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Patient Navigators for Serious Illnesses Can Now Bill Under New Medicare Codes
In a move that acknowledges the gauntlet the US health system poses for people facing serious and fatal illnesses, Medicare will pay for a new class of workers to help patients manage treatments for conditions like cancer and heart failure.
The 2024 Medicare physician fee schedule includes new billing codes, including G0023, to pay for 60 minutes a month of care coordination by certified or trained auxiliary personnel working under the direction of a clinician.
A diagnosis of cancer or another serious illness takes a toll beyond the physical effects of the disease. Patients often scramble to make adjustments in family and work schedules to manage treatment, said Samyukta Mullangi, MD, MBA, medical director of oncology at Thyme Care, a Nashville, Tennessee–based firm that provides navigation and coordination services to oncology practices and insurers.
“It just really does create a bit of a pressure cooker for patients,” Dr. Mullangi told this news organization.
Medicare has for many years paid for medical professionals to help patients cope with the complexities of disease, such as chronic care management (CCM) provided by physicians, nurses, and physician assistants.
The new principal illness navigation (PIN) payments are intended to pay for work that to date typically has been done by people without medical degrees, including those involved in peer support networks and community health programs. The US Centers for Medicare and Medicaid Services(CMS) expects these navigators will undergo training and work under the supervision of clinicians.
The new navigators may coordinate care transitions between medical settings, follow up with patients after emergency department (ED) visits, or communicate with skilled nursing facilities regarding the psychosocial needs and functional deficits of a patient, among other functions.
CMS expects the new navigators may:
- Conduct assessments to understand a patient’s life story, strengths, needs, goals, preferences, and desired outcomes, including understanding cultural and linguistic factors.
- Provide support to accomplish the clinician’s treatment plan.
- Coordinate the receipt of needed services from healthcare facilities, home- and community-based service providers, and caregivers.
Peers as Navigators
The new navigators can be former patients who have undergone similar treatments for serious diseases, CMS said. This approach sets the new program apart from other care management services Medicare already covers, program officials wrote in the 2024 physician fee schedule.
“For some conditions, patients are best able to engage with the healthcare system and access care if they have assistance from a single, dedicated individual who has ‘lived experience,’ ” according to the rule.
The agency has taken a broad initial approach in defining what kinds of illnesses a patient may have to qualify for services. Patients must have a serious condition that is expected to last at least 3 months, such as cancer, heart failure, or substance use disorder.
But those without a definitive diagnosis may also qualify to receive navigator services.
In the rule, CMS cited a case in which a CT scan identified a suspicious mass in a patient’s colon. A clinician might decide this person would benefit from navigation services due to the potential risks for an undiagnosed illness.
“Regardless of the definitive diagnosis of the mass, presence of a colonic mass for that patient may be a serious high-risk condition that could, for example, cause obstruction and lead the patient to present to the emergency department, as well as be potentially indicative of an underlying life-threatening illness such as colon cancer,” CMS wrote in the rule.
Navigators often start their work when cancer patients are screened and guide them through initial diagnosis, potential surgery, radiation, or chemotherapy, said Sharon Gentry, MSN, RN, a former nurse navigator who is now the editor in chief of the Journal of the Academy of Oncology Nurse & Patient Navigators.
The navigators are meant to be a trusted and continual presence for patients, who otherwise might be left to start anew in finding help at each phase of care.
The navigators “see the whole picture. They see the whole journey the patient takes, from pre-diagnosis all the way through diagnosis care out through survival,” Ms. Gentry said.
Gaining a special Medicare payment for these kinds of services will elevate this work, she said.
Many newer drugs can target specific mechanisms and proteins of cancer. Often, oncology treatment involves testing to find out if mutations are allowing the cancer cells to evade a patient’s immune system.
Checking these biomarkers takes time, however. Patients sometimes become frustrated because they are anxious to begin treatment. Patients may receive inaccurate information from friends or family who went through treatment previously. Navigators can provide knowledge on the current state of care for a patient’s disease, helping them better manage anxieties.
“You have to explain to them that things have changed since the guy you drink coffee with was diagnosed with cancer, and there may be a drug that could target that,” Ms. Gentry said.
Potential Challenges
Initial uptake of the new PIN codes may be slow going, however, as clinicians and health systems may already use well-established codes. These include CCM and principal care management services, which may pay higher rates, Mullangi said.
“There might be sensitivity around not wanting to cannibalize existing programs with a new program,” Dr. Mullangi said.
In addition, many patients will have a copay for the services of principal illness navigators, Dr. Mullangi said.
While many patients have additional insurance that would cover the service, not all do. People with traditional Medicare coverage can sometimes pay 20% of the cost of some medical services.
“I think that may give patients pause, particularly if they’re already feeling the financial burden of a cancer treatment journey,” Dr. Mullangi said.
Pay rates for PIN services involve calculations of regional price differences, which are posted publicly by CMS, and potential added fees for services provided by hospital-affiliated organizations.
Consider payments for code G0023, covering 60 minutes of principal navigation services provided in a single month.
A set reimbursement for patients cared for in independent medical practices exists, with variation for local costs. Medicare’s non-facility price for G0023 would be $102.41 in some parts of Silicon Valley in California, including San Jose. In Arkansas, where costs are lower, reimbursement would be $73.14 for this same service.
Patients who get services covered by code G0023 in independent medical practices would have monthly copays of about $15-$20, depending on where they live.
The tab for patients tends to be higher for these same services if delivered through a medical practice owned by a hospital, as this would trigger the addition of facility fees to the payments made to cover the services. Facility fees are difficult for the public to ascertain before getting a treatment or service.
Dr. Mullangi and Ms. Gentry reported no relevant financial disclosures outside of their employers.
A version of this article first appeared on Medscape.com.
In a move that acknowledges the gauntlet the US health system poses for people facing serious and fatal illnesses, Medicare will pay for a new class of workers to help patients manage treatments for conditions like cancer and heart failure.
The 2024 Medicare physician fee schedule includes new billing codes, including G0023, to pay for 60 minutes a month of care coordination by certified or trained auxiliary personnel working under the direction of a clinician.
A diagnosis of cancer or another serious illness takes a toll beyond the physical effects of the disease. Patients often scramble to make adjustments in family and work schedules to manage treatment, said Samyukta Mullangi, MD, MBA, medical director of oncology at Thyme Care, a Nashville, Tennessee–based firm that provides navigation and coordination services to oncology practices and insurers.
“It just really does create a bit of a pressure cooker for patients,” Dr. Mullangi told this news organization.
Medicare has for many years paid for medical professionals to help patients cope with the complexities of disease, such as chronic care management (CCM) provided by physicians, nurses, and physician assistants.
The new principal illness navigation (PIN) payments are intended to pay for work that to date typically has been done by people without medical degrees, including those involved in peer support networks and community health programs. The US Centers for Medicare and Medicaid Services(CMS) expects these navigators will undergo training and work under the supervision of clinicians.
The new navigators may coordinate care transitions between medical settings, follow up with patients after emergency department (ED) visits, or communicate with skilled nursing facilities regarding the psychosocial needs and functional deficits of a patient, among other functions.
CMS expects the new navigators may:
- Conduct assessments to understand a patient’s life story, strengths, needs, goals, preferences, and desired outcomes, including understanding cultural and linguistic factors.
- Provide support to accomplish the clinician’s treatment plan.
- Coordinate the receipt of needed services from healthcare facilities, home- and community-based service providers, and caregivers.
Peers as Navigators
The new navigators can be former patients who have undergone similar treatments for serious diseases, CMS said. This approach sets the new program apart from other care management services Medicare already covers, program officials wrote in the 2024 physician fee schedule.
“For some conditions, patients are best able to engage with the healthcare system and access care if they have assistance from a single, dedicated individual who has ‘lived experience,’ ” according to the rule.
The agency has taken a broad initial approach in defining what kinds of illnesses a patient may have to qualify for services. Patients must have a serious condition that is expected to last at least 3 months, such as cancer, heart failure, or substance use disorder.
But those without a definitive diagnosis may also qualify to receive navigator services.
In the rule, CMS cited a case in which a CT scan identified a suspicious mass in a patient’s colon. A clinician might decide this person would benefit from navigation services due to the potential risks for an undiagnosed illness.
“Regardless of the definitive diagnosis of the mass, presence of a colonic mass for that patient may be a serious high-risk condition that could, for example, cause obstruction and lead the patient to present to the emergency department, as well as be potentially indicative of an underlying life-threatening illness such as colon cancer,” CMS wrote in the rule.
Navigators often start their work when cancer patients are screened and guide them through initial diagnosis, potential surgery, radiation, or chemotherapy, said Sharon Gentry, MSN, RN, a former nurse navigator who is now the editor in chief of the Journal of the Academy of Oncology Nurse & Patient Navigators.
The navigators are meant to be a trusted and continual presence for patients, who otherwise might be left to start anew in finding help at each phase of care.
The navigators “see the whole picture. They see the whole journey the patient takes, from pre-diagnosis all the way through diagnosis care out through survival,” Ms. Gentry said.
Gaining a special Medicare payment for these kinds of services will elevate this work, she said.
Many newer drugs can target specific mechanisms and proteins of cancer. Often, oncology treatment involves testing to find out if mutations are allowing the cancer cells to evade a patient’s immune system.
Checking these biomarkers takes time, however. Patients sometimes become frustrated because they are anxious to begin treatment. Patients may receive inaccurate information from friends or family who went through treatment previously. Navigators can provide knowledge on the current state of care for a patient’s disease, helping them better manage anxieties.
“You have to explain to them that things have changed since the guy you drink coffee with was diagnosed with cancer, and there may be a drug that could target that,” Ms. Gentry said.
Potential Challenges
Initial uptake of the new PIN codes may be slow going, however, as clinicians and health systems may already use well-established codes. These include CCM and principal care management services, which may pay higher rates, Mullangi said.
“There might be sensitivity around not wanting to cannibalize existing programs with a new program,” Dr. Mullangi said.
In addition, many patients will have a copay for the services of principal illness navigators, Dr. Mullangi said.
While many patients have additional insurance that would cover the service, not all do. People with traditional Medicare coverage can sometimes pay 20% of the cost of some medical services.
“I think that may give patients pause, particularly if they’re already feeling the financial burden of a cancer treatment journey,” Dr. Mullangi said.
Pay rates for PIN services involve calculations of regional price differences, which are posted publicly by CMS, and potential added fees for services provided by hospital-affiliated organizations.
Consider payments for code G0023, covering 60 minutes of principal navigation services provided in a single month.
A set reimbursement for patients cared for in independent medical practices exists, with variation for local costs. Medicare’s non-facility price for G0023 would be $102.41 in some parts of Silicon Valley in California, including San Jose. In Arkansas, where costs are lower, reimbursement would be $73.14 for this same service.
Patients who get services covered by code G0023 in independent medical practices would have monthly copays of about $15-$20, depending on where they live.
The tab for patients tends to be higher for these same services if delivered through a medical practice owned by a hospital, as this would trigger the addition of facility fees to the payments made to cover the services. Facility fees are difficult for the public to ascertain before getting a treatment or service.
Dr. Mullangi and Ms. Gentry reported no relevant financial disclosures outside of their employers.
A version of this article first appeared on Medscape.com.
In a move that acknowledges the gauntlet the US health system poses for people facing serious and fatal illnesses, Medicare will pay for a new class of workers to help patients manage treatments for conditions like cancer and heart failure.
The 2024 Medicare physician fee schedule includes new billing codes, including G0023, to pay for 60 minutes a month of care coordination by certified or trained auxiliary personnel working under the direction of a clinician.
A diagnosis of cancer or another serious illness takes a toll beyond the physical effects of the disease. Patients often scramble to make adjustments in family and work schedules to manage treatment, said Samyukta Mullangi, MD, MBA, medical director of oncology at Thyme Care, a Nashville, Tennessee–based firm that provides navigation and coordination services to oncology practices and insurers.
“It just really does create a bit of a pressure cooker for patients,” Dr. Mullangi told this news organization.
Medicare has for many years paid for medical professionals to help patients cope with the complexities of disease, such as chronic care management (CCM) provided by physicians, nurses, and physician assistants.
The new principal illness navigation (PIN) payments are intended to pay for work that to date typically has been done by people without medical degrees, including those involved in peer support networks and community health programs. The US Centers for Medicare and Medicaid Services(CMS) expects these navigators will undergo training and work under the supervision of clinicians.
The new navigators may coordinate care transitions between medical settings, follow up with patients after emergency department (ED) visits, or communicate with skilled nursing facilities regarding the psychosocial needs and functional deficits of a patient, among other functions.
CMS expects the new navigators may:
- Conduct assessments to understand a patient’s life story, strengths, needs, goals, preferences, and desired outcomes, including understanding cultural and linguistic factors.
- Provide support to accomplish the clinician’s treatment plan.
- Coordinate the receipt of needed services from healthcare facilities, home- and community-based service providers, and caregivers.
Peers as Navigators
The new navigators can be former patients who have undergone similar treatments for serious diseases, CMS said. This approach sets the new program apart from other care management services Medicare already covers, program officials wrote in the 2024 physician fee schedule.
“For some conditions, patients are best able to engage with the healthcare system and access care if they have assistance from a single, dedicated individual who has ‘lived experience,’ ” according to the rule.
The agency has taken a broad initial approach in defining what kinds of illnesses a patient may have to qualify for services. Patients must have a serious condition that is expected to last at least 3 months, such as cancer, heart failure, or substance use disorder.
But those without a definitive diagnosis may also qualify to receive navigator services.
In the rule, CMS cited a case in which a CT scan identified a suspicious mass in a patient’s colon. A clinician might decide this person would benefit from navigation services due to the potential risks for an undiagnosed illness.
“Regardless of the definitive diagnosis of the mass, presence of a colonic mass for that patient may be a serious high-risk condition that could, for example, cause obstruction and lead the patient to present to the emergency department, as well as be potentially indicative of an underlying life-threatening illness such as colon cancer,” CMS wrote in the rule.
Navigators often start their work when cancer patients are screened and guide them through initial diagnosis, potential surgery, radiation, or chemotherapy, said Sharon Gentry, MSN, RN, a former nurse navigator who is now the editor in chief of the Journal of the Academy of Oncology Nurse & Patient Navigators.
The navigators are meant to be a trusted and continual presence for patients, who otherwise might be left to start anew in finding help at each phase of care.
The navigators “see the whole picture. They see the whole journey the patient takes, from pre-diagnosis all the way through diagnosis care out through survival,” Ms. Gentry said.
Gaining a special Medicare payment for these kinds of services will elevate this work, she said.
Many newer drugs can target specific mechanisms and proteins of cancer. Often, oncology treatment involves testing to find out if mutations are allowing the cancer cells to evade a patient’s immune system.
Checking these biomarkers takes time, however. Patients sometimes become frustrated because they are anxious to begin treatment. Patients may receive inaccurate information from friends or family who went through treatment previously. Navigators can provide knowledge on the current state of care for a patient’s disease, helping them better manage anxieties.
“You have to explain to them that things have changed since the guy you drink coffee with was diagnosed with cancer, and there may be a drug that could target that,” Ms. Gentry said.
Potential Challenges
Initial uptake of the new PIN codes may be slow going, however, as clinicians and health systems may already use well-established codes. These include CCM and principal care management services, which may pay higher rates, Mullangi said.
“There might be sensitivity around not wanting to cannibalize existing programs with a new program,” Dr. Mullangi said.
In addition, many patients will have a copay for the services of principal illness navigators, Dr. Mullangi said.
While many patients have additional insurance that would cover the service, not all do. People with traditional Medicare coverage can sometimes pay 20% of the cost of some medical services.
“I think that may give patients pause, particularly if they’re already feeling the financial burden of a cancer treatment journey,” Dr. Mullangi said.
Pay rates for PIN services involve calculations of regional price differences, which are posted publicly by CMS, and potential added fees for services provided by hospital-affiliated organizations.
Consider payments for code G0023, covering 60 minutes of principal navigation services provided in a single month.
A set reimbursement for patients cared for in independent medical practices exists, with variation for local costs. Medicare’s non-facility price for G0023 would be $102.41 in some parts of Silicon Valley in California, including San Jose. In Arkansas, where costs are lower, reimbursement would be $73.14 for this same service.
Patients who get services covered by code G0023 in independent medical practices would have monthly copays of about $15-$20, depending on where they live.
The tab for patients tends to be higher for these same services if delivered through a medical practice owned by a hospital, as this would trigger the addition of facility fees to the payments made to cover the services. Facility fees are difficult for the public to ascertain before getting a treatment or service.
Dr. Mullangi and Ms. Gentry reported no relevant financial disclosures outside of their employers.
A version of this article first appeared on Medscape.com.
To Combat Leukemia, Researchers Harness CD37
TOPLINE:
METHODOLOGY:
- Researchers analyzed CD37 expression in 55 untreated, newly diagnosed primary AML samples, along with normal hematopoietic stem cells, peripheral blood mononuclear cells, and AML cell lines.
- Analysis included internalization assays using anti-CD37 antibody conjugated to fluorochrome Alexa Fluor 647, with cells incubated for 2 hours at 37 °C vs on ice to quantify surface and intracellular CD37.
- Investigators conducted in vivo studies using NOD scid gamma mice and NRGS mice treated with 25 mg/mL busulfan, followed by weekly monitoring of disease burden through flow cytometry.
TAKEAWAY:
- CD37 surface expression was identified on all primary AML blasts examined, with varying levels of expression not correlating with European LeukemiaNet classification or overall survival.
- AML blasts demonstrated significantly higher CD37 internalization frequency than normal B cells (P = .001) and monocytes (P = .01), independent of surface expression levels.
- Primary AML samples with activating signaling mutations showed a trend toward increased CD37 internalization frequency (P = .053) than those without signaling mutations.
- Treatment with anti–CD37-DM1 significantly improved clinical outcomes and overall survival in multiple in vivo models of AML while showing minimal toxicity in humanized CD37 knockin mice.
IN PRACTICE:
“CD37 is a surface receptor present on most AML blasts, which has unique internalization properties when compared with normal blood cells. Treatment of AML with anti-CD37 ADC demonstrates specific cytotoxicity in vitro and improved overall survival in vivo,” wrote the authors of the study.
SOURCE:
The study was led by Erin Jeremy and Esthela Artiga, Ohio State University, Columbus. It was published online on January 14 in Blood Advances.
LIMITATIONS:
According to the authors, variations in CD37 expression in response to laboratory manipulations such as Ficoll-Hypaque cell separation and cryopreservation may have affected the detection of CD37 on AML cells with inherently lower levels of expression. The researchers also note that they were unable to associate pathologic characteristics with membrane trafficking and cytotoxic activity within their cohort of samples.
DISCLOSURES:
Karilyn T. Larkin received research funding from Debiopharm. The remaining authors reported no competing financial interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers analyzed CD37 expression in 55 untreated, newly diagnosed primary AML samples, along with normal hematopoietic stem cells, peripheral blood mononuclear cells, and AML cell lines.
- Analysis included internalization assays using anti-CD37 antibody conjugated to fluorochrome Alexa Fluor 647, with cells incubated for 2 hours at 37 °C vs on ice to quantify surface and intracellular CD37.
- Investigators conducted in vivo studies using NOD scid gamma mice and NRGS mice treated with 25 mg/mL busulfan, followed by weekly monitoring of disease burden through flow cytometry.
TAKEAWAY:
- CD37 surface expression was identified on all primary AML blasts examined, with varying levels of expression not correlating with European LeukemiaNet classification or overall survival.
- AML blasts demonstrated significantly higher CD37 internalization frequency than normal B cells (P = .001) and monocytes (P = .01), independent of surface expression levels.
- Primary AML samples with activating signaling mutations showed a trend toward increased CD37 internalization frequency (P = .053) than those without signaling mutations.
- Treatment with anti–CD37-DM1 significantly improved clinical outcomes and overall survival in multiple in vivo models of AML while showing minimal toxicity in humanized CD37 knockin mice.
IN PRACTICE:
“CD37 is a surface receptor present on most AML blasts, which has unique internalization properties when compared with normal blood cells. Treatment of AML with anti-CD37 ADC demonstrates specific cytotoxicity in vitro and improved overall survival in vivo,” wrote the authors of the study.
SOURCE:
The study was led by Erin Jeremy and Esthela Artiga, Ohio State University, Columbus. It was published online on January 14 in Blood Advances.
LIMITATIONS:
According to the authors, variations in CD37 expression in response to laboratory manipulations such as Ficoll-Hypaque cell separation and cryopreservation may have affected the detection of CD37 on AML cells with inherently lower levels of expression. The researchers also note that they were unable to associate pathologic characteristics with membrane trafficking and cytotoxic activity within their cohort of samples.
DISCLOSURES:
Karilyn T. Larkin received research funding from Debiopharm. The remaining authors reported no competing financial interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers analyzed CD37 expression in 55 untreated, newly diagnosed primary AML samples, along with normal hematopoietic stem cells, peripheral blood mononuclear cells, and AML cell lines.
- Analysis included internalization assays using anti-CD37 antibody conjugated to fluorochrome Alexa Fluor 647, with cells incubated for 2 hours at 37 °C vs on ice to quantify surface and intracellular CD37.
- Investigators conducted in vivo studies using NOD scid gamma mice and NRGS mice treated with 25 mg/mL busulfan, followed by weekly monitoring of disease burden through flow cytometry.
TAKEAWAY:
- CD37 surface expression was identified on all primary AML blasts examined, with varying levels of expression not correlating with European LeukemiaNet classification or overall survival.
- AML blasts demonstrated significantly higher CD37 internalization frequency than normal B cells (P = .001) and monocytes (P = .01), independent of surface expression levels.
- Primary AML samples with activating signaling mutations showed a trend toward increased CD37 internalization frequency (P = .053) than those without signaling mutations.
- Treatment with anti–CD37-DM1 significantly improved clinical outcomes and overall survival in multiple in vivo models of AML while showing minimal toxicity in humanized CD37 knockin mice.
IN PRACTICE:
“CD37 is a surface receptor present on most AML blasts, which has unique internalization properties when compared with normal blood cells. Treatment of AML with anti-CD37 ADC demonstrates specific cytotoxicity in vitro and improved overall survival in vivo,” wrote the authors of the study.
SOURCE:
The study was led by Erin Jeremy and Esthela Artiga, Ohio State University, Columbus. It was published online on January 14 in Blood Advances.
LIMITATIONS:
According to the authors, variations in CD37 expression in response to laboratory manipulations such as Ficoll-Hypaque cell separation and cryopreservation may have affected the detection of CD37 on AML cells with inherently lower levels of expression. The researchers also note that they were unable to associate pathologic characteristics with membrane trafficking and cytotoxic activity within their cohort of samples.
DISCLOSURES:
Karilyn T. Larkin received research funding from Debiopharm. The remaining authors reported no competing financial interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Myeloma: Can Failed Drugs Work Again?
TOPLINE:
METHODOLOGY:
- Researchers retrospectively reviewed patients with relapsed/refractory multiple myeloma who started new systemic therapy for disease progression between January 2015 and April 2022 at their institution.
- Analysis included 315 patients treated with a drug that their disease had previously been refractory to, defined as disease progression while receiving the drug or within 60 days of the last dose.
- Patient characteristics collected at diagnosis included age, sex, International Staging System stage, revised International Staging System stage, and interphase fluorescence in situ hybridization abnormalities.
- Investigators considered the first relapse after January 2015 requiring new systemic therapy as the index relapse and study start time.
TAKEAWAY:
- Analysis revealed an overall response rate of 56.2% and median progression-free survival of 11 months with retreatment.
- Patients with longer initial therapy duration with index drug (> 28.4 months) demonstrated superior progression-free survival (median, 16.9 vs 8.1 months; P < .001).
- Researchers found that patients with longer time gap between initial therapy and retreatment (> 46.1 months) showed better progression-free survival (median, 28.2 vs 8.9 months; P = .016).
- Among the 285 evaluable patients, 26% achieved partial response and 30.2% achieved very good partial response or better with retreatment.
IN PRACTICE:
“Retreatment with previously refractory drugs is a viable option for late-line [relapsed/refractory multiple myeloma]. Patients with a longer gap between initial line of therapy with index drug and retreatment had superior outcomes with retreatment,” wrote the authors of the study.
SOURCE:
The study was led by Utkarsh Goel, Division of Hematology, Mayo Clinic in Rochester, Minnesota. It was published online on December 24, 2024, in Blood Advances.
LIMITATIONS:
The retrospective nature and single-institution design of the study may introduce bias in terms of patient population and practice patterns. The favorable outcomes observed in patients with longer initial therapy duration and greater time between treatments could reflect selection bias toward more indolent disease biology. Despite adjusting for nonrefractory partner drugs during index relapse, residual bias may limit the ability to attribute outcomes solely to retreatment. The heterogeneous nature of treatments received during index relapse may limit comparisons across different groups.
DISCLOSURES:
Nelson Leung reported ties with AbbVie, Senseonics, Verrica Pharmaceuticals, and Omeros. Yi Lin disclosed relationships with multiple institutions, including Bristol Myers Squibb, Caribou Biosciences, and Janssen Oncology. Shaji Kumar reported ties with AbbVie, Bristol-Myers Squibb/Celgene, and Janssen Oncology. Additional disclosures were noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers retrospectively reviewed patients with relapsed/refractory multiple myeloma who started new systemic therapy for disease progression between January 2015 and April 2022 at their institution.
- Analysis included 315 patients treated with a drug that their disease had previously been refractory to, defined as disease progression while receiving the drug or within 60 days of the last dose.
- Patient characteristics collected at diagnosis included age, sex, International Staging System stage, revised International Staging System stage, and interphase fluorescence in situ hybridization abnormalities.
- Investigators considered the first relapse after January 2015 requiring new systemic therapy as the index relapse and study start time.
TAKEAWAY:
- Analysis revealed an overall response rate of 56.2% and median progression-free survival of 11 months with retreatment.
- Patients with longer initial therapy duration with index drug (> 28.4 months) demonstrated superior progression-free survival (median, 16.9 vs 8.1 months; P < .001).
- Researchers found that patients with longer time gap between initial therapy and retreatment (> 46.1 months) showed better progression-free survival (median, 28.2 vs 8.9 months; P = .016).
- Among the 285 evaluable patients, 26% achieved partial response and 30.2% achieved very good partial response or better with retreatment.
IN PRACTICE:
“Retreatment with previously refractory drugs is a viable option for late-line [relapsed/refractory multiple myeloma]. Patients with a longer gap between initial line of therapy with index drug and retreatment had superior outcomes with retreatment,” wrote the authors of the study.
SOURCE:
The study was led by Utkarsh Goel, Division of Hematology, Mayo Clinic in Rochester, Minnesota. It was published online on December 24, 2024, in Blood Advances.
LIMITATIONS:
The retrospective nature and single-institution design of the study may introduce bias in terms of patient population and practice patterns. The favorable outcomes observed in patients with longer initial therapy duration and greater time between treatments could reflect selection bias toward more indolent disease biology. Despite adjusting for nonrefractory partner drugs during index relapse, residual bias may limit the ability to attribute outcomes solely to retreatment. The heterogeneous nature of treatments received during index relapse may limit comparisons across different groups.
DISCLOSURES:
Nelson Leung reported ties with AbbVie, Senseonics, Verrica Pharmaceuticals, and Omeros. Yi Lin disclosed relationships with multiple institutions, including Bristol Myers Squibb, Caribou Biosciences, and Janssen Oncology. Shaji Kumar reported ties with AbbVie, Bristol-Myers Squibb/Celgene, and Janssen Oncology. Additional disclosures were noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers retrospectively reviewed patients with relapsed/refractory multiple myeloma who started new systemic therapy for disease progression between January 2015 and April 2022 at their institution.
- Analysis included 315 patients treated with a drug that their disease had previously been refractory to, defined as disease progression while receiving the drug or within 60 days of the last dose.
- Patient characteristics collected at diagnosis included age, sex, International Staging System stage, revised International Staging System stage, and interphase fluorescence in situ hybridization abnormalities.
- Investigators considered the first relapse after January 2015 requiring new systemic therapy as the index relapse and study start time.
TAKEAWAY:
- Analysis revealed an overall response rate of 56.2% and median progression-free survival of 11 months with retreatment.
- Patients with longer initial therapy duration with index drug (> 28.4 months) demonstrated superior progression-free survival (median, 16.9 vs 8.1 months; P < .001).
- Researchers found that patients with longer time gap between initial therapy and retreatment (> 46.1 months) showed better progression-free survival (median, 28.2 vs 8.9 months; P = .016).
- Among the 285 evaluable patients, 26% achieved partial response and 30.2% achieved very good partial response or better with retreatment.
IN PRACTICE:
“Retreatment with previously refractory drugs is a viable option for late-line [relapsed/refractory multiple myeloma]. Patients with a longer gap between initial line of therapy with index drug and retreatment had superior outcomes with retreatment,” wrote the authors of the study.
SOURCE:
The study was led by Utkarsh Goel, Division of Hematology, Mayo Clinic in Rochester, Minnesota. It was published online on December 24, 2024, in Blood Advances.
LIMITATIONS:
The retrospective nature and single-institution design of the study may introduce bias in terms of patient population and practice patterns. The favorable outcomes observed in patients with longer initial therapy duration and greater time between treatments could reflect selection bias toward more indolent disease biology. Despite adjusting for nonrefractory partner drugs during index relapse, residual bias may limit the ability to attribute outcomes solely to retreatment. The heterogeneous nature of treatments received during index relapse may limit comparisons across different groups.
DISCLOSURES:
Nelson Leung reported ties with AbbVie, Senseonics, Verrica Pharmaceuticals, and Omeros. Yi Lin disclosed relationships with multiple institutions, including Bristol Myers Squibb, Caribou Biosciences, and Janssen Oncology. Shaji Kumar reported ties with AbbVie, Bristol-Myers Squibb/Celgene, and Janssen Oncology. Additional disclosures were noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
New Proposed Health Cybersecurity Rule: What Physicians Should Know
A new federal rule could force hospitals and doctors’ groups to boost health cybersecurity measures to better protect patients’ health information and prevent ransomware attacks.
The proposed rule, issued by the US Department of Health & Human Services (HHS) and published on January 6 in the Federal Register, marks the first time in a decade that the federal government has updated regulations governing the security of private health information (PHI) that’s kept or shared online. Comments on the rule are due on March 6.
Because the risks for cyberattacks have increased exponentially, “there is a greater need to invest than ever before in both people and technologies to secure patient information,” Adam Greene, an attorney at Davis Wright Tremaine in Washington, DC, who advises healthcare clients on cybersecurity, said in an interview.
Bad actors continue to evolve and are often far ahead of their targets, added Mark Fox, privacy and research compliance officer for the American College of Cardiology.
In the proposed rule, HHS noted that breaches have risen by more than 50% since 2020. Damages from health data breaches are more expensive than in any other sector, averaging $10 million per incident, said HHS.
The damage can continue for years, as much of the data — such as date of birth — in PHI are “immutable,” unlike a credit card number, the agency said. A review of breach reports made to HHS’ Office for Civil Rights shows near-daily data breaches affecting hundreds to tens of thousands of patients. Since December 1 alone, healthcare providers reported breaches affecting nearly 3 million US patients, according to federal data.
Debi Carr, a Florida-based cybersecurity consultant for small physician and dental practices, welcomed the new proposal. “Many practices are clinging to doing things the way they have always done it, and hackers are taking full advantage of that mindset,” she said in an interview. “We have to change our mindset.”
Among the proposal’s recommendations:
- A shift away from making security specifications “addressable” to required. Fox said that many interpreted addressable to mean optional. The clarification is important. The government will require greater accountability, including a requirement to annually revise the risk analysis, to review policies and procedures and implementation, and to perform penetration testing, said Greene.
- Requiring multifactor authentication (MFA) and encryption of PHI at rest and in transit. “A reasonable person who does security will tell you that should be a requirement,” said Fox. Carr added that the February 2024 Change Healthcare ransomware attack happened because workers at the payment processing company were not using MFA.
- Requiring all entities to verify at least once a year that “business associates” have put into place the required safeguards; the associates would need to provide a written analysis of relevant electronic information systems by a subject matter expert and a written certification that the analysis has been performed and is accurate. In the past, the rule “only required that you sign a business associate agreement” with the associate, which could be a payer, a pharmacy, or another physician practice, said Fox. The rule would require all entities to get certification that the controls are in place.
- Requiring a detailed map of an electronic network. For a physician practice, that means creating an inventory of all the technology assets, including devices, applications, and anything that would touch electronic PHI, and then creating a map of how it comes into the office, flows through it, and departs, said Greene.
- Having a plan of action in the case of a breach. The rule will require written procedures to restore certain relevant systems and data within 72 hours and written incident response plans.
Some physician practices — especially those still relying on passwords instead of more sophisticated MFA or encryption — may have to invest significantly to strengthen their information security, said Greene. Smaller organizations, for example, may need to upgrade systems to ensure that user access is terminated within an hour after someone’s employment ends.
Carr said practices should not view the investments as a burden. The regulation “will force practices to implement best cybersecurity practices,” she said.
Implementing those best practices serves as insurance, said Fox. He suggests that anyone in doubt “talk to someone who’s actually lived through a breach and had to recover.”
Tampa General Hospital in Florida, for instance, recently settled a class action suit, agreeing to pay $6.8 million to patients whose PHI was compromised.
It is not certain whether or when the health cybersecurity rule will be made final.
The incoming Trump administration could cancel or delay the rulemaking process.
Even if it continues, “I would not expect a final rule in 2025,” said Greene. He estimates that the rule would not take effect until at least 2026; healthcare entities would have 180 days to comply. Still, those 180 days can go by fast.
“I would say don’t panic, but don’t ignore it either,” he said.
A version of this article first appeared on Medscape.com.
A new federal rule could force hospitals and doctors’ groups to boost health cybersecurity measures to better protect patients’ health information and prevent ransomware attacks.
The proposed rule, issued by the US Department of Health & Human Services (HHS) and published on January 6 in the Federal Register, marks the first time in a decade that the federal government has updated regulations governing the security of private health information (PHI) that’s kept or shared online. Comments on the rule are due on March 6.
Because the risks for cyberattacks have increased exponentially, “there is a greater need to invest than ever before in both people and technologies to secure patient information,” Adam Greene, an attorney at Davis Wright Tremaine in Washington, DC, who advises healthcare clients on cybersecurity, said in an interview.
Bad actors continue to evolve and are often far ahead of their targets, added Mark Fox, privacy and research compliance officer for the American College of Cardiology.
In the proposed rule, HHS noted that breaches have risen by more than 50% since 2020. Damages from health data breaches are more expensive than in any other sector, averaging $10 million per incident, said HHS.
The damage can continue for years, as much of the data — such as date of birth — in PHI are “immutable,” unlike a credit card number, the agency said. A review of breach reports made to HHS’ Office for Civil Rights shows near-daily data breaches affecting hundreds to tens of thousands of patients. Since December 1 alone, healthcare providers reported breaches affecting nearly 3 million US patients, according to federal data.
Debi Carr, a Florida-based cybersecurity consultant for small physician and dental practices, welcomed the new proposal. “Many practices are clinging to doing things the way they have always done it, and hackers are taking full advantage of that mindset,” she said in an interview. “We have to change our mindset.”
Among the proposal’s recommendations:
- A shift away from making security specifications “addressable” to required. Fox said that many interpreted addressable to mean optional. The clarification is important. The government will require greater accountability, including a requirement to annually revise the risk analysis, to review policies and procedures and implementation, and to perform penetration testing, said Greene.
- Requiring multifactor authentication (MFA) and encryption of PHI at rest and in transit. “A reasonable person who does security will tell you that should be a requirement,” said Fox. Carr added that the February 2024 Change Healthcare ransomware attack happened because workers at the payment processing company were not using MFA.
- Requiring all entities to verify at least once a year that “business associates” have put into place the required safeguards; the associates would need to provide a written analysis of relevant electronic information systems by a subject matter expert and a written certification that the analysis has been performed and is accurate. In the past, the rule “only required that you sign a business associate agreement” with the associate, which could be a payer, a pharmacy, or another physician practice, said Fox. The rule would require all entities to get certification that the controls are in place.
- Requiring a detailed map of an electronic network. For a physician practice, that means creating an inventory of all the technology assets, including devices, applications, and anything that would touch electronic PHI, and then creating a map of how it comes into the office, flows through it, and departs, said Greene.
- Having a plan of action in the case of a breach. The rule will require written procedures to restore certain relevant systems and data within 72 hours and written incident response plans.
Some physician practices — especially those still relying on passwords instead of more sophisticated MFA or encryption — may have to invest significantly to strengthen their information security, said Greene. Smaller organizations, for example, may need to upgrade systems to ensure that user access is terminated within an hour after someone’s employment ends.
Carr said practices should not view the investments as a burden. The regulation “will force practices to implement best cybersecurity practices,” she said.
Implementing those best practices serves as insurance, said Fox. He suggests that anyone in doubt “talk to someone who’s actually lived through a breach and had to recover.”
Tampa General Hospital in Florida, for instance, recently settled a class action suit, agreeing to pay $6.8 million to patients whose PHI was compromised.
It is not certain whether or when the health cybersecurity rule will be made final.
The incoming Trump administration could cancel or delay the rulemaking process.
Even if it continues, “I would not expect a final rule in 2025,” said Greene. He estimates that the rule would not take effect until at least 2026; healthcare entities would have 180 days to comply. Still, those 180 days can go by fast.
“I would say don’t panic, but don’t ignore it either,” he said.
A version of this article first appeared on Medscape.com.
A new federal rule could force hospitals and doctors’ groups to boost health cybersecurity measures to better protect patients’ health information and prevent ransomware attacks.
The proposed rule, issued by the US Department of Health & Human Services (HHS) and published on January 6 in the Federal Register, marks the first time in a decade that the federal government has updated regulations governing the security of private health information (PHI) that’s kept or shared online. Comments on the rule are due on March 6.
Because the risks for cyberattacks have increased exponentially, “there is a greater need to invest than ever before in both people and technologies to secure patient information,” Adam Greene, an attorney at Davis Wright Tremaine in Washington, DC, who advises healthcare clients on cybersecurity, said in an interview.
Bad actors continue to evolve and are often far ahead of their targets, added Mark Fox, privacy and research compliance officer for the American College of Cardiology.
In the proposed rule, HHS noted that breaches have risen by more than 50% since 2020. Damages from health data breaches are more expensive than in any other sector, averaging $10 million per incident, said HHS.
The damage can continue for years, as much of the data — such as date of birth — in PHI are “immutable,” unlike a credit card number, the agency said. A review of breach reports made to HHS’ Office for Civil Rights shows near-daily data breaches affecting hundreds to tens of thousands of patients. Since December 1 alone, healthcare providers reported breaches affecting nearly 3 million US patients, according to federal data.
Debi Carr, a Florida-based cybersecurity consultant for small physician and dental practices, welcomed the new proposal. “Many practices are clinging to doing things the way they have always done it, and hackers are taking full advantage of that mindset,” she said in an interview. “We have to change our mindset.”
Among the proposal’s recommendations:
- A shift away from making security specifications “addressable” to required. Fox said that many interpreted addressable to mean optional. The clarification is important. The government will require greater accountability, including a requirement to annually revise the risk analysis, to review policies and procedures and implementation, and to perform penetration testing, said Greene.
- Requiring multifactor authentication (MFA) and encryption of PHI at rest and in transit. “A reasonable person who does security will tell you that should be a requirement,” said Fox. Carr added that the February 2024 Change Healthcare ransomware attack happened because workers at the payment processing company were not using MFA.
- Requiring all entities to verify at least once a year that “business associates” have put into place the required safeguards; the associates would need to provide a written analysis of relevant electronic information systems by a subject matter expert and a written certification that the analysis has been performed and is accurate. In the past, the rule “only required that you sign a business associate agreement” with the associate, which could be a payer, a pharmacy, or another physician practice, said Fox. The rule would require all entities to get certification that the controls are in place.
- Requiring a detailed map of an electronic network. For a physician practice, that means creating an inventory of all the technology assets, including devices, applications, and anything that would touch electronic PHI, and then creating a map of how it comes into the office, flows through it, and departs, said Greene.
- Having a plan of action in the case of a breach. The rule will require written procedures to restore certain relevant systems and data within 72 hours and written incident response plans.
Some physician practices — especially those still relying on passwords instead of more sophisticated MFA or encryption — may have to invest significantly to strengthen their information security, said Greene. Smaller organizations, for example, may need to upgrade systems to ensure that user access is terminated within an hour after someone’s employment ends.
Carr said practices should not view the investments as a burden. The regulation “will force practices to implement best cybersecurity practices,” she said.
Implementing those best practices serves as insurance, said Fox. He suggests that anyone in doubt “talk to someone who’s actually lived through a breach and had to recover.”
Tampa General Hospital in Florida, for instance, recently settled a class action suit, agreeing to pay $6.8 million to patients whose PHI was compromised.
It is not certain whether or when the health cybersecurity rule will be made final.
The incoming Trump administration could cancel or delay the rulemaking process.
Even if it continues, “I would not expect a final rule in 2025,” said Greene. He estimates that the rule would not take effect until at least 2026; healthcare entities would have 180 days to comply. Still, those 180 days can go by fast.
“I would say don’t panic, but don’t ignore it either,” he said.
A version of this article first appeared on Medscape.com.
Leaving ED Without Being Seen Entails Increasing Risks
Higher rates of leaving the emergency department (ED) without being seen are linked to increased short-term mortality or hospitalization, according to a cohort study in Ontario, Canada.
“We found that after 2020, there was a 14% higher risk for death or hospitalization within 7 days” among patients who left without being seen (LWBS), Candace McNaughton, MD, PhD, associate professor of medicine at the University of Toronto and scientist at Sunnybrook Research Institute, both in Toronto, Ontario, Canada, told this news organization.
“When we looked at death by itself, there was a 46% higher risk after 2020,” she said. “Even 30 days after a LWBS ED visit, there was still a 5% increased risk for death/hospitalization and a 24% increased risk for death.”
The study was published in the Journal of the American College of Emergency Physicians Open.
LWBS Rates Increased
Researchers used linked administrative data to analyze temporal trends in monthly rates of ED and LWBS visits for adults in Ontario from 2014 to 2023.
They compared the composite outcome of 7-day all-cause mortality or hospitalization following an LWBS ED visit in April 2022‒March 2023 (recent period) with that following an LWBS ED visit in April 2014‒March 2020 (baseline period), after adjustment for age, sex, and Charlson Comorbidity Index (CCI).
In the two periods, patient characteristics were similar across age, sex, neighborhood-level income quartile, history of being unhoused, rurality, CCI, day, time, and mode of arrival. The median age was 40 years for the baseline period and 42 years for the recent period.
Temporal trends showed sustained increases in monthly LWBS rates after 2020, despite fewer monthly ED visits. The rate of LWBS ED visits after April 1, 2020, exceeded the baseline period’s single-month LWBS maximum of 4% in 15 of 36 months.
The rate of 7-day all-cause mortality or hospitalization was 3.4% in the recent period vs 2.9% in the baseline period (adjusted risk ratio [aRR], 1.14), despite similar rates of post-ED outpatient visits (7-day recent and baseline, 38.9% and 39.7%, respectively).
Similar trends were seen at 30 days for all-cause mortality or hospitalization (6.2% in the recent period vs 5.8% at baseline; aRR, 1.05) despite similar rates of post-ED outpatient visits (59.4% and 59.7%, respectively).
After April 1, 2020, monthly ED visits and the proportion of patients who LWBS varied widely.
The proportion of LWBS visits categorized as emergent on the Canadian Triage and Acuity Scale was higher during the recent period (12.9% vs 9.2% in the baseline period), and fewer visits were categorized as semiurgent (22.6% vs 31.9%, respectively). This finding suggested a higher acuity of illness among patients who LWBS in the recent period.
LWBS Visits ‘Not Benign’
Results of a preplanned subgroup analysis examining the risk for all-cause mortality after an LWBS visit were “particularly notable,” the authors wrote, with a 46% higher adjusted risk for death at 7 days and 24% higher adjusted risk at 30 days.
The observational study had several limitations, however. The authors could not draw conclusions regarding direct causes of the increased risk for severe short-term adverse health outcomes after an LWBS ED visit, and residual confounding is possible. Cause-of-death information was not available to generate hypotheses for future studies of potential causes. Furthermore, the findings may not be generalizable to systems without universal access to healthcare.
Nevertheless, the findings are a “concerning signal [and] should prompt interventions to address system- and population-level causes,” the authors wrote.
“Unfortunately, because of politics, since 2020, ED closures in Ontario have become more and more common and seem to be affecting more and more Ontarians,” said McNaughton. “It would be surprising if ED closure didn’t play some role in our findings.”
She added, “It is important to note that people in our study were relatively young, with a median age in their 40s; this makes our findings all the more concerning. Clinicians should be aware that LWBS ED visits are not necessarily benign, particularly when rates of LWBS ED visits are high.”
Unanswered Questions
The study raised the following questions that the authors are or will be investigating, according to McNaughton:
- Which patients are at greatest risk for bad outcomes if they leave the ED without being seen, and why?
- How much of the findings might be related to recent ED closures, longer ED wait times, or other factors? Are there geographic variations in risk?
- What can be done in the ED to prevent LWBS ED visits, and what can be changed outside the ED to prevent LWBS ED visits? For example, what can hospitals do to reduce boarding in the ED? If patients leave without being seen, should they be contacted to try to meet their health needs in other ways?
- What worked in terms of maintaining access to outpatient medical care, despite the considerable disruptions starting in 2020, and how can continued success be ensured?
To address the current situation, McNaughton said, “We need consistent, predictable, and sustained investment in our public healthcare system. We need long-term, consistent funding for primary care, ED care, as well as hospital and long-term care.”
“It takes years to recruit and train the teams of people necessary to provide the high-quality medical care that Canadians have a right to. There are no shortcuts,” she concluded.
‘Tragic Situation’
American College of Emergency Physicians (ACEP) spokesperson Jesse Pines, MD, chief of clinical innovation at US Acute Care Solutions; clinical professor of emergency medicine at George Washington University in Washington, DC; and professor of emergency medicine at Drexel University in Philadelphia, commented on the study for this news organization.
“Similar to what the authors found in their report, LWBS and other metrics — specifically boarding — have progressively increased in the United States, in particular, since the early part of 2021,” he said. “The primary factor in the US driving this, and one that ACEP is trying to address on a national scale, is the boarding of admitted patients.”
When the number of boarded patients increases, there is less space in the ED for new patients, and waits increase, Pines explained. Some patients leave without being seen, and a subset of those patients experience poor outcomes. “It’s a tragic situation that is worsening.”
“Emergency physicians like me always worry when patients leave without being seen,” he said. While some of those patients have self-limited conditions that will improve on their own, “some have critical life-threatening conditions that require care and hospitalization. The worry is that these patients experience poorer outcomes,” Pines said. “The authors showed that this is increasingly the case in Canada. The same is likely true in the US.”
The study was funded by the Canadian Institutes of Health Research. McNaughton and Pines declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Higher rates of leaving the emergency department (ED) without being seen are linked to increased short-term mortality or hospitalization, according to a cohort study in Ontario, Canada.
“We found that after 2020, there was a 14% higher risk for death or hospitalization within 7 days” among patients who left without being seen (LWBS), Candace McNaughton, MD, PhD, associate professor of medicine at the University of Toronto and scientist at Sunnybrook Research Institute, both in Toronto, Ontario, Canada, told this news organization.
“When we looked at death by itself, there was a 46% higher risk after 2020,” she said. “Even 30 days after a LWBS ED visit, there was still a 5% increased risk for death/hospitalization and a 24% increased risk for death.”
The study was published in the Journal of the American College of Emergency Physicians Open.
LWBS Rates Increased
Researchers used linked administrative data to analyze temporal trends in monthly rates of ED and LWBS visits for adults in Ontario from 2014 to 2023.
They compared the composite outcome of 7-day all-cause mortality or hospitalization following an LWBS ED visit in April 2022‒March 2023 (recent period) with that following an LWBS ED visit in April 2014‒March 2020 (baseline period), after adjustment for age, sex, and Charlson Comorbidity Index (CCI).
In the two periods, patient characteristics were similar across age, sex, neighborhood-level income quartile, history of being unhoused, rurality, CCI, day, time, and mode of arrival. The median age was 40 years for the baseline period and 42 years for the recent period.
Temporal trends showed sustained increases in monthly LWBS rates after 2020, despite fewer monthly ED visits. The rate of LWBS ED visits after April 1, 2020, exceeded the baseline period’s single-month LWBS maximum of 4% in 15 of 36 months.
The rate of 7-day all-cause mortality or hospitalization was 3.4% in the recent period vs 2.9% in the baseline period (adjusted risk ratio [aRR], 1.14), despite similar rates of post-ED outpatient visits (7-day recent and baseline, 38.9% and 39.7%, respectively).
Similar trends were seen at 30 days for all-cause mortality or hospitalization (6.2% in the recent period vs 5.8% at baseline; aRR, 1.05) despite similar rates of post-ED outpatient visits (59.4% and 59.7%, respectively).
After April 1, 2020, monthly ED visits and the proportion of patients who LWBS varied widely.
The proportion of LWBS visits categorized as emergent on the Canadian Triage and Acuity Scale was higher during the recent period (12.9% vs 9.2% in the baseline period), and fewer visits were categorized as semiurgent (22.6% vs 31.9%, respectively). This finding suggested a higher acuity of illness among patients who LWBS in the recent period.
LWBS Visits ‘Not Benign’
Results of a preplanned subgroup analysis examining the risk for all-cause mortality after an LWBS visit were “particularly notable,” the authors wrote, with a 46% higher adjusted risk for death at 7 days and 24% higher adjusted risk at 30 days.
The observational study had several limitations, however. The authors could not draw conclusions regarding direct causes of the increased risk for severe short-term adverse health outcomes after an LWBS ED visit, and residual confounding is possible. Cause-of-death information was not available to generate hypotheses for future studies of potential causes. Furthermore, the findings may not be generalizable to systems without universal access to healthcare.
Nevertheless, the findings are a “concerning signal [and] should prompt interventions to address system- and population-level causes,” the authors wrote.
“Unfortunately, because of politics, since 2020, ED closures in Ontario have become more and more common and seem to be affecting more and more Ontarians,” said McNaughton. “It would be surprising if ED closure didn’t play some role in our findings.”
She added, “It is important to note that people in our study were relatively young, with a median age in their 40s; this makes our findings all the more concerning. Clinicians should be aware that LWBS ED visits are not necessarily benign, particularly when rates of LWBS ED visits are high.”
Unanswered Questions
The study raised the following questions that the authors are or will be investigating, according to McNaughton:
- Which patients are at greatest risk for bad outcomes if they leave the ED without being seen, and why?
- How much of the findings might be related to recent ED closures, longer ED wait times, or other factors? Are there geographic variations in risk?
- What can be done in the ED to prevent LWBS ED visits, and what can be changed outside the ED to prevent LWBS ED visits? For example, what can hospitals do to reduce boarding in the ED? If patients leave without being seen, should they be contacted to try to meet their health needs in other ways?
- What worked in terms of maintaining access to outpatient medical care, despite the considerable disruptions starting in 2020, and how can continued success be ensured?
To address the current situation, McNaughton said, “We need consistent, predictable, and sustained investment in our public healthcare system. We need long-term, consistent funding for primary care, ED care, as well as hospital and long-term care.”
“It takes years to recruit and train the teams of people necessary to provide the high-quality medical care that Canadians have a right to. There are no shortcuts,” she concluded.
‘Tragic Situation’
American College of Emergency Physicians (ACEP) spokesperson Jesse Pines, MD, chief of clinical innovation at US Acute Care Solutions; clinical professor of emergency medicine at George Washington University in Washington, DC; and professor of emergency medicine at Drexel University in Philadelphia, commented on the study for this news organization.
“Similar to what the authors found in their report, LWBS and other metrics — specifically boarding — have progressively increased in the United States, in particular, since the early part of 2021,” he said. “The primary factor in the US driving this, and one that ACEP is trying to address on a national scale, is the boarding of admitted patients.”
When the number of boarded patients increases, there is less space in the ED for new patients, and waits increase, Pines explained. Some patients leave without being seen, and a subset of those patients experience poor outcomes. “It’s a tragic situation that is worsening.”
“Emergency physicians like me always worry when patients leave without being seen,” he said. While some of those patients have self-limited conditions that will improve on their own, “some have critical life-threatening conditions that require care and hospitalization. The worry is that these patients experience poorer outcomes,” Pines said. “The authors showed that this is increasingly the case in Canada. The same is likely true in the US.”
The study was funded by the Canadian Institutes of Health Research. McNaughton and Pines declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Higher rates of leaving the emergency department (ED) without being seen are linked to increased short-term mortality or hospitalization, according to a cohort study in Ontario, Canada.
“We found that after 2020, there was a 14% higher risk for death or hospitalization within 7 days” among patients who left without being seen (LWBS), Candace McNaughton, MD, PhD, associate professor of medicine at the University of Toronto and scientist at Sunnybrook Research Institute, both in Toronto, Ontario, Canada, told this news organization.
“When we looked at death by itself, there was a 46% higher risk after 2020,” she said. “Even 30 days after a LWBS ED visit, there was still a 5% increased risk for death/hospitalization and a 24% increased risk for death.”
The study was published in the Journal of the American College of Emergency Physicians Open.
LWBS Rates Increased
Researchers used linked administrative data to analyze temporal trends in monthly rates of ED and LWBS visits for adults in Ontario from 2014 to 2023.
They compared the composite outcome of 7-day all-cause mortality or hospitalization following an LWBS ED visit in April 2022‒March 2023 (recent period) with that following an LWBS ED visit in April 2014‒March 2020 (baseline period), after adjustment for age, sex, and Charlson Comorbidity Index (CCI).
In the two periods, patient characteristics were similar across age, sex, neighborhood-level income quartile, history of being unhoused, rurality, CCI, day, time, and mode of arrival. The median age was 40 years for the baseline period and 42 years for the recent period.
Temporal trends showed sustained increases in monthly LWBS rates after 2020, despite fewer monthly ED visits. The rate of LWBS ED visits after April 1, 2020, exceeded the baseline period’s single-month LWBS maximum of 4% in 15 of 36 months.
The rate of 7-day all-cause mortality or hospitalization was 3.4% in the recent period vs 2.9% in the baseline period (adjusted risk ratio [aRR], 1.14), despite similar rates of post-ED outpatient visits (7-day recent and baseline, 38.9% and 39.7%, respectively).
Similar trends were seen at 30 days for all-cause mortality or hospitalization (6.2% in the recent period vs 5.8% at baseline; aRR, 1.05) despite similar rates of post-ED outpatient visits (59.4% and 59.7%, respectively).
After April 1, 2020, monthly ED visits and the proportion of patients who LWBS varied widely.
The proportion of LWBS visits categorized as emergent on the Canadian Triage and Acuity Scale was higher during the recent period (12.9% vs 9.2% in the baseline period), and fewer visits were categorized as semiurgent (22.6% vs 31.9%, respectively). This finding suggested a higher acuity of illness among patients who LWBS in the recent period.
LWBS Visits ‘Not Benign’
Results of a preplanned subgroup analysis examining the risk for all-cause mortality after an LWBS visit were “particularly notable,” the authors wrote, with a 46% higher adjusted risk for death at 7 days and 24% higher adjusted risk at 30 days.
The observational study had several limitations, however. The authors could not draw conclusions regarding direct causes of the increased risk for severe short-term adverse health outcomes after an LWBS ED visit, and residual confounding is possible. Cause-of-death information was not available to generate hypotheses for future studies of potential causes. Furthermore, the findings may not be generalizable to systems without universal access to healthcare.
Nevertheless, the findings are a “concerning signal [and] should prompt interventions to address system- and population-level causes,” the authors wrote.
“Unfortunately, because of politics, since 2020, ED closures in Ontario have become more and more common and seem to be affecting more and more Ontarians,” said McNaughton. “It would be surprising if ED closure didn’t play some role in our findings.”
She added, “It is important to note that people in our study were relatively young, with a median age in their 40s; this makes our findings all the more concerning. Clinicians should be aware that LWBS ED visits are not necessarily benign, particularly when rates of LWBS ED visits are high.”
Unanswered Questions
The study raised the following questions that the authors are or will be investigating, according to McNaughton:
- Which patients are at greatest risk for bad outcomes if they leave the ED without being seen, and why?
- How much of the findings might be related to recent ED closures, longer ED wait times, or other factors? Are there geographic variations in risk?
- What can be done in the ED to prevent LWBS ED visits, and what can be changed outside the ED to prevent LWBS ED visits? For example, what can hospitals do to reduce boarding in the ED? If patients leave without being seen, should they be contacted to try to meet their health needs in other ways?
- What worked in terms of maintaining access to outpatient medical care, despite the considerable disruptions starting in 2020, and how can continued success be ensured?
To address the current situation, McNaughton said, “We need consistent, predictable, and sustained investment in our public healthcare system. We need long-term, consistent funding for primary care, ED care, as well as hospital and long-term care.”
“It takes years to recruit and train the teams of people necessary to provide the high-quality medical care that Canadians have a right to. There are no shortcuts,” she concluded.
‘Tragic Situation’
American College of Emergency Physicians (ACEP) spokesperson Jesse Pines, MD, chief of clinical innovation at US Acute Care Solutions; clinical professor of emergency medicine at George Washington University in Washington, DC; and professor of emergency medicine at Drexel University in Philadelphia, commented on the study for this news organization.
“Similar to what the authors found in their report, LWBS and other metrics — specifically boarding — have progressively increased in the United States, in particular, since the early part of 2021,” he said. “The primary factor in the US driving this, and one that ACEP is trying to address on a national scale, is the boarding of admitted patients.”
When the number of boarded patients increases, there is less space in the ED for new patients, and waits increase, Pines explained. Some patients leave without being seen, and a subset of those patients experience poor outcomes. “It’s a tragic situation that is worsening.”
“Emergency physicians like me always worry when patients leave without being seen,” he said. While some of those patients have self-limited conditions that will improve on their own, “some have critical life-threatening conditions that require care and hospitalization. The worry is that these patients experience poorer outcomes,” Pines said. “The authors showed that this is increasingly the case in Canada. The same is likely true in the US.”
The study was funded by the Canadian Institutes of Health Research. McNaughton and Pines declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Scientific Publications Face Credibility Crisis
The quality and credibility of scientific publications have received increasing scrutiny. Findings from studies by Maria Ángeles Oviedo-García, PhD, from the Department of Business and Marketing at the University of Seville in Spain, highlight growing concerns about the integrity of published research. Insights from the journal Science and the US blog Retraction Watch reveal similar concerns regarding research integrity.
Artificial Intelligence (AI) Spurs Low-Quality Submissions
According to a report in Science, journals are inundated with low-quality contributions such as letters and comments generated by AI. Daniel Prevedello, MD, editor in chief of Neurosurgical Review, announced that the journal would temporarily stop accepting these submissions because of their poor quality.
Neurosurgical Review is not the only journal to experience low-quality submissions. In the journal Oral Oncology Reports (Elsevier), comments comprised 70% of the content, whereas in the International Journal of Surgery Open (Wolters Kluwer), they accounted for nearly half. In Neurosurgical Review, letters, comments, and editorials made up 58% of the total content from January to October 2024, compared with only 9% in the previous year.
This trend benefits authors by allowing them to inflate their publication lists with quickly produced contributions that bypass peer review. Publishers may also profit, as many charge fees to publish comments. Additionally, universities and research institutions find this type of content generation useful as more publications can enhance their reputation.
Concerns Over Peer Reviews
The troubling behavior described by Oviedo-García in the journal Scientometrics raises further doubts. An analysis of 263 peer reviews from 37 journals revealed that reviewers often used identical or very similar phrases in their evaluations, regardless of the content. In one case, the reviewer used the same wording in 52 reviews. This suggests that some reviewers read the studies that they are supposed to evaluate only superficially. Such practices can lead to valueless reviews and jeopardize the integrity of scientific literature. “Some other researchers will probably base their future research on these fake reports, which is frightening, especially when it comes to health and medicine,” Oviedo-García stated.
She suspects that the reviewers may have relied on templates to produce their reports quickly. This allowed them to list this work on their resumes for potential career advantages. Some reviewers have reportedly even “requested” the authors of the studies they reviewed to cite their own scientific work.
AI Complicates Peer Review
The process of research and publication has become increasingly challenging in recent years, and more standard and predatory journals allow anyone to publish their work for a fee. Roger W. Byard, MD, PhD, from the University of Adelaide in Australia, explained this trend in the journal Forensic Science, Medicine and Pathology. AI is increasingly being used to generate articles. At international conferences, experts have highlighted claims that AI can complete papers in just a few weeks and dissertations in less than a year. According to the authors of a letter in Critical Care, generative AI is infiltrating the peer review process.
Moreover, the peer review process can be bypassed by publishing research findings on online platforms (eg, preprint servers). Another issue is that some publications have hundreds of authors who can extend their publication list in this manner, even if their contribution to the publication is ambiguous or not substantial.
In a guest article for the Laborjournal, Ulrich Dirnagl, MD, PhD, from the Charité — Universitätsmedizin Berlin in Germany, emphasized that the scientific papers have become so complex that two or three experts often cannot thoroughly assess everything presented. The review process is time-consuming and can take several days for reviewers. Currently, very few people have time, especially because it is an unpaid and anonymous task. Dirnagl stated, “the self-correction of science no longer works as it claims.”
The old Russian saying ‘Dowjerjaj, no prowjerjaj: Trust, but verify’ remains a timeless recommendation that is likely to stay relevant for years to come.
This story was translated from Univadis Germany using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
The quality and credibility of scientific publications have received increasing scrutiny. Findings from studies by Maria Ángeles Oviedo-García, PhD, from the Department of Business and Marketing at the University of Seville in Spain, highlight growing concerns about the integrity of published research. Insights from the journal Science and the US blog Retraction Watch reveal similar concerns regarding research integrity.
Artificial Intelligence (AI) Spurs Low-Quality Submissions
According to a report in Science, journals are inundated with low-quality contributions such as letters and comments generated by AI. Daniel Prevedello, MD, editor in chief of Neurosurgical Review, announced that the journal would temporarily stop accepting these submissions because of their poor quality.
Neurosurgical Review is not the only journal to experience low-quality submissions. In the journal Oral Oncology Reports (Elsevier), comments comprised 70% of the content, whereas in the International Journal of Surgery Open (Wolters Kluwer), they accounted for nearly half. In Neurosurgical Review, letters, comments, and editorials made up 58% of the total content from January to October 2024, compared with only 9% in the previous year.
This trend benefits authors by allowing them to inflate their publication lists with quickly produced contributions that bypass peer review. Publishers may also profit, as many charge fees to publish comments. Additionally, universities and research institutions find this type of content generation useful as more publications can enhance their reputation.
Concerns Over Peer Reviews
The troubling behavior described by Oviedo-García in the journal Scientometrics raises further doubts. An analysis of 263 peer reviews from 37 journals revealed that reviewers often used identical or very similar phrases in their evaluations, regardless of the content. In one case, the reviewer used the same wording in 52 reviews. This suggests that some reviewers read the studies that they are supposed to evaluate only superficially. Such practices can lead to valueless reviews and jeopardize the integrity of scientific literature. “Some other researchers will probably base their future research on these fake reports, which is frightening, especially when it comes to health and medicine,” Oviedo-García stated.
She suspects that the reviewers may have relied on templates to produce their reports quickly. This allowed them to list this work on their resumes for potential career advantages. Some reviewers have reportedly even “requested” the authors of the studies they reviewed to cite their own scientific work.
AI Complicates Peer Review
The process of research and publication has become increasingly challenging in recent years, and more standard and predatory journals allow anyone to publish their work for a fee. Roger W. Byard, MD, PhD, from the University of Adelaide in Australia, explained this trend in the journal Forensic Science, Medicine and Pathology. AI is increasingly being used to generate articles. At international conferences, experts have highlighted claims that AI can complete papers in just a few weeks and dissertations in less than a year. According to the authors of a letter in Critical Care, generative AI is infiltrating the peer review process.
Moreover, the peer review process can be bypassed by publishing research findings on online platforms (eg, preprint servers). Another issue is that some publications have hundreds of authors who can extend their publication list in this manner, even if their contribution to the publication is ambiguous or not substantial.
In a guest article for the Laborjournal, Ulrich Dirnagl, MD, PhD, from the Charité — Universitätsmedizin Berlin in Germany, emphasized that the scientific papers have become so complex that two or three experts often cannot thoroughly assess everything presented. The review process is time-consuming and can take several days for reviewers. Currently, very few people have time, especially because it is an unpaid and anonymous task. Dirnagl stated, “the self-correction of science no longer works as it claims.”
The old Russian saying ‘Dowjerjaj, no prowjerjaj: Trust, but verify’ remains a timeless recommendation that is likely to stay relevant for years to come.
This story was translated from Univadis Germany using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
The quality and credibility of scientific publications have received increasing scrutiny. Findings from studies by Maria Ángeles Oviedo-García, PhD, from the Department of Business and Marketing at the University of Seville in Spain, highlight growing concerns about the integrity of published research. Insights from the journal Science and the US blog Retraction Watch reveal similar concerns regarding research integrity.
Artificial Intelligence (AI) Spurs Low-Quality Submissions
According to a report in Science, journals are inundated with low-quality contributions such as letters and comments generated by AI. Daniel Prevedello, MD, editor in chief of Neurosurgical Review, announced that the journal would temporarily stop accepting these submissions because of their poor quality.
Neurosurgical Review is not the only journal to experience low-quality submissions. In the journal Oral Oncology Reports (Elsevier), comments comprised 70% of the content, whereas in the International Journal of Surgery Open (Wolters Kluwer), they accounted for nearly half. In Neurosurgical Review, letters, comments, and editorials made up 58% of the total content from January to October 2024, compared with only 9% in the previous year.
This trend benefits authors by allowing them to inflate their publication lists with quickly produced contributions that bypass peer review. Publishers may also profit, as many charge fees to publish comments. Additionally, universities and research institutions find this type of content generation useful as more publications can enhance their reputation.
Concerns Over Peer Reviews
The troubling behavior described by Oviedo-García in the journal Scientometrics raises further doubts. An analysis of 263 peer reviews from 37 journals revealed that reviewers often used identical or very similar phrases in their evaluations, regardless of the content. In one case, the reviewer used the same wording in 52 reviews. This suggests that some reviewers read the studies that they are supposed to evaluate only superficially. Such practices can lead to valueless reviews and jeopardize the integrity of scientific literature. “Some other researchers will probably base their future research on these fake reports, which is frightening, especially when it comes to health and medicine,” Oviedo-García stated.
She suspects that the reviewers may have relied on templates to produce their reports quickly. This allowed them to list this work on their resumes for potential career advantages. Some reviewers have reportedly even “requested” the authors of the studies they reviewed to cite their own scientific work.
AI Complicates Peer Review
The process of research and publication has become increasingly challenging in recent years, and more standard and predatory journals allow anyone to publish their work for a fee. Roger W. Byard, MD, PhD, from the University of Adelaide in Australia, explained this trend in the journal Forensic Science, Medicine and Pathology. AI is increasingly being used to generate articles. At international conferences, experts have highlighted claims that AI can complete papers in just a few weeks and dissertations in less than a year. According to the authors of a letter in Critical Care, generative AI is infiltrating the peer review process.
Moreover, the peer review process can be bypassed by publishing research findings on online platforms (eg, preprint servers). Another issue is that some publications have hundreds of authors who can extend their publication list in this manner, even if their contribution to the publication is ambiguous or not substantial.
In a guest article for the Laborjournal, Ulrich Dirnagl, MD, PhD, from the Charité — Universitätsmedizin Berlin in Germany, emphasized that the scientific papers have become so complex that two or three experts often cannot thoroughly assess everything presented. The review process is time-consuming and can take several days for reviewers. Currently, very few people have time, especially because it is an unpaid and anonymous task. Dirnagl stated, “the self-correction of science no longer works as it claims.”
The old Russian saying ‘Dowjerjaj, no prowjerjaj: Trust, but verify’ remains a timeless recommendation that is likely to stay relevant for years to come.
This story was translated from Univadis Germany using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article appeared on Medscape.com.
Can Glucarpidase Help Reverse Methotrexate Kidney Damage?
TOPLINE:
METHODOLOGY:
- Researchers conducted a multicenter cohort study involving 708 adults with methotrexate-associated acute kidney injury from 28 cancer centers across the United States.
- Analysis utilized a sequential target trial emulation framework to compare outcomes between 209 patients who received glucarpidase within 4 days of methotrexate initiation and 499 patients who did not.
- The primary endpoint was kidney recovery at hospital discharge, defined as survival with serum creatinine < 1.5-fold baseline without dialysis dependence.
- Secondary endpoints included time-to-kidney recovery, neutropenia and transaminitis on day 7, and time-to-death.
TAKEAWAY:
- Glucarpidase administration was associated with adjusted odds ratio [aOR] of 2.70 (95% CI, 1.69-4.31) and adjusted hazard ratio [aHR] of 1.88 (95% CI, 1.18-3.33) for time-to-kidney recovery.
- Treatment with glucarpidase reduced the risk for grade ≥ 2 neutropenia (aOR, 0.50; 95% CI, 0.28-0.91) and grade ≥ 2 transaminitis (aOR, 0.31; 95% CI, 0.13-0.77) on day 7.
- Female patients showed greater benefit from glucarpidase treatment than male patients (P = .02 for interaction).
- No significant difference was observed in time-to-death between glucarpidase-treated and glucarpidase-untreated patients (aHR, 0.76; 95% CI, 0.49-1.18).
IN PRACTICE:
“These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI [methotrexate-acute kidney injury],” the authors of the study wrote.
SOURCE:
This study was led by Shruti Gupta, MD, MPH, and David E. Leaf, MD, MMSc, Brigham and Women’s Hospital in Boston, Massachusetts. It was published online in Blood.
LIMITATIONS:
According to the authors, residual confounding cannot be excluded despite adjustment for multiple variables. While glucarpidase-treated patients had similar distributions of most baseline characteristics, they showed greater severity of illness, including more comorbidities, concomitant nephrotoxic medications, higher 24-hour methotrexate levels, and more severe acute kidney injury. This study was limited to patients treated at large, US-based academic centers, potentially affecting generalizability to smaller hospitals or countries where glucarpidase is unavailable.
DISCLOSURES:
This study was funded by BTG International. Gupta disclosed ties with BTG International, Dana-Farber Cancer Institute’s Wong Foundation, Janssen, AstraZeneca, and the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK125672). Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers conducted a multicenter cohort study involving 708 adults with methotrexate-associated acute kidney injury from 28 cancer centers across the United States.
- Analysis utilized a sequential target trial emulation framework to compare outcomes between 209 patients who received glucarpidase within 4 days of methotrexate initiation and 499 patients who did not.
- The primary endpoint was kidney recovery at hospital discharge, defined as survival with serum creatinine < 1.5-fold baseline without dialysis dependence.
- Secondary endpoints included time-to-kidney recovery, neutropenia and transaminitis on day 7, and time-to-death.
TAKEAWAY:
- Glucarpidase administration was associated with adjusted odds ratio [aOR] of 2.70 (95% CI, 1.69-4.31) and adjusted hazard ratio [aHR] of 1.88 (95% CI, 1.18-3.33) for time-to-kidney recovery.
- Treatment with glucarpidase reduced the risk for grade ≥ 2 neutropenia (aOR, 0.50; 95% CI, 0.28-0.91) and grade ≥ 2 transaminitis (aOR, 0.31; 95% CI, 0.13-0.77) on day 7.
- Female patients showed greater benefit from glucarpidase treatment than male patients (P = .02 for interaction).
- No significant difference was observed in time-to-death between glucarpidase-treated and glucarpidase-untreated patients (aHR, 0.76; 95% CI, 0.49-1.18).
IN PRACTICE:
“These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI [methotrexate-acute kidney injury],” the authors of the study wrote.
SOURCE:
This study was led by Shruti Gupta, MD, MPH, and David E. Leaf, MD, MMSc, Brigham and Women’s Hospital in Boston, Massachusetts. It was published online in Blood.
LIMITATIONS:
According to the authors, residual confounding cannot be excluded despite adjustment for multiple variables. While glucarpidase-treated patients had similar distributions of most baseline characteristics, they showed greater severity of illness, including more comorbidities, concomitant nephrotoxic medications, higher 24-hour methotrexate levels, and more severe acute kidney injury. This study was limited to patients treated at large, US-based academic centers, potentially affecting generalizability to smaller hospitals or countries where glucarpidase is unavailable.
DISCLOSURES:
This study was funded by BTG International. Gupta disclosed ties with BTG International, Dana-Farber Cancer Institute’s Wong Foundation, Janssen, AstraZeneca, and the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK125672). Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers conducted a multicenter cohort study involving 708 adults with methotrexate-associated acute kidney injury from 28 cancer centers across the United States.
- Analysis utilized a sequential target trial emulation framework to compare outcomes between 209 patients who received glucarpidase within 4 days of methotrexate initiation and 499 patients who did not.
- The primary endpoint was kidney recovery at hospital discharge, defined as survival with serum creatinine < 1.5-fold baseline without dialysis dependence.
- Secondary endpoints included time-to-kidney recovery, neutropenia and transaminitis on day 7, and time-to-death.
TAKEAWAY:
- Glucarpidase administration was associated with adjusted odds ratio [aOR] of 2.70 (95% CI, 1.69-4.31) and adjusted hazard ratio [aHR] of 1.88 (95% CI, 1.18-3.33) for time-to-kidney recovery.
- Treatment with glucarpidase reduced the risk for grade ≥ 2 neutropenia (aOR, 0.50; 95% CI, 0.28-0.91) and grade ≥ 2 transaminitis (aOR, 0.31; 95% CI, 0.13-0.77) on day 7.
- Female patients showed greater benefit from glucarpidase treatment than male patients (P = .02 for interaction).
- No significant difference was observed in time-to-death between glucarpidase-treated and glucarpidase-untreated patients (aHR, 0.76; 95% CI, 0.49-1.18).
IN PRACTICE:
“These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI [methotrexate-acute kidney injury],” the authors of the study wrote.
SOURCE:
This study was led by Shruti Gupta, MD, MPH, and David E. Leaf, MD, MMSc, Brigham and Women’s Hospital in Boston, Massachusetts. It was published online in Blood.
LIMITATIONS:
According to the authors, residual confounding cannot be excluded despite adjustment for multiple variables. While glucarpidase-treated patients had similar distributions of most baseline characteristics, they showed greater severity of illness, including more comorbidities, concomitant nephrotoxic medications, higher 24-hour methotrexate levels, and more severe acute kidney injury. This study was limited to patients treated at large, US-based academic centers, potentially affecting generalizability to smaller hospitals or countries where glucarpidase is unavailable.
DISCLOSURES:
This study was funded by BTG International. Gupta disclosed ties with BTG International, Dana-Farber Cancer Institute’s Wong Foundation, Janssen, AstraZeneca, and the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK125672). Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Hemophilia A: Bleeds Plummet After Experimental Gene Therapy
SAN DIEGO — Promising early results from an ongoing randomized, open-label, single-arm, phase 3 study could pave the way for a Pfizer product to become the second US Food and Drug Administration (FDA)–approved gene therapy for hemophilia A.
In an efficacy population of 50 patients with hemophilia A, the AFFINE trial found that their mean annualized bleeding rate (ABR) fell from 4.73 pre-infusion with giroctocogene fitelparvovec to 1.24 post-infusion (week 12 to 15 or more months, −3.49, −6.06 to −0.91; P = .004), researchers reported earlier this month at American Society of Hematology (ASH) 2024 Annual Meeting. Sixty-four percent had no bleeding events over a median follow-up of 33.6 months (14.5-44.4).
The ABR for treated bleeds fell from 4.08 to 0.07 (−4.01, −5.57 to −2.45; P < .0001), and 88% had no treated bleeds over the same follow-up period.
“The primary endpoint for this trial was a reduction in total bleeds in patients, and that was achieved,” hematologist and first author Andrew D. Leavitt, MD, of the University of California at San Francisco, said in an interview. “More impressive was the reduction in treated bleeds, a kind of a surrogate marker for bleeds of clinical significance to the individual. And as one would expect or hope to see in a gene therapy trial, there was a significant and marked reduction in the use of factor.”
Moving forward, he said, the message to clinicians is that “there’s every reason to believe that they will have yet another option for their patients.”
Gene Therapy on the Rise in Hemophilia
Gene therapy has arisen as an approved therapy for hemophilia over just the last few years. Two gene therapies for hemophilia B have been approved by the FDA since 2022, and one was approved for hemophilia A, the more common type, in 2023.
As Leavitt noted, one-time treatment with gene therapy offers an alternative to treatment with blood factor, long the mainstay of hemophilia therapy.
“One of the real pluses of gene therapy is the potential to remove the burden of hemophilia, which is large and, I suspect, underappreciated even by providers,” he said. “You have to sit down with your patients and really get a real good sense of just how difficult it is for them to manage with many products on the market over the last few decades.”
Why is there a need for multiple gene therapy products? “A patient may have neutralizing antibodies against the proteins on the surface of gene therapy product A that prevents its use, but not on gene therapy B, which allows use of product B,” Leavitt said. “We need a few flavors so that we can offer gene therapy to the maximum number of interested patients.”
High Efficacy and an ‘Acceptable’ Safety Profile
For the study, researchers dosed 75 patients (mean age, 32.3 [19-59]; 100% men, 74.7% White and 18.7% Asian,) with hemophilia A with giroctocogene fitelparvovec, a hepatocyte-directed recombinant adeno-associated virus serotype 6 vector encoding a B-domain–deleted variant of human factor VIII. The efficacy population is 50 patients with at least 6 months of follow-up in the lead-in study.
The annualized infusion rate of exogenous FVIII was 124.39 mean annualized infusion rate prior to the treatment infusion vs 0.21 post-infusion, week 12 through at least 15 months (−124.18, −139.47 to −108.89; P < .0001).
Leavitt said the results are similar to other gene therapies for hemophilia in that “it is difficult to predict how high your factor level will become. There’s a broad range of outcomes for individuals, and the duration of expression remains an unknown.”
The study authors described the treatment as “generally well tolerated” with “an acceptable and manageable safety profile.”
Of the 75 subjects, 98.7% had adverse effects (AEs, 740 events) and 90.7% had treatment-related AEs. Common treatment-related AEs included hepatotoxicity (62.7%) and infusion-related reactions (73.3%). No subjects discontinued therapy due to AEs.
Nearly two thirds — 62.7% — of subjects used corticosteroids for a mean 114.6 days (11-296).
Study Findings ‘Look Really Good’
In an interview, Guy Young, MD, director of the Hemostasis and Thrombosis Program at Children’s Hospital Los Angeles and professor of pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, said that “generally speaking, the new data looks really good.” Young, who didn’t take part in the study, noted that factor levels following treatment were high, and one subject actually had a thrombotic event and needed to be treated with an anticoagulant.
The high factor levels could actually be a sign of lasting benefit vs valoctocogene roxaparvovec (Roctavian), the sole FDA-approved gene therapy for hemophilia A, which is linked to significant drops in factor level after 6 months, he said. “Wouldn’t it be better to start really high?”
Gene therapy for hemophilia is highly expensive, although proponents noted that insurers may save money over the long run if patients don’t require prophylactic treatment or therapy for bleeds.
A Pfizer spokesman declined to comment on the new therapy’s potential cost. In regard to when the therapy may receive FDA approval, he said “Pfizer is discussing this data with regulatory authorities.”
Pfizer funded this study. Leavitt disclosed ties with HEMA, Merck, Catalyst, Genentech, Pfizer, BioMarin, and Sangamo. Other study authors reported relationships with Pfizer. Young disclosed ties with Pfizer and BioMarin.
A version of this article appeared on Medscape.com.
SAN DIEGO — Promising early results from an ongoing randomized, open-label, single-arm, phase 3 study could pave the way for a Pfizer product to become the second US Food and Drug Administration (FDA)–approved gene therapy for hemophilia A.
In an efficacy population of 50 patients with hemophilia A, the AFFINE trial found that their mean annualized bleeding rate (ABR) fell from 4.73 pre-infusion with giroctocogene fitelparvovec to 1.24 post-infusion (week 12 to 15 or more months, −3.49, −6.06 to −0.91; P = .004), researchers reported earlier this month at American Society of Hematology (ASH) 2024 Annual Meeting. Sixty-four percent had no bleeding events over a median follow-up of 33.6 months (14.5-44.4).
The ABR for treated bleeds fell from 4.08 to 0.07 (−4.01, −5.57 to −2.45; P < .0001), and 88% had no treated bleeds over the same follow-up period.
“The primary endpoint for this trial was a reduction in total bleeds in patients, and that was achieved,” hematologist and first author Andrew D. Leavitt, MD, of the University of California at San Francisco, said in an interview. “More impressive was the reduction in treated bleeds, a kind of a surrogate marker for bleeds of clinical significance to the individual. And as one would expect or hope to see in a gene therapy trial, there was a significant and marked reduction in the use of factor.”
Moving forward, he said, the message to clinicians is that “there’s every reason to believe that they will have yet another option for their patients.”
Gene Therapy on the Rise in Hemophilia
Gene therapy has arisen as an approved therapy for hemophilia over just the last few years. Two gene therapies for hemophilia B have been approved by the FDA since 2022, and one was approved for hemophilia A, the more common type, in 2023.
As Leavitt noted, one-time treatment with gene therapy offers an alternative to treatment with blood factor, long the mainstay of hemophilia therapy.
“One of the real pluses of gene therapy is the potential to remove the burden of hemophilia, which is large and, I suspect, underappreciated even by providers,” he said. “You have to sit down with your patients and really get a real good sense of just how difficult it is for them to manage with many products on the market over the last few decades.”
Why is there a need for multiple gene therapy products? “A patient may have neutralizing antibodies against the proteins on the surface of gene therapy product A that prevents its use, but not on gene therapy B, which allows use of product B,” Leavitt said. “We need a few flavors so that we can offer gene therapy to the maximum number of interested patients.”
High Efficacy and an ‘Acceptable’ Safety Profile
For the study, researchers dosed 75 patients (mean age, 32.3 [19-59]; 100% men, 74.7% White and 18.7% Asian,) with hemophilia A with giroctocogene fitelparvovec, a hepatocyte-directed recombinant adeno-associated virus serotype 6 vector encoding a B-domain–deleted variant of human factor VIII. The efficacy population is 50 patients with at least 6 months of follow-up in the lead-in study.
The annualized infusion rate of exogenous FVIII was 124.39 mean annualized infusion rate prior to the treatment infusion vs 0.21 post-infusion, week 12 through at least 15 months (−124.18, −139.47 to −108.89; P < .0001).
Leavitt said the results are similar to other gene therapies for hemophilia in that “it is difficult to predict how high your factor level will become. There’s a broad range of outcomes for individuals, and the duration of expression remains an unknown.”
The study authors described the treatment as “generally well tolerated” with “an acceptable and manageable safety profile.”
Of the 75 subjects, 98.7% had adverse effects (AEs, 740 events) and 90.7% had treatment-related AEs. Common treatment-related AEs included hepatotoxicity (62.7%) and infusion-related reactions (73.3%). No subjects discontinued therapy due to AEs.
Nearly two thirds — 62.7% — of subjects used corticosteroids for a mean 114.6 days (11-296).
Study Findings ‘Look Really Good’
In an interview, Guy Young, MD, director of the Hemostasis and Thrombosis Program at Children’s Hospital Los Angeles and professor of pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, said that “generally speaking, the new data looks really good.” Young, who didn’t take part in the study, noted that factor levels following treatment were high, and one subject actually had a thrombotic event and needed to be treated with an anticoagulant.
The high factor levels could actually be a sign of lasting benefit vs valoctocogene roxaparvovec (Roctavian), the sole FDA-approved gene therapy for hemophilia A, which is linked to significant drops in factor level after 6 months, he said. “Wouldn’t it be better to start really high?”
Gene therapy for hemophilia is highly expensive, although proponents noted that insurers may save money over the long run if patients don’t require prophylactic treatment or therapy for bleeds.
A Pfizer spokesman declined to comment on the new therapy’s potential cost. In regard to when the therapy may receive FDA approval, he said “Pfizer is discussing this data with regulatory authorities.”
Pfizer funded this study. Leavitt disclosed ties with HEMA, Merck, Catalyst, Genentech, Pfizer, BioMarin, and Sangamo. Other study authors reported relationships with Pfizer. Young disclosed ties with Pfizer and BioMarin.
A version of this article appeared on Medscape.com.
SAN DIEGO — Promising early results from an ongoing randomized, open-label, single-arm, phase 3 study could pave the way for a Pfizer product to become the second US Food and Drug Administration (FDA)–approved gene therapy for hemophilia A.
In an efficacy population of 50 patients with hemophilia A, the AFFINE trial found that their mean annualized bleeding rate (ABR) fell from 4.73 pre-infusion with giroctocogene fitelparvovec to 1.24 post-infusion (week 12 to 15 or more months, −3.49, −6.06 to −0.91; P = .004), researchers reported earlier this month at American Society of Hematology (ASH) 2024 Annual Meeting. Sixty-four percent had no bleeding events over a median follow-up of 33.6 months (14.5-44.4).
The ABR for treated bleeds fell from 4.08 to 0.07 (−4.01, −5.57 to −2.45; P < .0001), and 88% had no treated bleeds over the same follow-up period.
“The primary endpoint for this trial was a reduction in total bleeds in patients, and that was achieved,” hematologist and first author Andrew D. Leavitt, MD, of the University of California at San Francisco, said in an interview. “More impressive was the reduction in treated bleeds, a kind of a surrogate marker for bleeds of clinical significance to the individual. And as one would expect or hope to see in a gene therapy trial, there was a significant and marked reduction in the use of factor.”
Moving forward, he said, the message to clinicians is that “there’s every reason to believe that they will have yet another option for their patients.”
Gene Therapy on the Rise in Hemophilia
Gene therapy has arisen as an approved therapy for hemophilia over just the last few years. Two gene therapies for hemophilia B have been approved by the FDA since 2022, and one was approved for hemophilia A, the more common type, in 2023.
As Leavitt noted, one-time treatment with gene therapy offers an alternative to treatment with blood factor, long the mainstay of hemophilia therapy.
“One of the real pluses of gene therapy is the potential to remove the burden of hemophilia, which is large and, I suspect, underappreciated even by providers,” he said. “You have to sit down with your patients and really get a real good sense of just how difficult it is for them to manage with many products on the market over the last few decades.”
Why is there a need for multiple gene therapy products? “A patient may have neutralizing antibodies against the proteins on the surface of gene therapy product A that prevents its use, but not on gene therapy B, which allows use of product B,” Leavitt said. “We need a few flavors so that we can offer gene therapy to the maximum number of interested patients.”
High Efficacy and an ‘Acceptable’ Safety Profile
For the study, researchers dosed 75 patients (mean age, 32.3 [19-59]; 100% men, 74.7% White and 18.7% Asian,) with hemophilia A with giroctocogene fitelparvovec, a hepatocyte-directed recombinant adeno-associated virus serotype 6 vector encoding a B-domain–deleted variant of human factor VIII. The efficacy population is 50 patients with at least 6 months of follow-up in the lead-in study.
The annualized infusion rate of exogenous FVIII was 124.39 mean annualized infusion rate prior to the treatment infusion vs 0.21 post-infusion, week 12 through at least 15 months (−124.18, −139.47 to −108.89; P < .0001).
Leavitt said the results are similar to other gene therapies for hemophilia in that “it is difficult to predict how high your factor level will become. There’s a broad range of outcomes for individuals, and the duration of expression remains an unknown.”
The study authors described the treatment as “generally well tolerated” with “an acceptable and manageable safety profile.”
Of the 75 subjects, 98.7% had adverse effects (AEs, 740 events) and 90.7% had treatment-related AEs. Common treatment-related AEs included hepatotoxicity (62.7%) and infusion-related reactions (73.3%). No subjects discontinued therapy due to AEs.
Nearly two thirds — 62.7% — of subjects used corticosteroids for a mean 114.6 days (11-296).
Study Findings ‘Look Really Good’
In an interview, Guy Young, MD, director of the Hemostasis and Thrombosis Program at Children’s Hospital Los Angeles and professor of pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, said that “generally speaking, the new data looks really good.” Young, who didn’t take part in the study, noted that factor levels following treatment were high, and one subject actually had a thrombotic event and needed to be treated with an anticoagulant.
The high factor levels could actually be a sign of lasting benefit vs valoctocogene roxaparvovec (Roctavian), the sole FDA-approved gene therapy for hemophilia A, which is linked to significant drops in factor level after 6 months, he said. “Wouldn’t it be better to start really high?”
Gene therapy for hemophilia is highly expensive, although proponents noted that insurers may save money over the long run if patients don’t require prophylactic treatment or therapy for bleeds.
A Pfizer spokesman declined to comment on the new therapy’s potential cost. In regard to when the therapy may receive FDA approval, he said “Pfizer is discussing this data with regulatory authorities.”
Pfizer funded this study. Leavitt disclosed ties with HEMA, Merck, Catalyst, Genentech, Pfizer, BioMarin, and Sangamo. Other study authors reported relationships with Pfizer. Young disclosed ties with Pfizer and BioMarin.
A version of this article appeared on Medscape.com.
FROM ASH 2024
Cellular Therapies for Solid Tumors: The Next Big Thing?
The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.
First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue.
“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”
As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs).
“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.
‘Reverse Engineering’
In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.
Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.
“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer?
Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand.
“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”
In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.
Cell Therapies Include CAR T Cells and TCRT
In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.
In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).
In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner.
“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.
TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies.
Decades in the Making
The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.
Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics.
“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.”
Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.
“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.
In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas.
The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.
Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”
Risk-Benefit Profiles Depend on Mechanism of Action
If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor.
“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.
A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.
“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”
A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner.
In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes.
“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”
Promise of PRAME
Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study.
“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”
Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).
The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.
Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile.
Accelerated Approvals, Boxed Warnings
The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT.
Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.
With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.
The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses.
The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).
In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel.
The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.
New Hope for Patients
Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.
“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”
For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.
“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.
Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.
A version of this article appeared on Medscape.com.
The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.
First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue.
“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”
As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs).
“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.
‘Reverse Engineering’
In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.
Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.
“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer?
Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand.
“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”
In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.
Cell Therapies Include CAR T Cells and TCRT
In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.
In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).
In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner.
“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.
TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies.
Decades in the Making
The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.
Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics.
“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.”
Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.
“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.
In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas.
The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.
Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”
Risk-Benefit Profiles Depend on Mechanism of Action
If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor.
“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.
A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.
“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”
A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner.
In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes.
“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”
Promise of PRAME
Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study.
“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”
Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).
The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.
Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile.
Accelerated Approvals, Boxed Warnings
The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT.
Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.
With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.
The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses.
The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).
In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel.
The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.
New Hope for Patients
Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.
“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”
For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.
“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.
Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.
A version of this article appeared on Medscape.com.
The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.
First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue.
“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”
As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs).
“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.
‘Reverse Engineering’
In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.
Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.
“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer?
Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand.
“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”
In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.
Cell Therapies Include CAR T Cells and TCRT
In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.
In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).
In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner.
“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.
TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies.
Decades in the Making
The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.
Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics.
“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.”
Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.
“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.
In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas.
The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.
Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”
Risk-Benefit Profiles Depend on Mechanism of Action
If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor.
“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.
A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.
“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”
A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner.
In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes.
“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”
Promise of PRAME
Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study.
“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”
Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).
The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.
Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile.
Accelerated Approvals, Boxed Warnings
The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT.
Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.
With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.
The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses.
The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).
In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel.
The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.
New Hope for Patients
Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.
“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”
For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.
“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.
Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.
A version of this article appeared on Medscape.com.
COVID-19 Takes a Greater Toll on Kidneys Than Pneumonia
TOPLINE:
This decline in kidney function, measured by the estimated glomerular filtration rate (eGFR), is particularly steep among individuals who require hospitalization for COVID-19.
METHODOLOGY:
- SARS-CoV-2, the virus that causes COVID-19, has been associated with acute kidney injury, but its potential impact on long-term kidney function remains unclear.
- Researchers investigated the decline in kidney function after COVID-19 vs pneumonia by including all hospitalized and nonhospitalized adults from the Stockholm Creatinine Measurements Project who had at least one eGFR measurement in the 2 years before a positive COVID-19 test result or pneumonia diagnosis.
- Overall, 134,565 individuals (median age, 51 years; 55.6% women) who had their first SARS-CoV-2 infection between February 2020 and January 2022 were included, of whom 13.3% required hospitalization within 28 days of their first positive COVID-19 test result.
- They were compared with 35,987 patients (median age, 71 years; 53.8% women) who were diagnosed with pneumonia between February 2018 and January 2020; 46.5% of them required hospitalization.
- The primary outcome measure focused on the mean annual change in eGFR slopes before and after each infection; the secondary outcome assessed was the annual change in postinfection eGFR slopes between COVID-19 and pneumonia cases.
TAKEAWAY:
- Before COVID-19, eGFR changes were minimal, but after the infection, the average decline increased to 4.1 (95% CI, 3.8-4.4) mL/min/1.73 m2; however, in the pneumonia cohort, a decline in eGFR was noted both before and after the infection.
- After COVID-19, the mean annual decline in eGFR was 3.4% (95% CI, 3.2%-3.5%), increasing to 5.4% (95% CI, 5.2%-5.6%) for those who were hospitalized.
- In contrast, the pneumonia group experienced an average annual decline of 2.3% (95% CI, 2.1%-2.5%) after the infection, which remained unchanged when analyzing only patients who were hospitalized.
- The risk for a 25% reduction in eGFR was higher in patients with COVID-19 than in those with pneumonia (hazard ratio [HR], 1.19; 95% CI, 1.07-1.34), with the risk being even higher among those who required hospitalization (HR, 1.42; 95% CI, 1.22-1.64).
IN PRACTICE:
“These findings help inform decisions regarding the need to monitor kidney function in survivors of COVID-19 and could have implications for policymakers regarding future healthcare planning and kidney service provision,” the authors wrote.
SOURCE:
This study was led by Viyaasan Mahalingasivam, MPhil, London School of Hygiene & Tropical Medicine, London, England. It was published online in JAMA Network Open.
LIMITATIONS:
This study lacked information on important confounders such as ethnicity and body mass index. The follow-up period was not long enough to fully evaluate the long-term association of COVID-19 with kidney function. Some individuals may have been misclassified as nonhospitalized if their first infection was mild and a subsequent infection required hospitalization.
DISCLOSURES:
This study was supported by grants from the National Institute for Health and Care Research, Njurfonden, Stig and Gunborg Westman Foundation, and the Swedish Research Council. One author reported receiving a Career Development Award from the National Institute for Health and Care Research, and another author reported receiving grants from Njurfonden, Stig and Gunborg Westman Foundation, Swedish Research Council, Swedish Heart Lung Foundation, and Region Stockholm during the conduct of the study.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
This decline in kidney function, measured by the estimated glomerular filtration rate (eGFR), is particularly steep among individuals who require hospitalization for COVID-19.
METHODOLOGY:
- SARS-CoV-2, the virus that causes COVID-19, has been associated with acute kidney injury, but its potential impact on long-term kidney function remains unclear.
- Researchers investigated the decline in kidney function after COVID-19 vs pneumonia by including all hospitalized and nonhospitalized adults from the Stockholm Creatinine Measurements Project who had at least one eGFR measurement in the 2 years before a positive COVID-19 test result or pneumonia diagnosis.
- Overall, 134,565 individuals (median age, 51 years; 55.6% women) who had their first SARS-CoV-2 infection between February 2020 and January 2022 were included, of whom 13.3% required hospitalization within 28 days of their first positive COVID-19 test result.
- They were compared with 35,987 patients (median age, 71 years; 53.8% women) who were diagnosed with pneumonia between February 2018 and January 2020; 46.5% of them required hospitalization.
- The primary outcome measure focused on the mean annual change in eGFR slopes before and after each infection; the secondary outcome assessed was the annual change in postinfection eGFR slopes between COVID-19 and pneumonia cases.
TAKEAWAY:
- Before COVID-19, eGFR changes were minimal, but after the infection, the average decline increased to 4.1 (95% CI, 3.8-4.4) mL/min/1.73 m2; however, in the pneumonia cohort, a decline in eGFR was noted both before and after the infection.
- After COVID-19, the mean annual decline in eGFR was 3.4% (95% CI, 3.2%-3.5%), increasing to 5.4% (95% CI, 5.2%-5.6%) for those who were hospitalized.
- In contrast, the pneumonia group experienced an average annual decline of 2.3% (95% CI, 2.1%-2.5%) after the infection, which remained unchanged when analyzing only patients who were hospitalized.
- The risk for a 25% reduction in eGFR was higher in patients with COVID-19 than in those with pneumonia (hazard ratio [HR], 1.19; 95% CI, 1.07-1.34), with the risk being even higher among those who required hospitalization (HR, 1.42; 95% CI, 1.22-1.64).
IN PRACTICE:
“These findings help inform decisions regarding the need to monitor kidney function in survivors of COVID-19 and could have implications for policymakers regarding future healthcare planning and kidney service provision,” the authors wrote.
SOURCE:
This study was led by Viyaasan Mahalingasivam, MPhil, London School of Hygiene & Tropical Medicine, London, England. It was published online in JAMA Network Open.
LIMITATIONS:
This study lacked information on important confounders such as ethnicity and body mass index. The follow-up period was not long enough to fully evaluate the long-term association of COVID-19 with kidney function. Some individuals may have been misclassified as nonhospitalized if their first infection was mild and a subsequent infection required hospitalization.
DISCLOSURES:
This study was supported by grants from the National Institute for Health and Care Research, Njurfonden, Stig and Gunborg Westman Foundation, and the Swedish Research Council. One author reported receiving a Career Development Award from the National Institute for Health and Care Research, and another author reported receiving grants from Njurfonden, Stig and Gunborg Westman Foundation, Swedish Research Council, Swedish Heart Lung Foundation, and Region Stockholm during the conduct of the study.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
This decline in kidney function, measured by the estimated glomerular filtration rate (eGFR), is particularly steep among individuals who require hospitalization for COVID-19.
METHODOLOGY:
- SARS-CoV-2, the virus that causes COVID-19, has been associated with acute kidney injury, but its potential impact on long-term kidney function remains unclear.
- Researchers investigated the decline in kidney function after COVID-19 vs pneumonia by including all hospitalized and nonhospitalized adults from the Stockholm Creatinine Measurements Project who had at least one eGFR measurement in the 2 years before a positive COVID-19 test result or pneumonia diagnosis.
- Overall, 134,565 individuals (median age, 51 years; 55.6% women) who had their first SARS-CoV-2 infection between February 2020 and January 2022 were included, of whom 13.3% required hospitalization within 28 days of their first positive COVID-19 test result.
- They were compared with 35,987 patients (median age, 71 years; 53.8% women) who were diagnosed with pneumonia between February 2018 and January 2020; 46.5% of them required hospitalization.
- The primary outcome measure focused on the mean annual change in eGFR slopes before and after each infection; the secondary outcome assessed was the annual change in postinfection eGFR slopes between COVID-19 and pneumonia cases.
TAKEAWAY:
- Before COVID-19, eGFR changes were minimal, but after the infection, the average decline increased to 4.1 (95% CI, 3.8-4.4) mL/min/1.73 m2; however, in the pneumonia cohort, a decline in eGFR was noted both before and after the infection.
- After COVID-19, the mean annual decline in eGFR was 3.4% (95% CI, 3.2%-3.5%), increasing to 5.4% (95% CI, 5.2%-5.6%) for those who were hospitalized.
- In contrast, the pneumonia group experienced an average annual decline of 2.3% (95% CI, 2.1%-2.5%) after the infection, which remained unchanged when analyzing only patients who were hospitalized.
- The risk for a 25% reduction in eGFR was higher in patients with COVID-19 than in those with pneumonia (hazard ratio [HR], 1.19; 95% CI, 1.07-1.34), with the risk being even higher among those who required hospitalization (HR, 1.42; 95% CI, 1.22-1.64).
IN PRACTICE:
“These findings help inform decisions regarding the need to monitor kidney function in survivors of COVID-19 and could have implications for policymakers regarding future healthcare planning and kidney service provision,” the authors wrote.
SOURCE:
This study was led by Viyaasan Mahalingasivam, MPhil, London School of Hygiene & Tropical Medicine, London, England. It was published online in JAMA Network Open.
LIMITATIONS:
This study lacked information on important confounders such as ethnicity and body mass index. The follow-up period was not long enough to fully evaluate the long-term association of COVID-19 with kidney function. Some individuals may have been misclassified as nonhospitalized if their first infection was mild and a subsequent infection required hospitalization.
DISCLOSURES:
This study was supported by grants from the National Institute for Health and Care Research, Njurfonden, Stig and Gunborg Westman Foundation, and the Swedish Research Council. One author reported receiving a Career Development Award from the National Institute for Health and Care Research, and another author reported receiving grants from Njurfonden, Stig and Gunborg Westman Foundation, Swedish Research Council, Swedish Heart Lung Foundation, and Region Stockholm during the conduct of the study.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.