, people with heart failure and pulmonary edema can get better without lung injury.”
In ARDS, however, “the epithelium is damaged. Cells die in the alveolar wall, the scaffolding is exposed, and the fluid in the alveoli cannot be cleared out. You’ve got a disaster on your hands because all of the fluid and red blood cells and inflammatory products in the blood are going right into the airspace. The patient gets extremely short of breath because their oxygen level falls.”
COVID-19 virus finds a weak spot in the lungs
COVID-19 is “a classic example of an attack on the alveolar epithelium,” Dr Martin said.
By chance, the virus evolved to recognize receptors in the epithelium, allowing it to enter and propagate. “To make matters worse, defense mechanisms in the body attack those dying epithelial cells because the virus is visible on the surface cells. So lymphocytes from the immune system and macrophages attack the outer walls and cause further damage.”
Other scientists agree about this general picture of ARDS. “Studies of human lung tissue support the notion that failure of alveolar repair and regeneration mechanisms underlie the chronic lung dysfunction that can result from ARD,” wrote researchers from Cedars-Sinai Medical Center, Los Angeles, California, and Icahn School of Medicine at Mount Sinai, New York, NY, in a 2022 report.
According to Dr Martin, researchers and clinicians have discovered a pair of strategies to help vanquish COVID-19: Control viral entry through antiviral medication and dampen the body’s inflammatory response via steroids.
Still, “although we’ve learned lessons from COVID-19, we’re not good at all at promoting repair,” Dr Martin said. While new drugs have dramatically improved treatment for lung diseases such as cystic fibrosis, he said, “we don’t have good examples of new therapies that promote repair in ARDS.”
Looking for a way to turn the tide of fluid buildup
Dr Zemans and colleagues have uncovered a crucial obstacle to repair: the failure of stem cells to fully differentiate and become functional alveolar epithelial cells.
Researchers only began to understand a few years ago that the stem cells go through a transitional stage from type 2 to type 1, which make up 98% of cells in the epithelial surface, Dr Zemans said. In patients with ARDS who don’t get better quickly, “it looks like the cells get hung up in this intermediate state. They can’t finish that regeneration.”
As a 2022 study by Dr Zemans and colleagues put it, this process can lead to “ongoing barrier permeability, noncardiogenic pulmonary edema, and ventilator dependence, and mortality.” In fact, she said, “when we look at the lungs of people who died of ARDS, their cells were all in that intermediate stage.”
The discovery of the intermediate state only came about because of new technology called single-cell RNA sequencing, she said. “Now, these transitional cells are being found in other organs.”
Why do the epithelial cells get only part way through the regeneration process? It’s not entirely clear, Dr Zemans said, but researcher are intrigued by the idea that “cross-talk” between cells is playing a role.
“When the cells are in that stage, they also activate neighboring cells, including inflammatory cells, like macrophages, and fibroblasts,” she said. “And once those cells become activated, they become pathologic. What we think is that those cells then can talk back to the epithelial cells and prevent the epithelial cells from finishing that differentiation. It’s really hard to snap out of that positive feedback loop.”
This interaction probably evolved “for a good reason,” she said, “but it also became pathologic.” If the cells stay in the intermediate stage too long, she said, fibrosis develops. “They have scar tissue that never goes away. It takes a lot of work to expand the lungs when they’re so stiff when they should be stretchy like a rubber band. Scar tissue also gets in the way of the oxygen absorption, so some people have low oxygen levels.”
Future directions: Teaching cells to get “unstuck”
What’s next for research? One direction is exploring the variety of types of cells in the epithelium. Recent finding are revealing “new cell subpopulations that maintain alveolar homeostasis, communicate injury signals, and participate in normal and maladaptive repair. Emerging data illuminate the complexity of alveolar physiology and pathology to provide a more complete picture of how alveoli maintain health and respond to injurious stimuli,” write the researchers from Cedars-Sinai Medical Center and Icahn School of Medicine at Mount Sinai in their 2022 report.
Meanwhile, “we’re trying to look at the signaling pathways, the proteins or molecules, to understand the signals that tell a cell how to get unstuck,” Dr Zemans said. And researchers are exploring whether knocking out certain genes expressed by transitional cells in mice will lead to better outcomes, she said.
The 2022 study by Dr Zeman and colleagues described the potential ramifications of better understanding of the entire process: “Ultimately, investigation of the cellular and molecular mechanisms underlying ineffectual alveolar regeneration in ARDS and fibrosis may lead to novel therapies to promote physiological regeneration, thus accelerating restoration of barrier integrity, resolution of edema, liberation from the ventilator and survival in ARDS, and preventing fibrosis in fibroproliferative ARDS and [idiopathic pulmonary fibrosis].”
To put it more simply, “if you can seal the barrier, you can get the fluid out of the lungs, and you can get the patients off the ventilator, get out of the ICU, and go home,” Dr Zemans said.
Dr Zemans and Dr Martin have no disclosures.
, the devastating disorder that floods the lungs with fluid and has ushered countless millions to death after infection with pneumonia, sepsis, and COVID-19.
Two centuries after the lung damage caused by the disorder was first described in medicine, it’s now clear that ARDS is an autoimmune condition spurred by the body’s overactive defenses. There’s interest in disrupting “crosstalk” between cells, and rise of a new form of genetic analysis is allowing researchers to test their hypotheses more effectively than ever before. And, perhaps most importantly, recent findings reveal how stem cells in the epithelial lining of the lungs get stalled in an intermediate stage before regenerating into new cells. Reversing this process could trigger repair and recovery.
There’s still a ways to go before clinical trials can test therapies to turn things around at the epithelial level, acknowledged University of Michigan, Ann Arbor, professor of internal medicine Rachel L. Zemans, MD, in an interview. Still, “it’s a pretty exciting time,” said Dr Zemans, who manages a lab that explores how the lung epithelium responds to injury.
A lung disorder’s deep roots in human history
A British doctor first described the traits of ARDS in 1821, although this form of pulmonary edema had been described in “ancient writings,” according to a 2005 report by Gordon Bernard, MD, of Vanderbilt University Medical Center, Nashville, Tennessee. Sometimes called “double pneumonia,” ARDS was almost always fatal until the last few decades of the 20th century. “The advent of well-equipped ICUs, well-trained staff, and the availability of reliable positive pressure ventilators has allowed patients to be kept alive much longer and thus have the opportunity to heal the pulmonary injury and survive,” Dr Bernard wrote.
According to the Mayo Clinic, there are many causes of ARDS. Sepsis is the most common, and others include severe pneumonia, head/chest injuries, massive blood transfusions, pancreatitis, burns, and inhalation of harmful substances. Since 2020, ARDS has been a hallmark of COVID-19.
In an interview, University of Washington, Seattle, emeritus professor of medicine Thomas R. Martin MD, explained that ARDS occurs when the epithelium barrier in the lungs breaks down. Unlike the permeable endothelial barrier, the alveolar epithelium is “like a brick wall or a big dam, keeping red cells and plasma out of the airspace.”
In cases of pulmonary edema due to heart failure, fluid can back up into the lungs, said Dr Martin, who studies ARDS. However, pumps in the epithelium can clear that excess fluid pretty quickly because the epithelium remains in a normal state, he said. “Given enough time and enough medical support, people with heart failure and pulmonary edema can get better without lung injury.”
In ARDS, however, “the epithelium is damaged. Cells die in the alveolar wall, the scaffolding is exposed, and the fluid in the alveoli cannot be cleared out. You’ve got a disaster on your hands because all of the fluid and red blood cells and inflammatory products in the blood are going right into the airspace. The patient gets extremely short of breath because their oxygen level falls.”
COVID-19 virus finds a weak spot in the lungs
COVID-19 is “a classic example of an attack on the alveolar epithelium,” Dr Martin said.
By chance, the virus evolved to recognize receptors in the epithelium, allowing it to enter and propagate. “To make matters worse, defense mechanisms in the body attack those dying epithelial cells because the virus is visible on the surface cells. So lymphocytes from the immune system and macrophages attack the outer walls and cause further damage.”
Other scientists agree about this general picture of ARDS. “Studies of human lung tissue support the notion that failure of alveolar repair and regeneration mechanisms underlie the chronic lung dysfunction that can result from ARD,” wrote researchers from Cedars-Sinai Medical Center, Los Angeles, California, and Icahn School of Medicine at Mount Sinai, New York, NY, in a 2022 report.
According to Dr Martin, researchers and clinicians have discovered a pair of strategies to help vanquish COVID-19: Control viral entry through antiviral medication and dampen the body’s inflammatory response via steroids.
Still, “although we’ve learned lessons from COVID-19, we’re not good at all at promoting repair,” Dr Martin said. While new drugs have dramatically improved treatment for lung diseases such as cystic fibrosis, he said, “we don’t have good examples of new therapies that promote repair in ARDS.”
Looking for a way to turn the tide of fluid buildup
Dr Zemans and colleagues have uncovered a crucial obstacle to repair: the failure of stem cells to fully differentiate and become functional alveolar epithelial cells.
Researchers only began to understand a few years ago that the stem cells go through a transitional stage from type 2 to type 1, which make up 98% of cells in the epithelial surface, Dr Zemans said. In patients with ARDS who don’t get better quickly, “it looks like the cells get hung up in this intermediate state. They can’t finish that regeneration.”
As a 2022 study by Dr Zemans and colleagues put it, this process can lead to “ongoing barrier permeability, noncardiogenic pulmonary edema, and ventilator dependence, and mortality.” In fact, she said, “when we look at the lungs of people who died of ARDS, their cells were all in that intermediate stage.”
The discovery of the intermediate state only came about because of new technology called single-cell RNA sequencing, she said. “Now, these transitional cells are being found in other organs.”
Why do the epithelial cells get only part way through the regeneration process? It’s not entirely clear, Dr Zemans said, but researcher are intrigued by the idea that “cross-talk” between cells is playing a role.
“When the cells are in that stage, they also activate neighboring cells, including inflammatory cells, like macrophages, and fibroblasts,” she said. “And once those cells become activated, they become pathologic. What we think is that those cells then can talk back to the epithelial cells and prevent the epithelial cells from finishing that differentiation. It’s really hard to snap out of that positive feedback loop.”
This interaction probably evolved “for a good reason,” she said, “but it also became pathologic.” If the cells stay in the intermediate stage too long, she said, fibrosis develops. “They have scar tissue that never goes away. It takes a lot of work to expand the lungs when they’re so stiff when they should be stretchy like a rubber band. Scar tissue also gets in the way of the oxygen absorption, so some people have low oxygen levels.”
Future directions: Teaching cells to get “unstuck”
What’s next for research? One direction is exploring the variety of types of cells in the epithelium. Recent finding are revealing “new cell subpopulations that maintain alveolar homeostasis, communicate injury signals, and participate in normal and maladaptive repair. Emerging data illuminate the complexity of alveolar physiology and pathology to provide a more complete picture of how alveoli maintain health and respond to injurious stimuli,” write the researchers from Cedars-Sinai Medical Center and Icahn School of Medicine at Mount Sinai in their 2022 report.
Meanwhile, “we’re trying to look at the signaling pathways, the proteins or molecules, to understand the signals that tell a cell how to get unstuck,” Dr Zemans said. And researchers are exploring whether knocking out certain genes expressed by transitional cells in mice will lead to better outcomes, she said.
The 2022 study by Dr Zeman and colleagues described the potential ramifications of better understanding of the entire process: “Ultimately, investigation of the cellular and molecular mechanisms underlying ineffectual alveolar regeneration in ARDS and fibrosis may lead to novel therapies to promote physiological regeneration, thus accelerating restoration of barrier integrity, resolution of edema, liberation from the ventilator and survival in ARDS, and preventing fibrosis in fibroproliferative ARDS and [idiopathic pulmonary fibrosis].”
To put it more simply, “if you can seal the barrier, you can get the fluid out of the lungs, and you can get the patients off the ventilator, get out of the ICU, and go home,” Dr Zemans said.
Dr Zemans and Dr Martin have no disclosures.