User login
Guide explains nonsurgical management of major hemorrhage
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM THE CANADIAN MEDICAL ASSOCIATION JOURNAL
“Terrific progress”: Adding blinatumomab for infant leukemia
.
Two-year disease-free and overall survival measures, as well as the percentage of children who had complete minimal residual disease (MRD) responses, were substantially higher among the 30 infants in the study than in historical controls treated with the same chemotherapy backbone in an earlier trial, Interfant-06.
“These outcome data are very promising, given the poor survival and lack of improvements in outcomes among infants with KMT2A-rearranged ALL in recent decades,” said the investigators, led by Inge M. van der Sluis, MD, PhD, a hematologist-oncologist at Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands.
“The low incidence of relapse after treatment with blinatumomab is remarkable, given that in historical controls relapses occur frequently and early during therapy,” the investigators stated. Although the “follow-up time was relatively short” in the study, “it included the period historically defined” as being at high risk of relapse, they said.
The team suggested that future research should assess whether infants benefit from multiple courses of blinatumomab, rather than the one course used in the study, and whether blinatumomab plus chemotherapy can replace stem cell transplants for high-risk infants.
Pediatric community responds
There was excitement on Twitter about the results; a number of pediatric blood cancer specialists were impressed and posted the study on that platform. Comments included, “Wow! After years of stagnation, a huge step forward for infant leukemia” and “great news for infant lymphoblastic leukemia.”
Akshay Sharma, MBBS, a pediatric bone marrow transplant and cellular therapy specialist at St. Jude Children’s Research Hospital, Memphis, also posted. He said in an interview that the findings are “very exciting.”
The “outcomes of children diagnosed with leukemia in their infancy, particularly if they have a KMT2A rearrangement, have been dismal. This is terrific progress and a testament to the role that immunotherapy and novel agents will be playing in treatment of several malignant diseases in the decade to come,” he said.
Another poster, Pratik “Tik” Patel, MD, a pediatric hematology/oncology fellow at Emory University in Atlanta, told this news organization that the study “is welcome news to pediatric oncologists” and highlights “the success in incorporating newer immune-based therapeutics upfront in treatment rather than in relapsed/refractory settings.”
The National Cancer Institute–funded Children’s Oncology Group is thinking the same way. The group is launching a large, randomized trial to test if adding blinatumomab to chemotherapy upfront for B-cell acute lymphoblastic leukemia and lymphoblastic lymphoma improves outcomes in children and young adults aged 1-31 years. Results are due after 2029.
Study details
Blinatumomab is an expensive “T-cell engager” that helps cytotoxic CD3+T cells link to and destroy leukemic CD19+ B cells. Past studies have shown that it’s safe and works in older children and adults with B-lineage ALL after intensive chemotherapy, but until now the approach hadn’t been tested in infants, the investigators said.
The 30 subjects in the study were under a year old and newly diagnosed with KMT2A-rearranged ALL. They were treated with the Interfant-06 chemotherapy regimen – cytosine arabinoside and other agents – plus one postinduction course of blinatumomab at 15 micrograms/m2 per day as a 4-week continuous infusion. Eight of nine high-risk patients had allogeneic hematopoietic stem cell transplants.
Overall survival was 93.3% over a median follow up of 26.3 months, substantially higher than the 65.8% in the Interfant-06 trial. Two-year disease-free survival was 81.6% versus 49.4% in Interfant-06.
Sixteen patients (53%) were MRD negative after blinatumomab infusion and 12 (40%) had low levels of MRD. All of the children who continued chemotherapy went on to become MRD negative.
There were no permanent blinatumomab discontinuations and no treatment related deaths. Serious toxic effects were consistent with those in older patients and included four fevers, four infections, and one case each of hypertension and vomiting.
There were no cases of severe cytokine release syndrome (CRS) because of the low tumor burden of the subjects. Likewise, there were no obvious neurologic adverse events – like CRS, a particular concern with blinatumomab – but “we cannot rule out underreporting of mild neurologic symptoms that may have been unrecognized in infants,” the investigators said.
Patients who relapsed in the study had CNS involvement at relapse. “This underscores the need for adequate intrathecal chemotherapy during the blinatumomab infusion, because the efficacy of blinatumomab for the treatment of CNS leukemia may be limited,” they said.
The work was supported by Amgen, the maker of blinatumomab, as well as the Princess Maxima Center Foundation, the Danish Childhood Cancer Foundation, and others. Dr. Sluis is a consultant and researcher for Amgen. Five other authors were also consultants/advisers/researchers for the company. Dr. Sharma and Dr. Patel didn’t have any relevant disclosures.
.
Two-year disease-free and overall survival measures, as well as the percentage of children who had complete minimal residual disease (MRD) responses, were substantially higher among the 30 infants in the study than in historical controls treated with the same chemotherapy backbone in an earlier trial, Interfant-06.
“These outcome data are very promising, given the poor survival and lack of improvements in outcomes among infants with KMT2A-rearranged ALL in recent decades,” said the investigators, led by Inge M. van der Sluis, MD, PhD, a hematologist-oncologist at Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands.
“The low incidence of relapse after treatment with blinatumomab is remarkable, given that in historical controls relapses occur frequently and early during therapy,” the investigators stated. Although the “follow-up time was relatively short” in the study, “it included the period historically defined” as being at high risk of relapse, they said.
The team suggested that future research should assess whether infants benefit from multiple courses of blinatumomab, rather than the one course used in the study, and whether blinatumomab plus chemotherapy can replace stem cell transplants for high-risk infants.
Pediatric community responds
There was excitement on Twitter about the results; a number of pediatric blood cancer specialists were impressed and posted the study on that platform. Comments included, “Wow! After years of stagnation, a huge step forward for infant leukemia” and “great news for infant lymphoblastic leukemia.”
Akshay Sharma, MBBS, a pediatric bone marrow transplant and cellular therapy specialist at St. Jude Children’s Research Hospital, Memphis, also posted. He said in an interview that the findings are “very exciting.”
The “outcomes of children diagnosed with leukemia in their infancy, particularly if they have a KMT2A rearrangement, have been dismal. This is terrific progress and a testament to the role that immunotherapy and novel agents will be playing in treatment of several malignant diseases in the decade to come,” he said.
Another poster, Pratik “Tik” Patel, MD, a pediatric hematology/oncology fellow at Emory University in Atlanta, told this news organization that the study “is welcome news to pediatric oncologists” and highlights “the success in incorporating newer immune-based therapeutics upfront in treatment rather than in relapsed/refractory settings.”
The National Cancer Institute–funded Children’s Oncology Group is thinking the same way. The group is launching a large, randomized trial to test if adding blinatumomab to chemotherapy upfront for B-cell acute lymphoblastic leukemia and lymphoblastic lymphoma improves outcomes in children and young adults aged 1-31 years. Results are due after 2029.
Study details
Blinatumomab is an expensive “T-cell engager” that helps cytotoxic CD3+T cells link to and destroy leukemic CD19+ B cells. Past studies have shown that it’s safe and works in older children and adults with B-lineage ALL after intensive chemotherapy, but until now the approach hadn’t been tested in infants, the investigators said.
The 30 subjects in the study were under a year old and newly diagnosed with KMT2A-rearranged ALL. They were treated with the Interfant-06 chemotherapy regimen – cytosine arabinoside and other agents – plus one postinduction course of blinatumomab at 15 micrograms/m2 per day as a 4-week continuous infusion. Eight of nine high-risk patients had allogeneic hematopoietic stem cell transplants.
Overall survival was 93.3% over a median follow up of 26.3 months, substantially higher than the 65.8% in the Interfant-06 trial. Two-year disease-free survival was 81.6% versus 49.4% in Interfant-06.
Sixteen patients (53%) were MRD negative after blinatumomab infusion and 12 (40%) had low levels of MRD. All of the children who continued chemotherapy went on to become MRD negative.
There were no permanent blinatumomab discontinuations and no treatment related deaths. Serious toxic effects were consistent with those in older patients and included four fevers, four infections, and one case each of hypertension and vomiting.
There were no cases of severe cytokine release syndrome (CRS) because of the low tumor burden of the subjects. Likewise, there were no obvious neurologic adverse events – like CRS, a particular concern with blinatumomab – but “we cannot rule out underreporting of mild neurologic symptoms that may have been unrecognized in infants,” the investigators said.
Patients who relapsed in the study had CNS involvement at relapse. “This underscores the need for adequate intrathecal chemotherapy during the blinatumomab infusion, because the efficacy of blinatumomab for the treatment of CNS leukemia may be limited,” they said.
The work was supported by Amgen, the maker of blinatumomab, as well as the Princess Maxima Center Foundation, the Danish Childhood Cancer Foundation, and others. Dr. Sluis is a consultant and researcher for Amgen. Five other authors were also consultants/advisers/researchers for the company. Dr. Sharma and Dr. Patel didn’t have any relevant disclosures.
.
Two-year disease-free and overall survival measures, as well as the percentage of children who had complete minimal residual disease (MRD) responses, were substantially higher among the 30 infants in the study than in historical controls treated with the same chemotherapy backbone in an earlier trial, Interfant-06.
“These outcome data are very promising, given the poor survival and lack of improvements in outcomes among infants with KMT2A-rearranged ALL in recent decades,” said the investigators, led by Inge M. van der Sluis, MD, PhD, a hematologist-oncologist at Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands.
“The low incidence of relapse after treatment with blinatumomab is remarkable, given that in historical controls relapses occur frequently and early during therapy,” the investigators stated. Although the “follow-up time was relatively short” in the study, “it included the period historically defined” as being at high risk of relapse, they said.
The team suggested that future research should assess whether infants benefit from multiple courses of blinatumomab, rather than the one course used in the study, and whether blinatumomab plus chemotherapy can replace stem cell transplants for high-risk infants.
Pediatric community responds
There was excitement on Twitter about the results; a number of pediatric blood cancer specialists were impressed and posted the study on that platform. Comments included, “Wow! After years of stagnation, a huge step forward for infant leukemia” and “great news for infant lymphoblastic leukemia.”
Akshay Sharma, MBBS, a pediatric bone marrow transplant and cellular therapy specialist at St. Jude Children’s Research Hospital, Memphis, also posted. He said in an interview that the findings are “very exciting.”
The “outcomes of children diagnosed with leukemia in their infancy, particularly if they have a KMT2A rearrangement, have been dismal. This is terrific progress and a testament to the role that immunotherapy and novel agents will be playing in treatment of several malignant diseases in the decade to come,” he said.
Another poster, Pratik “Tik” Patel, MD, a pediatric hematology/oncology fellow at Emory University in Atlanta, told this news organization that the study “is welcome news to pediatric oncologists” and highlights “the success in incorporating newer immune-based therapeutics upfront in treatment rather than in relapsed/refractory settings.”
The National Cancer Institute–funded Children’s Oncology Group is thinking the same way. The group is launching a large, randomized trial to test if adding blinatumomab to chemotherapy upfront for B-cell acute lymphoblastic leukemia and lymphoblastic lymphoma improves outcomes in children and young adults aged 1-31 years. Results are due after 2029.
Study details
Blinatumomab is an expensive “T-cell engager” that helps cytotoxic CD3+T cells link to and destroy leukemic CD19+ B cells. Past studies have shown that it’s safe and works in older children and adults with B-lineage ALL after intensive chemotherapy, but until now the approach hadn’t been tested in infants, the investigators said.
The 30 subjects in the study were under a year old and newly diagnosed with KMT2A-rearranged ALL. They were treated with the Interfant-06 chemotherapy regimen – cytosine arabinoside and other agents – plus one postinduction course of blinatumomab at 15 micrograms/m2 per day as a 4-week continuous infusion. Eight of nine high-risk patients had allogeneic hematopoietic stem cell transplants.
Overall survival was 93.3% over a median follow up of 26.3 months, substantially higher than the 65.8% in the Interfant-06 trial. Two-year disease-free survival was 81.6% versus 49.4% in Interfant-06.
Sixteen patients (53%) were MRD negative after blinatumomab infusion and 12 (40%) had low levels of MRD. All of the children who continued chemotherapy went on to become MRD negative.
There were no permanent blinatumomab discontinuations and no treatment related deaths. Serious toxic effects were consistent with those in older patients and included four fevers, four infections, and one case each of hypertension and vomiting.
There were no cases of severe cytokine release syndrome (CRS) because of the low tumor burden of the subjects. Likewise, there were no obvious neurologic adverse events – like CRS, a particular concern with blinatumomab – but “we cannot rule out underreporting of mild neurologic symptoms that may have been unrecognized in infants,” the investigators said.
Patients who relapsed in the study had CNS involvement at relapse. “This underscores the need for adequate intrathecal chemotherapy during the blinatumomab infusion, because the efficacy of blinatumomab for the treatment of CNS leukemia may be limited,” they said.
The work was supported by Amgen, the maker of blinatumomab, as well as the Princess Maxima Center Foundation, the Danish Childhood Cancer Foundation, and others. Dr. Sluis is a consultant and researcher for Amgen. Five other authors were also consultants/advisers/researchers for the company. Dr. Sharma and Dr. Patel didn’t have any relevant disclosures.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Dabigatran recalled over potential carcinogen
The nationwide recall, to the consumer level, is because of the detection of the nitrosamine impurity, N-nitroso-dabigatran, which may increase the risk of cancer with prolonged exposure to levels higher than acceptable.
To date, Ascend Laboratories has not received any reports of adverse events related to this recall.
The recalled product was distributed nationwide to wholesalers, distributors, and retailers in the United States from June 2022 to October 2022.
Complete details of the recalled product, including national drug code, lot numbers, expiration dates, and configuration/counts, are provided in a company announcement that was posted on the Food and Drug Administration website.
The company is advising patients who have any dabigatran that has been recalled to continue taking their medication and to contact their physician for advice regarding an alternative treatment.
Wholesalers/distributors and pharmacies with an existing inventory of the affected lots should stop use and distribution and quarantine the product immediately. Wholesalers and distributors should also recall the distributed product.
Questions regarding this recall can call Ascend Laboratories at 877.272.7901 (24 hours, 7 days a week).
Problems with this product should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article originally appeared on Medscape.com.
The nationwide recall, to the consumer level, is because of the detection of the nitrosamine impurity, N-nitroso-dabigatran, which may increase the risk of cancer with prolonged exposure to levels higher than acceptable.
To date, Ascend Laboratories has not received any reports of adverse events related to this recall.
The recalled product was distributed nationwide to wholesalers, distributors, and retailers in the United States from June 2022 to October 2022.
Complete details of the recalled product, including national drug code, lot numbers, expiration dates, and configuration/counts, are provided in a company announcement that was posted on the Food and Drug Administration website.
The company is advising patients who have any dabigatran that has been recalled to continue taking their medication and to contact their physician for advice regarding an alternative treatment.
Wholesalers/distributors and pharmacies with an existing inventory of the affected lots should stop use and distribution and quarantine the product immediately. Wholesalers and distributors should also recall the distributed product.
Questions regarding this recall can call Ascend Laboratories at 877.272.7901 (24 hours, 7 days a week).
Problems with this product should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article originally appeared on Medscape.com.
The nationwide recall, to the consumer level, is because of the detection of the nitrosamine impurity, N-nitroso-dabigatran, which may increase the risk of cancer with prolonged exposure to levels higher than acceptable.
To date, Ascend Laboratories has not received any reports of adverse events related to this recall.
The recalled product was distributed nationwide to wholesalers, distributors, and retailers in the United States from June 2022 to October 2022.
Complete details of the recalled product, including national drug code, lot numbers, expiration dates, and configuration/counts, are provided in a company announcement that was posted on the Food and Drug Administration website.
The company is advising patients who have any dabigatran that has been recalled to continue taking their medication and to contact their physician for advice regarding an alternative treatment.
Wholesalers/distributors and pharmacies with an existing inventory of the affected lots should stop use and distribution and quarantine the product immediately. Wholesalers and distributors should also recall the distributed product.
Questions regarding this recall can call Ascend Laboratories at 877.272.7901 (24 hours, 7 days a week).
Problems with this product should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article originally appeared on Medscape.com.
Hydroxyurea underused in youth with sickle cell anemia
Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.
SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.
In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
Low uptake even after guideline revision
Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.
After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.
Findings were published online in JAMA Network Open.
‘A national issue’
Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”
Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.
“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.
He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”
He said often providers aren’t giving a clear and consistent message to families.
“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
Bad rap from past indications
Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.
Now it’s used in a completely different way with SCA, but the fear of the association lingers.
“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”
The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”
The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
Medicaid support critical
Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.
“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.
The authors point to interventions in clinical trials that have had some success in hydroxyurea use.
Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.
The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.
Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.
“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.
He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.
“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.
Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.
The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.
SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.
In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
Low uptake even after guideline revision
Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.
After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.
Findings were published online in JAMA Network Open.
‘A national issue’
Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”
Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.
“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.
He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”
He said often providers aren’t giving a clear and consistent message to families.
“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
Bad rap from past indications
Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.
Now it’s used in a completely different way with SCA, but the fear of the association lingers.
“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”
The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”
The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
Medicaid support critical
Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.
“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.
The authors point to interventions in clinical trials that have had some success in hydroxyurea use.
Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.
The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.
Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.
“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.
He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.
“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.
Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.
The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.
SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.
In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
Low uptake even after guideline revision
Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.
After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.
Findings were published online in JAMA Network Open.
‘A national issue’
Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”
Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.
“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.
He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”
He said often providers aren’t giving a clear and consistent message to families.
“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
Bad rap from past indications
Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.
Now it’s used in a completely different way with SCA, but the fear of the association lingers.
“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”
The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”
The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
Medicaid support critical
Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.
“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.
The authors point to interventions in clinical trials that have had some success in hydroxyurea use.
Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.
The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.
Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.
“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.
He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.
“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.
Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.
The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
FROM JAMA NETWORK OPEN
Factors linked with increased VTE risk in COVID outpatients
Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.
The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
Nearly 400,000 patients studied
Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.
VTE risk was low overall for ambulatory COVID patients.
“It is a reassuring study,” Dr. Fang said in an interview.
The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
Factors linked with high VTE risk
They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.
The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
Are routine anticoagulants justified?
Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.
“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
Mild COVID VTE risk similar to general population
The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.
Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.
Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
Physicians should inform patients of their higher risk
“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.
”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.
Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
Unanswered questions
Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.
However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.
One is the change in the COVID variant landscape.
“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.
The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.
Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”
Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.
Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.
The research was funded through Patient-Centered Outcomes Research Institute.
Dr. Hopkins reports no relevant financial relationships.
Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.
The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
Nearly 400,000 patients studied
Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.
VTE risk was low overall for ambulatory COVID patients.
“It is a reassuring study,” Dr. Fang said in an interview.
The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
Factors linked with high VTE risk
They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.
The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
Are routine anticoagulants justified?
Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.
“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
Mild COVID VTE risk similar to general population
The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.
Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.
Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
Physicians should inform patients of their higher risk
“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.
”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.
Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
Unanswered questions
Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.
However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.
One is the change in the COVID variant landscape.
“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.
The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.
Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”
Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.
Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.
The research was funded through Patient-Centered Outcomes Research Institute.
Dr. Hopkins reports no relevant financial relationships.
Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.
The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
Nearly 400,000 patients studied
Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.
VTE risk was low overall for ambulatory COVID patients.
“It is a reassuring study,” Dr. Fang said in an interview.
The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
Factors linked with high VTE risk
They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.
The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
Are routine anticoagulants justified?
Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.
“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
Mild COVID VTE risk similar to general population
The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.
Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.
Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
Physicians should inform patients of their higher risk
“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.
”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.
Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
Unanswered questions
Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.
However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.
One is the change in the COVID variant landscape.
“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.
The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.
Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”
Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.
Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.
The research was funded through Patient-Centered Outcomes Research Institute.
Dr. Hopkins reports no relevant financial relationships.
FROM JAMA NETWORK OPEN
Neonatal bilirubin meters need better accuracy
Despite their convenience and low cost, , a systematic review and meta-analysis reports in JAMA Pediatrics. Lauren E.H. Westenberg, MD, of the division of neonatology at Erasmus MC Sophia Children’s Hospital in Rotterdam, the Netherlands, and colleagues reported that POC meters tended to underestimate neonatal bilirubin levels, compared with conventional laboratory-based quantification.
Furthermore, pooled estimates from 10 studies found these devices to be too imprecise overall, with substantial outer-confidence bounds. On the plus side, Dr. Westenberg’s group said POC bilirubin testing was as much as 60 times faster than lab measurement, and used 40-60 times less blood. “Conventional laboratory-based bilirubin quantification usually requires up to 500 mcL, but sometimes even 1,500 mcL, while POC tests require up to 50 mcL, which means less stress for the baby,” Dr. Westenberg said in an interview. “Especially when infants are cared for at home, it usually takes a few hours between deciding to quantify bilirubin and obtaining the test result. Meanwhile, bilirubin levels may rise unnoticed.”
On the positive side, POC devices are useful where laboratories in low-resource areas may be remote, poorly equipped, and not always able to provide an accurate bilirubin level. “As a result, the diagnosis of jaundice relies mainly on visual inspection, which is known to be unreliable,” she said. POC devices, however, need near-perfect conditions for optimal use, and results can be affected by humidity, preanalytic conditions such as test strip saturation, and hematocrit.
Yet results from these devices have recently proven to have acceptable accuracy, resulting, for example, in the same clinical decisions as the reference standard in 90.7% of times according to a 2022 study in a hospital in Malawi.
Nevertheless, the authors concluded that the devices’ imprecision limits their widespread use in neonatal jaundice management, especially when accurate lab-based bilirubin quantification is available. Results from these POC tests should be interpreted with caution, Dr. Westenberg said. In terms of clinical decision-making, POC devices entail a risk of missing neonates with jaundice who need phototherapy or, in the case of overestimation, of starting phototherapy too early.
The study
The meta-analysis included nine cross-sectional and one prospective cohort study representing 3,122 neonates in Europe, Africa, and East and Southeast Asia. Two tests with 30-minute turnaround times were evaluated in neonates 0-28 days old. The Bilistick device was evaluated in eight studies and the BiliSpec (now called BiliDX) in just two studies. Three of the studies had a high risk of bias.
A total of 3,122 measurements paired with lab quantification showed a pooled mean difference in total bilirubin levels for the POC devices of –14 micromol/L, with pooled 95% confidence bounds (CBs) of –106 to 78 micromol/L. For the Bilistick, the pooled mean difference was –17 micromol/L (95% CBs, –114 to 80 micromol/L). Of the two devices, the Bilistick was more likely to have a failed quantification against the reference standard.
Context for POC devices
Commenting on the meta-analysis but not involved in it, Rebecca Richards-Kortum, PhD, a professor of biomedical engineering at Rice University in Houston, noted that both devices were developed specifically to address needs in low-resource settings. “I don’t think the meta-analysis acknowledges this rationale sufficiently,” she said. “It feels like this paper is comparing apples to oranges and then criticizing the apples for not being oranges,” said Dr. Richards-Kortum, who helped develop the BiliSpec test.
Similarly, Anne S. Lee, MD, MPH, an associate professor of pediatrics at Brigham and Women’s Hospital in Boston, and not a participant in the meta-analysis, also stressed that POC devices are designed for scenarios where lab-based results are not widely available. “In a broad sense, the devices fill an important gap, both in low- and middle-income countries, as well as in the U.S. when laboratory capacity is not readily available,” said Dr. Lee. She was involved the development of the Bili-ruler icterometer, which proved to be diagnostically accurate in Bangladeshi newborns.
“Access to this technology is a critical way to address health disparities even in the U.S.,” Dr. Lee continued. “We have heard of the need for this technology from the Indian health services and Alaskan health services, where decisions are made to airlift a child based on a visual inspection alone.”
More broadly, however, cautioned Dr. Westenberg, the total allowable error and the permissible limits of uncertainty in neonatal bilirubin quantification need to be defined – irrespective of the method used. “Accurate measurement of bilirubin is difficult as has been demonstrated in so-called external quality assessment (EQA) programs that exist for laboratory-based bilirubin methods,” she said. “EQA programs for POC bilirubin devices that include a reference method as a gold standard may contribute to adaptation of the device and improving POC test imprecision.”
This work was supported by the Netherlands Organization for Health Research and Development. The authors had no conflicts of interest to disclose. Dr. Richards-Kortum and Dr. Lee have both been involved in the development of POC devices for assessing neonatal bilirubin levels.
Despite their convenience and low cost, , a systematic review and meta-analysis reports in JAMA Pediatrics. Lauren E.H. Westenberg, MD, of the division of neonatology at Erasmus MC Sophia Children’s Hospital in Rotterdam, the Netherlands, and colleagues reported that POC meters tended to underestimate neonatal bilirubin levels, compared with conventional laboratory-based quantification.
Furthermore, pooled estimates from 10 studies found these devices to be too imprecise overall, with substantial outer-confidence bounds. On the plus side, Dr. Westenberg’s group said POC bilirubin testing was as much as 60 times faster than lab measurement, and used 40-60 times less blood. “Conventional laboratory-based bilirubin quantification usually requires up to 500 mcL, but sometimes even 1,500 mcL, while POC tests require up to 50 mcL, which means less stress for the baby,” Dr. Westenberg said in an interview. “Especially when infants are cared for at home, it usually takes a few hours between deciding to quantify bilirubin and obtaining the test result. Meanwhile, bilirubin levels may rise unnoticed.”
On the positive side, POC devices are useful where laboratories in low-resource areas may be remote, poorly equipped, and not always able to provide an accurate bilirubin level. “As a result, the diagnosis of jaundice relies mainly on visual inspection, which is known to be unreliable,” she said. POC devices, however, need near-perfect conditions for optimal use, and results can be affected by humidity, preanalytic conditions such as test strip saturation, and hematocrit.
Yet results from these devices have recently proven to have acceptable accuracy, resulting, for example, in the same clinical decisions as the reference standard in 90.7% of times according to a 2022 study in a hospital in Malawi.
Nevertheless, the authors concluded that the devices’ imprecision limits their widespread use in neonatal jaundice management, especially when accurate lab-based bilirubin quantification is available. Results from these POC tests should be interpreted with caution, Dr. Westenberg said. In terms of clinical decision-making, POC devices entail a risk of missing neonates with jaundice who need phototherapy or, in the case of overestimation, of starting phototherapy too early.
The study
The meta-analysis included nine cross-sectional and one prospective cohort study representing 3,122 neonates in Europe, Africa, and East and Southeast Asia. Two tests with 30-minute turnaround times were evaluated in neonates 0-28 days old. The Bilistick device was evaluated in eight studies and the BiliSpec (now called BiliDX) in just two studies. Three of the studies had a high risk of bias.
A total of 3,122 measurements paired with lab quantification showed a pooled mean difference in total bilirubin levels for the POC devices of –14 micromol/L, with pooled 95% confidence bounds (CBs) of –106 to 78 micromol/L. For the Bilistick, the pooled mean difference was –17 micromol/L (95% CBs, –114 to 80 micromol/L). Of the two devices, the Bilistick was more likely to have a failed quantification against the reference standard.
Context for POC devices
Commenting on the meta-analysis but not involved in it, Rebecca Richards-Kortum, PhD, a professor of biomedical engineering at Rice University in Houston, noted that both devices were developed specifically to address needs in low-resource settings. “I don’t think the meta-analysis acknowledges this rationale sufficiently,” she said. “It feels like this paper is comparing apples to oranges and then criticizing the apples for not being oranges,” said Dr. Richards-Kortum, who helped develop the BiliSpec test.
Similarly, Anne S. Lee, MD, MPH, an associate professor of pediatrics at Brigham and Women’s Hospital in Boston, and not a participant in the meta-analysis, also stressed that POC devices are designed for scenarios where lab-based results are not widely available. “In a broad sense, the devices fill an important gap, both in low- and middle-income countries, as well as in the U.S. when laboratory capacity is not readily available,” said Dr. Lee. She was involved the development of the Bili-ruler icterometer, which proved to be diagnostically accurate in Bangladeshi newborns.
“Access to this technology is a critical way to address health disparities even in the U.S.,” Dr. Lee continued. “We have heard of the need for this technology from the Indian health services and Alaskan health services, where decisions are made to airlift a child based on a visual inspection alone.”
More broadly, however, cautioned Dr. Westenberg, the total allowable error and the permissible limits of uncertainty in neonatal bilirubin quantification need to be defined – irrespective of the method used. “Accurate measurement of bilirubin is difficult as has been demonstrated in so-called external quality assessment (EQA) programs that exist for laboratory-based bilirubin methods,” she said. “EQA programs for POC bilirubin devices that include a reference method as a gold standard may contribute to adaptation of the device and improving POC test imprecision.”
This work was supported by the Netherlands Organization for Health Research and Development. The authors had no conflicts of interest to disclose. Dr. Richards-Kortum and Dr. Lee have both been involved in the development of POC devices for assessing neonatal bilirubin levels.
Despite their convenience and low cost, , a systematic review and meta-analysis reports in JAMA Pediatrics. Lauren E.H. Westenberg, MD, of the division of neonatology at Erasmus MC Sophia Children’s Hospital in Rotterdam, the Netherlands, and colleagues reported that POC meters tended to underestimate neonatal bilirubin levels, compared with conventional laboratory-based quantification.
Furthermore, pooled estimates from 10 studies found these devices to be too imprecise overall, with substantial outer-confidence bounds. On the plus side, Dr. Westenberg’s group said POC bilirubin testing was as much as 60 times faster than lab measurement, and used 40-60 times less blood. “Conventional laboratory-based bilirubin quantification usually requires up to 500 mcL, but sometimes even 1,500 mcL, while POC tests require up to 50 mcL, which means less stress for the baby,” Dr. Westenberg said in an interview. “Especially when infants are cared for at home, it usually takes a few hours between deciding to quantify bilirubin and obtaining the test result. Meanwhile, bilirubin levels may rise unnoticed.”
On the positive side, POC devices are useful where laboratories in low-resource areas may be remote, poorly equipped, and not always able to provide an accurate bilirubin level. “As a result, the diagnosis of jaundice relies mainly on visual inspection, which is known to be unreliable,” she said. POC devices, however, need near-perfect conditions for optimal use, and results can be affected by humidity, preanalytic conditions such as test strip saturation, and hematocrit.
Yet results from these devices have recently proven to have acceptable accuracy, resulting, for example, in the same clinical decisions as the reference standard in 90.7% of times according to a 2022 study in a hospital in Malawi.
Nevertheless, the authors concluded that the devices’ imprecision limits their widespread use in neonatal jaundice management, especially when accurate lab-based bilirubin quantification is available. Results from these POC tests should be interpreted with caution, Dr. Westenberg said. In terms of clinical decision-making, POC devices entail a risk of missing neonates with jaundice who need phototherapy or, in the case of overestimation, of starting phototherapy too early.
The study
The meta-analysis included nine cross-sectional and one prospective cohort study representing 3,122 neonates in Europe, Africa, and East and Southeast Asia. Two tests with 30-minute turnaround times were evaluated in neonates 0-28 days old. The Bilistick device was evaluated in eight studies and the BiliSpec (now called BiliDX) in just two studies. Three of the studies had a high risk of bias.
A total of 3,122 measurements paired with lab quantification showed a pooled mean difference in total bilirubin levels for the POC devices of –14 micromol/L, with pooled 95% confidence bounds (CBs) of –106 to 78 micromol/L. For the Bilistick, the pooled mean difference was –17 micromol/L (95% CBs, –114 to 80 micromol/L). Of the two devices, the Bilistick was more likely to have a failed quantification against the reference standard.
Context for POC devices
Commenting on the meta-analysis but not involved in it, Rebecca Richards-Kortum, PhD, a professor of biomedical engineering at Rice University in Houston, noted that both devices were developed specifically to address needs in low-resource settings. “I don’t think the meta-analysis acknowledges this rationale sufficiently,” she said. “It feels like this paper is comparing apples to oranges and then criticizing the apples for not being oranges,” said Dr. Richards-Kortum, who helped develop the BiliSpec test.
Similarly, Anne S. Lee, MD, MPH, an associate professor of pediatrics at Brigham and Women’s Hospital in Boston, and not a participant in the meta-analysis, also stressed that POC devices are designed for scenarios where lab-based results are not widely available. “In a broad sense, the devices fill an important gap, both in low- and middle-income countries, as well as in the U.S. when laboratory capacity is not readily available,” said Dr. Lee. She was involved the development of the Bili-ruler icterometer, which proved to be diagnostically accurate in Bangladeshi newborns.
“Access to this technology is a critical way to address health disparities even in the U.S.,” Dr. Lee continued. “We have heard of the need for this technology from the Indian health services and Alaskan health services, where decisions are made to airlift a child based on a visual inspection alone.”
More broadly, however, cautioned Dr. Westenberg, the total allowable error and the permissible limits of uncertainty in neonatal bilirubin quantification need to be defined – irrespective of the method used. “Accurate measurement of bilirubin is difficult as has been demonstrated in so-called external quality assessment (EQA) programs that exist for laboratory-based bilirubin methods,” she said. “EQA programs for POC bilirubin devices that include a reference method as a gold standard may contribute to adaptation of the device and improving POC test imprecision.”
This work was supported by the Netherlands Organization for Health Research and Development. The authors had no conflicts of interest to disclose. Dr. Richards-Kortum and Dr. Lee have both been involved in the development of POC devices for assessing neonatal bilirubin levels.
JAMA PEDIATRICS
Surviving CLL: Higher risk of other cancer DXs
The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.
“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.
Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”
Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.
It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”
With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”
Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).
“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”
Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”
She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”
Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”
Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”
Study funding was not reported. The authors and Dr. Bond report no disclosures.
The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.
“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.
Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”
Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.
It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”
With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”
Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).
“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”
Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”
She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”
Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”
Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”
Study funding was not reported. The authors and Dr. Bond report no disclosures.
The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.
“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.
Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”
Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.
It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”
With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”
Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).
“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”
Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”
She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”
Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”
Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”
Study funding was not reported. The authors and Dr. Bond report no disclosures.
FROM BLOOD CANCER JOURNAL
Doctors are disappearing from emergency departments as hospitals look to cut costs
She didn’t know much about miscarriage, but this seemed like one.
In the emergency department, she was examined then sent home, she said. She went back when her cramping became excruciating. Then home again. It ultimately took three trips to the ED on 3 consecutive days, generating three separate bills, before she saw a doctor who looked at her blood work and confirmed her fears.
“At the time I wasn’t thinking, ‘Oh, I need to see a doctor,’ ” Ms. Valle recalled. “But when you think about it, it’s like, ‘Well, dang – why didn’t I see a doctor?’ ” It’s unclear whether the repeat visits were due to delays in seeing a physician, but the experience worried her. And she’s still paying the bills.
The hospital declined to discuss Ms. Valle’s care, citing patient privacy. But 17 months before her 3-day ordeal, Tennova had outsourced its emergency departments to American Physician Partners, a medical staffing company owned by private equity investors. APP employs fewer doctors in its EDs as one of its cost-saving initiatives to increase earnings, according to a confidential company document obtained by KHN and NPR.
This staffing strategy has permeated hospitals, and particularly emergency departments, that seek to reduce their top expense: physician labor. While diagnosing and treating patients was once their domain, doctors are increasingly being replaced by nurse practitioners and physician assistants, collectively known as “midlevel practitioners,” who can perform many of the same duties and generate much of the same revenue for less than half of the pay.
“APP has numerous cost saving initiatives underway as part of the Company’s continual focus on cost optimization,” the document says, including a “shift of staffing” between doctors and midlevel practitioners.
In a statement to KHN, American Physician Partners said this strategy is a way to ensure all EDs remain fully staffed, calling it a “blended model” that allows doctors, nurse practitioners, and physician assistants “to provide care to their fullest potential.”
Critics of this strategy say the quest to save money results in treatment meted out by someone with far less training than a physician, leaving patients vulnerable to misdiagnoses, higher medical bills, and inadequate care. And these fears are bolstered by evidence that suggests dropping doctors from EDs may not be good for patients.
A working paper, published in October by the National Bureau of Economic Research, analyzed roughly 1.1 million visits to 44 EDs throughout the Veterans Health Administration, where nurse practitioners can treat patients without oversight from doctors.
Researchers found that treatment by a nurse practitioner resulted on average in a 7% increase in cost of care and an 11% increase in length of stay, extending patients’ time in the ED by minutes for minor visits and hours for longer ones. These gaps widened among patients with more severe diagnoses, the study said, but could be somewhat mitigated by nurse practitioners with more experience.
The study also found that ED patients treated by a nurse practitioner were 20% more likely to be readmitted to the hospital for a preventable reason within 30 days, although the overall risk of readmission remained very small.
Yiqun Chen, PhD, who is an assistant professor of economics at the University of Illinois at Chicago and coauthored the study, said these findings are not an indictment of nurse practitioners in the ED. Instead, she said, she hopes the study will guide how to best deploy nurse practitioners: in treatment of simpler patients or circumstances when no doctor is available.
“It’s not just a simple question of if we can substitute physicians with nurse practitioners or not,” Dr. Chen said. “It depends on how we use them. If we just use them as independent providers, especially ... for relatively complicated patients, it doesn’t seem to be a very good use.”
Dr. Chen’s research echoes smaller studies, like one from The Harvey L. Neiman Health Policy Institute that found nonphysician practitioners in EDs were associated with a 5.3% increase in imaging, which could unnecessarily increase bills for patients. Separately, a study at the Hattiesburg Clinic in Mississippi found that midlevel practitioners in primary care – not in the emergency department – increased the out-of-pocket costs to patients while also leading to worse performance on 9 of 10 quality-of-care metrics, including cancer screenings and vaccination rates.
But definitive evidence remains elusive that replacing ER doctors with nonphysicians has a negative impact on patients, said Cameron Gettel, MD, an assistant professor of emergency medicine at Yale University, New Haven, Conn. Private equity investment and the use of midlevel practitioners rose in lockstep in the ED, Dr. Gettel said, and in the absence of game-changing research, the pattern will likely continue.
“Worse patient outcomes haven’t really been shown across the board,” he said. “And I think until that is shown, then they will continue to play an increasing role.”
For private equity, dropping ED docs is a “simple equation”
Private equity companies pool money from wealthy investors to buy their way into various industries, often slashing spending and seeking to flip businesses in 3 to 7 years. While this business model is a proven moneymaker on Wall Street, it raises concerns in health care, where critics worry the pressure to turn big profits will influence life-or-death decisions that were once left solely to medical professionals.
Nearly $1 trillion in private equity funds have gone into almost 8,000 health care transactions over the past decade, according to industry tracker PitchBook, including buying into medical staffing companies that many hospitals hire to manage their emergency departments.
Two firms dominate the ED staffing industry: TeamHealth, bought by private equity firm Blackstone in 2016, and Envision Healthcare, bought by KKR in 2018. Trying to undercut these staffing giants is American Physician Partners, a rapidly expanding company that runs EDs in at least 17 states and is 50% owned by private equity firm BBH Capital Partners.
These staffing companies have been among the most aggressive in replacing doctors to cut costs, said Robert McNamara, MD, a founder of the American Academy of Emergency Medicine and chair of emergency medicine at Temple University, Philadelphia.
“It’s a relatively simple equation,” Dr. McNamara said. “Their No. 1 expense is the board-certified emergency physician. So they are going to want to keep that expense as low as possible.”
Not everyone sees the trend of private equity in ED staffing in a negative light. Jennifer Orozco, president of the American Academy of Physician Associates, which represents physician assistants, said even if the change – to use more nonphysician providers – is driven by the staffing firms’ desire to make more money, patients are still well served by a team approach that includes nurse practitioners and physician assistants.
“Though I see that shift, it’s not about profits at the end of the day,” Ms. Orozco said. “It’s about the patient.”
The “shift” is nearly invisible to patients because hospitals rarely promote branding from their ED staffing firms and there is little public documentation of private equity investments.
Arthur Smolensky, MD, a Tennessee emergency medicine specialist attempting to measure private equity’s intrusion into EDs, said his review of hospital job postings and employment contracts in 14 major metropolitan areas found that 43% of ED patients were seen in EDs staffed by companies with nonphysician owners, nearly all of whom are private equity investors.
Dr. Smolensky hopes to publish his full study, expanding to 55 metro areas, later this year. But this research will merely quantify what many doctors already know: The ED has changed. Demoralized by an increased focus on profit, and wary of a looming surplus of emergency medicine residents because there are fewer jobs to fill, many experienced doctors are leaving the ED on their own, he said.
“Most of us didn’t go into medicine to supervise an army of people that are not as well trained as we are,” Dr. Smolensky said. “We want to take care of patients.”
“I guess we’re the first guinea pigs for our ER”
Joshua Allen, a nurse practitioner at a small Kentucky hospital, snaked a rubber hose through a rack of pork ribs to practice inserting a chest tube to fix a collapsed lung.
It was 2020, and American Physician Partners was restructuring the ED where Mr. Allen worked, reducing shifts from two doctors to one. Once Mr. Allen had placed 10 tubes under a doctor’s supervision, he would be allowed to do it on his own.
“I guess we’re the first guinea pigs for our ER,” he said. “If we do have a major trauma and multiple victims come in, there’s only one doctor there. ... We need to be prepared.”
Mr. Allen is one of many midlevel practitioners finding work in emergency departments. Nurse practitioners and physician assistants are among the fastest-growing occupations in the nation, according to the U.S. Bureau of Labor Statistics.
Generally, they have master’s degrees and receive several years of specialized schooling but have significantly less training than doctors. Many are permitted to diagnose patients and prescribe medication with little or no supervision from a doctor, although limitations vary by state.
The Neiman Institute found that the share of ED visits in which a midlevel practitioner was the main clinician increased by more than 172% between 2005 and 2020. Another study, in the Journal of Emergency Medicine, reported that if trends continue there may be equal numbers of midlevel practitioners and doctors in EDs by 2030.
There is little mystery as to why. Federal data shows emergency medicine doctors are paid about $310,000 a year on average, while nurse practitioners and physician assistants earn less than $120,000. Generally, hospitals can bill for care by a midlevel practitioner at 85% the rate of a doctor while paying them less than half as much.
Private equity can make millions in the gap.
For example, Envision once encouraged EDs to employ “the least expensive resource” and treat up to 35% of patients with midlevel practitioners, according to a 2017 PowerPoint presentation. The presentation drew scorn on social media and disappeared from Envision’s website.
Envision declined a request for a phone interview. In a written statement to KHN, spokesperson Aliese Polk said the company does not direct its physician leaders on how to care for patients and called the presentation a “concept guide” that does not represent current views.
American Physician Partners touted roughly the same staffing strategy in 2021 in response to the No Surprises Act, which threatened the company’s profits by outlawing surprise medical bills. In its confidential pitch to lenders, the company estimated it could cut almost $6 million by shifting more staffing from physicians to midlevel practitioners.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
She didn’t know much about miscarriage, but this seemed like one.
In the emergency department, she was examined then sent home, she said. She went back when her cramping became excruciating. Then home again. It ultimately took three trips to the ED on 3 consecutive days, generating three separate bills, before she saw a doctor who looked at her blood work and confirmed her fears.
“At the time I wasn’t thinking, ‘Oh, I need to see a doctor,’ ” Ms. Valle recalled. “But when you think about it, it’s like, ‘Well, dang – why didn’t I see a doctor?’ ” It’s unclear whether the repeat visits were due to delays in seeing a physician, but the experience worried her. And she’s still paying the bills.
The hospital declined to discuss Ms. Valle’s care, citing patient privacy. But 17 months before her 3-day ordeal, Tennova had outsourced its emergency departments to American Physician Partners, a medical staffing company owned by private equity investors. APP employs fewer doctors in its EDs as one of its cost-saving initiatives to increase earnings, according to a confidential company document obtained by KHN and NPR.
This staffing strategy has permeated hospitals, and particularly emergency departments, that seek to reduce their top expense: physician labor. While diagnosing and treating patients was once their domain, doctors are increasingly being replaced by nurse practitioners and physician assistants, collectively known as “midlevel practitioners,” who can perform many of the same duties and generate much of the same revenue for less than half of the pay.
“APP has numerous cost saving initiatives underway as part of the Company’s continual focus on cost optimization,” the document says, including a “shift of staffing” between doctors and midlevel practitioners.
In a statement to KHN, American Physician Partners said this strategy is a way to ensure all EDs remain fully staffed, calling it a “blended model” that allows doctors, nurse practitioners, and physician assistants “to provide care to their fullest potential.”
Critics of this strategy say the quest to save money results in treatment meted out by someone with far less training than a physician, leaving patients vulnerable to misdiagnoses, higher medical bills, and inadequate care. And these fears are bolstered by evidence that suggests dropping doctors from EDs may not be good for patients.
A working paper, published in October by the National Bureau of Economic Research, analyzed roughly 1.1 million visits to 44 EDs throughout the Veterans Health Administration, where nurse practitioners can treat patients without oversight from doctors.
Researchers found that treatment by a nurse practitioner resulted on average in a 7% increase in cost of care and an 11% increase in length of stay, extending patients’ time in the ED by minutes for minor visits and hours for longer ones. These gaps widened among patients with more severe diagnoses, the study said, but could be somewhat mitigated by nurse practitioners with more experience.
The study also found that ED patients treated by a nurse practitioner were 20% more likely to be readmitted to the hospital for a preventable reason within 30 days, although the overall risk of readmission remained very small.
Yiqun Chen, PhD, who is an assistant professor of economics at the University of Illinois at Chicago and coauthored the study, said these findings are not an indictment of nurse practitioners in the ED. Instead, she said, she hopes the study will guide how to best deploy nurse practitioners: in treatment of simpler patients or circumstances when no doctor is available.
“It’s not just a simple question of if we can substitute physicians with nurse practitioners or not,” Dr. Chen said. “It depends on how we use them. If we just use them as independent providers, especially ... for relatively complicated patients, it doesn’t seem to be a very good use.”
Dr. Chen’s research echoes smaller studies, like one from The Harvey L. Neiman Health Policy Institute that found nonphysician practitioners in EDs were associated with a 5.3% increase in imaging, which could unnecessarily increase bills for patients. Separately, a study at the Hattiesburg Clinic in Mississippi found that midlevel practitioners in primary care – not in the emergency department – increased the out-of-pocket costs to patients while also leading to worse performance on 9 of 10 quality-of-care metrics, including cancer screenings and vaccination rates.
But definitive evidence remains elusive that replacing ER doctors with nonphysicians has a negative impact on patients, said Cameron Gettel, MD, an assistant professor of emergency medicine at Yale University, New Haven, Conn. Private equity investment and the use of midlevel practitioners rose in lockstep in the ED, Dr. Gettel said, and in the absence of game-changing research, the pattern will likely continue.
“Worse patient outcomes haven’t really been shown across the board,” he said. “And I think until that is shown, then they will continue to play an increasing role.”
For private equity, dropping ED docs is a “simple equation”
Private equity companies pool money from wealthy investors to buy their way into various industries, often slashing spending and seeking to flip businesses in 3 to 7 years. While this business model is a proven moneymaker on Wall Street, it raises concerns in health care, where critics worry the pressure to turn big profits will influence life-or-death decisions that were once left solely to medical professionals.
Nearly $1 trillion in private equity funds have gone into almost 8,000 health care transactions over the past decade, according to industry tracker PitchBook, including buying into medical staffing companies that many hospitals hire to manage their emergency departments.
Two firms dominate the ED staffing industry: TeamHealth, bought by private equity firm Blackstone in 2016, and Envision Healthcare, bought by KKR in 2018. Trying to undercut these staffing giants is American Physician Partners, a rapidly expanding company that runs EDs in at least 17 states and is 50% owned by private equity firm BBH Capital Partners.
These staffing companies have been among the most aggressive in replacing doctors to cut costs, said Robert McNamara, MD, a founder of the American Academy of Emergency Medicine and chair of emergency medicine at Temple University, Philadelphia.
“It’s a relatively simple equation,” Dr. McNamara said. “Their No. 1 expense is the board-certified emergency physician. So they are going to want to keep that expense as low as possible.”
Not everyone sees the trend of private equity in ED staffing in a negative light. Jennifer Orozco, president of the American Academy of Physician Associates, which represents physician assistants, said even if the change – to use more nonphysician providers – is driven by the staffing firms’ desire to make more money, patients are still well served by a team approach that includes nurse practitioners and physician assistants.
“Though I see that shift, it’s not about profits at the end of the day,” Ms. Orozco said. “It’s about the patient.”
The “shift” is nearly invisible to patients because hospitals rarely promote branding from their ED staffing firms and there is little public documentation of private equity investments.
Arthur Smolensky, MD, a Tennessee emergency medicine specialist attempting to measure private equity’s intrusion into EDs, said his review of hospital job postings and employment contracts in 14 major metropolitan areas found that 43% of ED patients were seen in EDs staffed by companies with nonphysician owners, nearly all of whom are private equity investors.
Dr. Smolensky hopes to publish his full study, expanding to 55 metro areas, later this year. But this research will merely quantify what many doctors already know: The ED has changed. Demoralized by an increased focus on profit, and wary of a looming surplus of emergency medicine residents because there are fewer jobs to fill, many experienced doctors are leaving the ED on their own, he said.
“Most of us didn’t go into medicine to supervise an army of people that are not as well trained as we are,” Dr. Smolensky said. “We want to take care of patients.”
“I guess we’re the first guinea pigs for our ER”
Joshua Allen, a nurse practitioner at a small Kentucky hospital, snaked a rubber hose through a rack of pork ribs to practice inserting a chest tube to fix a collapsed lung.
It was 2020, and American Physician Partners was restructuring the ED where Mr. Allen worked, reducing shifts from two doctors to one. Once Mr. Allen had placed 10 tubes under a doctor’s supervision, he would be allowed to do it on his own.
“I guess we’re the first guinea pigs for our ER,” he said. “If we do have a major trauma and multiple victims come in, there’s only one doctor there. ... We need to be prepared.”
Mr. Allen is one of many midlevel practitioners finding work in emergency departments. Nurse practitioners and physician assistants are among the fastest-growing occupations in the nation, according to the U.S. Bureau of Labor Statistics.
Generally, they have master’s degrees and receive several years of specialized schooling but have significantly less training than doctors. Many are permitted to diagnose patients and prescribe medication with little or no supervision from a doctor, although limitations vary by state.
The Neiman Institute found that the share of ED visits in which a midlevel practitioner was the main clinician increased by more than 172% between 2005 and 2020. Another study, in the Journal of Emergency Medicine, reported that if trends continue there may be equal numbers of midlevel practitioners and doctors in EDs by 2030.
There is little mystery as to why. Federal data shows emergency medicine doctors are paid about $310,000 a year on average, while nurse practitioners and physician assistants earn less than $120,000. Generally, hospitals can bill for care by a midlevel practitioner at 85% the rate of a doctor while paying them less than half as much.
Private equity can make millions in the gap.
For example, Envision once encouraged EDs to employ “the least expensive resource” and treat up to 35% of patients with midlevel practitioners, according to a 2017 PowerPoint presentation. The presentation drew scorn on social media and disappeared from Envision’s website.
Envision declined a request for a phone interview. In a written statement to KHN, spokesperson Aliese Polk said the company does not direct its physician leaders on how to care for patients and called the presentation a “concept guide” that does not represent current views.
American Physician Partners touted roughly the same staffing strategy in 2021 in response to the No Surprises Act, which threatened the company’s profits by outlawing surprise medical bills. In its confidential pitch to lenders, the company estimated it could cut almost $6 million by shifting more staffing from physicians to midlevel practitioners.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
She didn’t know much about miscarriage, but this seemed like one.
In the emergency department, she was examined then sent home, she said. She went back when her cramping became excruciating. Then home again. It ultimately took three trips to the ED on 3 consecutive days, generating three separate bills, before she saw a doctor who looked at her blood work and confirmed her fears.
“At the time I wasn’t thinking, ‘Oh, I need to see a doctor,’ ” Ms. Valle recalled. “But when you think about it, it’s like, ‘Well, dang – why didn’t I see a doctor?’ ” It’s unclear whether the repeat visits were due to delays in seeing a physician, but the experience worried her. And she’s still paying the bills.
The hospital declined to discuss Ms. Valle’s care, citing patient privacy. But 17 months before her 3-day ordeal, Tennova had outsourced its emergency departments to American Physician Partners, a medical staffing company owned by private equity investors. APP employs fewer doctors in its EDs as one of its cost-saving initiatives to increase earnings, according to a confidential company document obtained by KHN and NPR.
This staffing strategy has permeated hospitals, and particularly emergency departments, that seek to reduce their top expense: physician labor. While diagnosing and treating patients was once their domain, doctors are increasingly being replaced by nurse practitioners and physician assistants, collectively known as “midlevel practitioners,” who can perform many of the same duties and generate much of the same revenue for less than half of the pay.
“APP has numerous cost saving initiatives underway as part of the Company’s continual focus on cost optimization,” the document says, including a “shift of staffing” between doctors and midlevel practitioners.
In a statement to KHN, American Physician Partners said this strategy is a way to ensure all EDs remain fully staffed, calling it a “blended model” that allows doctors, nurse practitioners, and physician assistants “to provide care to their fullest potential.”
Critics of this strategy say the quest to save money results in treatment meted out by someone with far less training than a physician, leaving patients vulnerable to misdiagnoses, higher medical bills, and inadequate care. And these fears are bolstered by evidence that suggests dropping doctors from EDs may not be good for patients.
A working paper, published in October by the National Bureau of Economic Research, analyzed roughly 1.1 million visits to 44 EDs throughout the Veterans Health Administration, where nurse practitioners can treat patients without oversight from doctors.
Researchers found that treatment by a nurse practitioner resulted on average in a 7% increase in cost of care and an 11% increase in length of stay, extending patients’ time in the ED by minutes for minor visits and hours for longer ones. These gaps widened among patients with more severe diagnoses, the study said, but could be somewhat mitigated by nurse practitioners with more experience.
The study also found that ED patients treated by a nurse practitioner were 20% more likely to be readmitted to the hospital for a preventable reason within 30 days, although the overall risk of readmission remained very small.
Yiqun Chen, PhD, who is an assistant professor of economics at the University of Illinois at Chicago and coauthored the study, said these findings are not an indictment of nurse practitioners in the ED. Instead, she said, she hopes the study will guide how to best deploy nurse practitioners: in treatment of simpler patients or circumstances when no doctor is available.
“It’s not just a simple question of if we can substitute physicians with nurse practitioners or not,” Dr. Chen said. “It depends on how we use them. If we just use them as independent providers, especially ... for relatively complicated patients, it doesn’t seem to be a very good use.”
Dr. Chen’s research echoes smaller studies, like one from The Harvey L. Neiman Health Policy Institute that found nonphysician practitioners in EDs were associated with a 5.3% increase in imaging, which could unnecessarily increase bills for patients. Separately, a study at the Hattiesburg Clinic in Mississippi found that midlevel practitioners in primary care – not in the emergency department – increased the out-of-pocket costs to patients while also leading to worse performance on 9 of 10 quality-of-care metrics, including cancer screenings and vaccination rates.
But definitive evidence remains elusive that replacing ER doctors with nonphysicians has a negative impact on patients, said Cameron Gettel, MD, an assistant professor of emergency medicine at Yale University, New Haven, Conn. Private equity investment and the use of midlevel practitioners rose in lockstep in the ED, Dr. Gettel said, and in the absence of game-changing research, the pattern will likely continue.
“Worse patient outcomes haven’t really been shown across the board,” he said. “And I think until that is shown, then they will continue to play an increasing role.”
For private equity, dropping ED docs is a “simple equation”
Private equity companies pool money from wealthy investors to buy their way into various industries, often slashing spending and seeking to flip businesses in 3 to 7 years. While this business model is a proven moneymaker on Wall Street, it raises concerns in health care, where critics worry the pressure to turn big profits will influence life-or-death decisions that were once left solely to medical professionals.
Nearly $1 trillion in private equity funds have gone into almost 8,000 health care transactions over the past decade, according to industry tracker PitchBook, including buying into medical staffing companies that many hospitals hire to manage their emergency departments.
Two firms dominate the ED staffing industry: TeamHealth, bought by private equity firm Blackstone in 2016, and Envision Healthcare, bought by KKR in 2018. Trying to undercut these staffing giants is American Physician Partners, a rapidly expanding company that runs EDs in at least 17 states and is 50% owned by private equity firm BBH Capital Partners.
These staffing companies have been among the most aggressive in replacing doctors to cut costs, said Robert McNamara, MD, a founder of the American Academy of Emergency Medicine and chair of emergency medicine at Temple University, Philadelphia.
“It’s a relatively simple equation,” Dr. McNamara said. “Their No. 1 expense is the board-certified emergency physician. So they are going to want to keep that expense as low as possible.”
Not everyone sees the trend of private equity in ED staffing in a negative light. Jennifer Orozco, president of the American Academy of Physician Associates, which represents physician assistants, said even if the change – to use more nonphysician providers – is driven by the staffing firms’ desire to make more money, patients are still well served by a team approach that includes nurse practitioners and physician assistants.
“Though I see that shift, it’s not about profits at the end of the day,” Ms. Orozco said. “It’s about the patient.”
The “shift” is nearly invisible to patients because hospitals rarely promote branding from their ED staffing firms and there is little public documentation of private equity investments.
Arthur Smolensky, MD, a Tennessee emergency medicine specialist attempting to measure private equity’s intrusion into EDs, said his review of hospital job postings and employment contracts in 14 major metropolitan areas found that 43% of ED patients were seen in EDs staffed by companies with nonphysician owners, nearly all of whom are private equity investors.
Dr. Smolensky hopes to publish his full study, expanding to 55 metro areas, later this year. But this research will merely quantify what many doctors already know: The ED has changed. Demoralized by an increased focus on profit, and wary of a looming surplus of emergency medicine residents because there are fewer jobs to fill, many experienced doctors are leaving the ED on their own, he said.
“Most of us didn’t go into medicine to supervise an army of people that are not as well trained as we are,” Dr. Smolensky said. “We want to take care of patients.”
“I guess we’re the first guinea pigs for our ER”
Joshua Allen, a nurse practitioner at a small Kentucky hospital, snaked a rubber hose through a rack of pork ribs to practice inserting a chest tube to fix a collapsed lung.
It was 2020, and American Physician Partners was restructuring the ED where Mr. Allen worked, reducing shifts from two doctors to one. Once Mr. Allen had placed 10 tubes under a doctor’s supervision, he would be allowed to do it on his own.
“I guess we’re the first guinea pigs for our ER,” he said. “If we do have a major trauma and multiple victims come in, there’s only one doctor there. ... We need to be prepared.”
Mr. Allen is one of many midlevel practitioners finding work in emergency departments. Nurse practitioners and physician assistants are among the fastest-growing occupations in the nation, according to the U.S. Bureau of Labor Statistics.
Generally, they have master’s degrees and receive several years of specialized schooling but have significantly less training than doctors. Many are permitted to diagnose patients and prescribe medication with little or no supervision from a doctor, although limitations vary by state.
The Neiman Institute found that the share of ED visits in which a midlevel practitioner was the main clinician increased by more than 172% between 2005 and 2020. Another study, in the Journal of Emergency Medicine, reported that if trends continue there may be equal numbers of midlevel practitioners and doctors in EDs by 2030.
There is little mystery as to why. Federal data shows emergency medicine doctors are paid about $310,000 a year on average, while nurse practitioners and physician assistants earn less than $120,000. Generally, hospitals can bill for care by a midlevel practitioner at 85% the rate of a doctor while paying them less than half as much.
Private equity can make millions in the gap.
For example, Envision once encouraged EDs to employ “the least expensive resource” and treat up to 35% of patients with midlevel practitioners, according to a 2017 PowerPoint presentation. The presentation drew scorn on social media and disappeared from Envision’s website.
Envision declined a request for a phone interview. In a written statement to KHN, spokesperson Aliese Polk said the company does not direct its physician leaders on how to care for patients and called the presentation a “concept guide” that does not represent current views.
American Physician Partners touted roughly the same staffing strategy in 2021 in response to the No Surprises Act, which threatened the company’s profits by outlawing surprise medical bills. In its confidential pitch to lenders, the company estimated it could cut almost $6 million by shifting more staffing from physicians to midlevel practitioners.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Despite limits, COVID vaccines protect CLL patients
These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.
“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.
Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.
“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.
Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”
The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.
The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.
By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.
The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.
Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.
The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.
Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.
In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”
Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”
As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”
The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.
These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.
“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.
Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.
“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.
Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”
The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.
The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.
By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.
The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.
Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.
The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.
Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.
In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”
Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”
As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”
The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.
These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.
“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.
Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.
“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.
Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”
The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.
The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.
By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.
The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.
Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.
The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.
Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.
In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”
Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”
As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”
The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.
FROM BLOOD ADVANCES
FDA approves pirtobrutinib for r/r mantle cell lymphoma
Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.
“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.
The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.
Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.
The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.
Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.
Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.
“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.
Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”
Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”
The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.
Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.
“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.
The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.
Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.
The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.
Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.
Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.
“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.
Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”
Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”
The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.
Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.
“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.
The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.
Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.
The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.
Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.
Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.
“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.
Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”
Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”
The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.
Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.