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FDA approves pirtobrutinib for previously treated CLL/SLL
The agent was initially approved in January 2023 for patients with mantle cell lymphoma who had previously received a BTK inhibitor.
Like the mantle cell approval, the CLL/SLL approval was based on findings from the open-label, single-arm, phase 1/2 BRUIN study that included adults with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
The trial included 108 patients with either CLL or SLL. Overall, patients demonstrated an overall response rate of 72%, all of which were partial responses, and median duration of response of 12.2 months.
Before starting pirtobrutinib, 77% of patients with CLL or SLL had discontinued their last BTK inhibitor for refractory or progressive disease.
“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients,” William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, said in an Eli Lilly press release.
Treatment during the study included the recommended dose of 200 mg given orally once daily until disease progression or unacceptable toxicity. Common adverse reactions that occurred in at least 20% of patients included fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. Grade 3 or 4 laboratory abnormalities occurring in more than 10% of patients included decreased neutrophil counts, anemia, and decreased platelet counts.
Serious infections occurred in 32% of patients, including fatal infections in 10% of patients. The prescribing information for pirtobrutinib includes warnings about infections, hemorrhage, cytopenias, cardiac arrhythmias, and secondary primary malignancies.
A version of this article first appeared on Medscape.com.
The agent was initially approved in January 2023 for patients with mantle cell lymphoma who had previously received a BTK inhibitor.
Like the mantle cell approval, the CLL/SLL approval was based on findings from the open-label, single-arm, phase 1/2 BRUIN study that included adults with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
The trial included 108 patients with either CLL or SLL. Overall, patients demonstrated an overall response rate of 72%, all of which were partial responses, and median duration of response of 12.2 months.
Before starting pirtobrutinib, 77% of patients with CLL or SLL had discontinued their last BTK inhibitor for refractory or progressive disease.
“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients,” William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, said in an Eli Lilly press release.
Treatment during the study included the recommended dose of 200 mg given orally once daily until disease progression or unacceptable toxicity. Common adverse reactions that occurred in at least 20% of patients included fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. Grade 3 or 4 laboratory abnormalities occurring in more than 10% of patients included decreased neutrophil counts, anemia, and decreased platelet counts.
Serious infections occurred in 32% of patients, including fatal infections in 10% of patients. The prescribing information for pirtobrutinib includes warnings about infections, hemorrhage, cytopenias, cardiac arrhythmias, and secondary primary malignancies.
A version of this article first appeared on Medscape.com.
The agent was initially approved in January 2023 for patients with mantle cell lymphoma who had previously received a BTK inhibitor.
Like the mantle cell approval, the CLL/SLL approval was based on findings from the open-label, single-arm, phase 1/2 BRUIN study that included adults with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
The trial included 108 patients with either CLL or SLL. Overall, patients demonstrated an overall response rate of 72%, all of which were partial responses, and median duration of response of 12.2 months.
Before starting pirtobrutinib, 77% of patients with CLL or SLL had discontinued their last BTK inhibitor for refractory or progressive disease.
“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients,” William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, said in an Eli Lilly press release.
Treatment during the study included the recommended dose of 200 mg given orally once daily until disease progression or unacceptable toxicity. Common adverse reactions that occurred in at least 20% of patients included fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. Grade 3 or 4 laboratory abnormalities occurring in more than 10% of patients included decreased neutrophil counts, anemia, and decreased platelet counts.
Serious infections occurred in 32% of patients, including fatal infections in 10% of patients. The prescribing information for pirtobrutinib includes warnings about infections, hemorrhage, cytopenias, cardiac arrhythmias, and secondary primary malignancies.
A version of this article first appeared on Medscape.com.
Small-volume blood sample tubes may reduce anemia and transfusions in intensive care
according to a new study. The change does not appear to impair biospecimen sufficiency for lab analysis.
In addition, by reducing blood transfusion during ICU admission by about 10 units per 100 patients, the change may enable hospitals and health systems to sustain blood product supply during ongoing worldwide shortages.
“It doesn’t take long working in a hospital or being a patient or family member to realize how much blood we take to do lab work. As a result, patients may develop anemia and low RBC counts, which can be associated with worse health outcomes,” lead author Deborah Siegal, MD, a hematologist at the Ottawa Hospital and associate professor of medicine at the University of Ottawa, said in an interview.
“Unfortunately, the majority of the blood we take is discarded as waste,” she said. “Here’s an opportunity to move the needle on reducing anemia in hospitalized patients, where the benefit also doesn’t come at a cost.”
The study was published online in JAMA.
Reducing Blood Loss
Among ICU patients with critical illness, there is a high prevalence of anemia, Siegal noted. More than 90% of these patients have some degree of anemia after a 3-day stay. Typically, RBC transfusions are given to correct the low blood counts, and as many as 40% of ICU patients receive at least one RBC transfusion. Anemia and RBC transfusion are each associated with adverse outcomes, including higher mortality and longer ICU and hospital stays.
Although anemia in critically ill ICU patients can have several causes, blood sampling can be substantial because of the need to draw multiple tubes several times per day. During 8 days in an ICU, the amount of blood drawn equals about 1 unit of whole blood, the authors noted, and ICU patients often struggle to increase RBC production and compensate for blood loss.
Even then, only 10% of the blood collected is required for lab testing; the remaining 90% is often discarded as waste, the authors noted. Small-volume tubes (1.8 to 3.5 mL), which are designed to draw about 50% less than standard-volume tubes (4 to 6 mL) by using less vacuum strength, are of the same size and cost as standard-volume tubes, and the collection technique is the same. They are produced by the same manufacturers and are compatible with existing lab equipment.
Siegal and colleagues conducted a stepped-wedge cluster randomized trial to test the switch to small-volume tubes in 25 adult medical-surgical ICUs in Canada between February 2019 and January 2021. They analyzed data from more than 27,000 patients admitted to the ICU for 48 hours or longer. ICUs were randomly assigned to switch from standard-volume tubes to small-volume tubes for lab testing. The research team primarily assessed RBC transfusion in units per patient per ICU stay, as well as hemoglobin decrease during ICU stay, length of stay in the ICU and hospital, mortality in the ICU and hospital, and specimen tubes with insufficient volume for testing.
In a primary analysis of 21,201 patients, which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference between tube-volume groups in RBC units per patient per ICU stay (relative risk [RR], 0.91). However, there was an absolute reduction of 7.24 RBC units per 100 patients per ICU stay in the small-volume group.
In addition, in a prespecified secondary analysis of 27,411 patients, RBC units per patient per ICU stay significantly decreased (RR, 0.88) after the switch to small-volume tubes, and there was an absolute reduction of 9.84 RBC units per 100 patients per ICU stay.
Overall, the median decrease in transfusion-adjusted hemoglobin wasn’t significantly different in the primary analysis but was lower in the secondary analysis. The frequency of specimens with insufficient volume for testing was low (≤0.03%) before and after the transition to small-volume tubes.
About 36,000 units of blood were given to ICU patients during the study period. The use of small-volume tubes may have saved about 1500 RBC units, the authors estimated.
“This could be an important way to help preserve the supply of blood products for patients who need them, including those undergoing cancer treatment, surgery, trauma, or other medical illnesses,” Siegal said. “The other great aspect is that this was implemented by people on the ground in the ICUs, and it’s still in use in most of those hospitals today.”
The investigators noted the need to study the switch in other patient populations, such as non-ICU hospitalized patients or outpatient settings. For instance, ICU patients often have central venous or arterial catheters for blood draws, but small-volume tubes can be used with venipuncture and could lead to additional benefits there as well.
Implementing Change
Commenting on the findings for this article, Lisa Hicks, MD, a hematologist at St. Michael’s Hospital and associate professor of medicine at the University of Toronto, said, “Routinely collecting smaller volumes of blood for diagnostic testing appears to be feasible and does not cause problems with inadequate sampling. Whether this strategy decreases transfusion is more complicated.” Hicks did not participate in the study.
“At the end of the day, we still don’t know with certainty whether reduced-volume blood collection tubes decrease transfusion burden in ICU patients — it’s possible that there are so many other factors driving down hemoglobin in this population that the impact of blood collection volume is modest to negligible,” she said. “On the other hand, it’s also possible that there is an important impact that was masked by the relatively short ICU stays in the included population.”
Hicks has researched ways to reduce unnecessary diagnostic phlebotomy in ICUs. She and colleagues found that targeting clinicians’ test ordering behavior can decrease blood draws and RBC transfusions.
“What we now know, thanks to Siegal et al, is that we don’t need to collect nearly as much blood from our ICU patients as we do, raising the question of which strategy should really be standard,” she said. “My vote goes for more blood in the patient and less in the bin.”
The study was funded by a peer-reviewed grant from the Academic Health Sciences Centers AFP Innovation Fund/Hamilton Academic Health Sciences Organization and the Hamilton Health Sciences Research Institute through the Population Health Research Institute. Siegal, who is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease, reported honoraria for presentations paid indirectly to her institution from BMS-Pfizer, AstraZeneca, Servier, and Roche outside of the submitted work. Hicks reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
according to a new study. The change does not appear to impair biospecimen sufficiency for lab analysis.
In addition, by reducing blood transfusion during ICU admission by about 10 units per 100 patients, the change may enable hospitals and health systems to sustain blood product supply during ongoing worldwide shortages.
“It doesn’t take long working in a hospital or being a patient or family member to realize how much blood we take to do lab work. As a result, patients may develop anemia and low RBC counts, which can be associated with worse health outcomes,” lead author Deborah Siegal, MD, a hematologist at the Ottawa Hospital and associate professor of medicine at the University of Ottawa, said in an interview.
“Unfortunately, the majority of the blood we take is discarded as waste,” she said. “Here’s an opportunity to move the needle on reducing anemia in hospitalized patients, where the benefit also doesn’t come at a cost.”
The study was published online in JAMA.
Reducing Blood Loss
Among ICU patients with critical illness, there is a high prevalence of anemia, Siegal noted. More than 90% of these patients have some degree of anemia after a 3-day stay. Typically, RBC transfusions are given to correct the low blood counts, and as many as 40% of ICU patients receive at least one RBC transfusion. Anemia and RBC transfusion are each associated with adverse outcomes, including higher mortality and longer ICU and hospital stays.
Although anemia in critically ill ICU patients can have several causes, blood sampling can be substantial because of the need to draw multiple tubes several times per day. During 8 days in an ICU, the amount of blood drawn equals about 1 unit of whole blood, the authors noted, and ICU patients often struggle to increase RBC production and compensate for blood loss.
Even then, only 10% of the blood collected is required for lab testing; the remaining 90% is often discarded as waste, the authors noted. Small-volume tubes (1.8 to 3.5 mL), which are designed to draw about 50% less than standard-volume tubes (4 to 6 mL) by using less vacuum strength, are of the same size and cost as standard-volume tubes, and the collection technique is the same. They are produced by the same manufacturers and are compatible with existing lab equipment.
Siegal and colleagues conducted a stepped-wedge cluster randomized trial to test the switch to small-volume tubes in 25 adult medical-surgical ICUs in Canada between February 2019 and January 2021. They analyzed data from more than 27,000 patients admitted to the ICU for 48 hours or longer. ICUs were randomly assigned to switch from standard-volume tubes to small-volume tubes for lab testing. The research team primarily assessed RBC transfusion in units per patient per ICU stay, as well as hemoglobin decrease during ICU stay, length of stay in the ICU and hospital, mortality in the ICU and hospital, and specimen tubes with insufficient volume for testing.
In a primary analysis of 21,201 patients, which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference between tube-volume groups in RBC units per patient per ICU stay (relative risk [RR], 0.91). However, there was an absolute reduction of 7.24 RBC units per 100 patients per ICU stay in the small-volume group.
In addition, in a prespecified secondary analysis of 27,411 patients, RBC units per patient per ICU stay significantly decreased (RR, 0.88) after the switch to small-volume tubes, and there was an absolute reduction of 9.84 RBC units per 100 patients per ICU stay.
Overall, the median decrease in transfusion-adjusted hemoglobin wasn’t significantly different in the primary analysis but was lower in the secondary analysis. The frequency of specimens with insufficient volume for testing was low (≤0.03%) before and after the transition to small-volume tubes.
About 36,000 units of blood were given to ICU patients during the study period. The use of small-volume tubes may have saved about 1500 RBC units, the authors estimated.
“This could be an important way to help preserve the supply of blood products for patients who need them, including those undergoing cancer treatment, surgery, trauma, or other medical illnesses,” Siegal said. “The other great aspect is that this was implemented by people on the ground in the ICUs, and it’s still in use in most of those hospitals today.”
The investigators noted the need to study the switch in other patient populations, such as non-ICU hospitalized patients or outpatient settings. For instance, ICU patients often have central venous or arterial catheters for blood draws, but small-volume tubes can be used with venipuncture and could lead to additional benefits there as well.
Implementing Change
Commenting on the findings for this article, Lisa Hicks, MD, a hematologist at St. Michael’s Hospital and associate professor of medicine at the University of Toronto, said, “Routinely collecting smaller volumes of blood for diagnostic testing appears to be feasible and does not cause problems with inadequate sampling. Whether this strategy decreases transfusion is more complicated.” Hicks did not participate in the study.
“At the end of the day, we still don’t know with certainty whether reduced-volume blood collection tubes decrease transfusion burden in ICU patients — it’s possible that there are so many other factors driving down hemoglobin in this population that the impact of blood collection volume is modest to negligible,” she said. “On the other hand, it’s also possible that there is an important impact that was masked by the relatively short ICU stays in the included population.”
Hicks has researched ways to reduce unnecessary diagnostic phlebotomy in ICUs. She and colleagues found that targeting clinicians’ test ordering behavior can decrease blood draws and RBC transfusions.
“What we now know, thanks to Siegal et al, is that we don’t need to collect nearly as much blood from our ICU patients as we do, raising the question of which strategy should really be standard,” she said. “My vote goes for more blood in the patient and less in the bin.”
The study was funded by a peer-reviewed grant from the Academic Health Sciences Centers AFP Innovation Fund/Hamilton Academic Health Sciences Organization and the Hamilton Health Sciences Research Institute through the Population Health Research Institute. Siegal, who is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease, reported honoraria for presentations paid indirectly to her institution from BMS-Pfizer, AstraZeneca, Servier, and Roche outside of the submitted work. Hicks reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
according to a new study. The change does not appear to impair biospecimen sufficiency for lab analysis.
In addition, by reducing blood transfusion during ICU admission by about 10 units per 100 patients, the change may enable hospitals and health systems to sustain blood product supply during ongoing worldwide shortages.
“It doesn’t take long working in a hospital or being a patient or family member to realize how much blood we take to do lab work. As a result, patients may develop anemia and low RBC counts, which can be associated with worse health outcomes,” lead author Deborah Siegal, MD, a hematologist at the Ottawa Hospital and associate professor of medicine at the University of Ottawa, said in an interview.
“Unfortunately, the majority of the blood we take is discarded as waste,” she said. “Here’s an opportunity to move the needle on reducing anemia in hospitalized patients, where the benefit also doesn’t come at a cost.”
The study was published online in JAMA.
Reducing Blood Loss
Among ICU patients with critical illness, there is a high prevalence of anemia, Siegal noted. More than 90% of these patients have some degree of anemia after a 3-day stay. Typically, RBC transfusions are given to correct the low blood counts, and as many as 40% of ICU patients receive at least one RBC transfusion. Anemia and RBC transfusion are each associated with adverse outcomes, including higher mortality and longer ICU and hospital stays.
Although anemia in critically ill ICU patients can have several causes, blood sampling can be substantial because of the need to draw multiple tubes several times per day. During 8 days in an ICU, the amount of blood drawn equals about 1 unit of whole blood, the authors noted, and ICU patients often struggle to increase RBC production and compensate for blood loss.
Even then, only 10% of the blood collected is required for lab testing; the remaining 90% is often discarded as waste, the authors noted. Small-volume tubes (1.8 to 3.5 mL), which are designed to draw about 50% less than standard-volume tubes (4 to 6 mL) by using less vacuum strength, are of the same size and cost as standard-volume tubes, and the collection technique is the same. They are produced by the same manufacturers and are compatible with existing lab equipment.
Siegal and colleagues conducted a stepped-wedge cluster randomized trial to test the switch to small-volume tubes in 25 adult medical-surgical ICUs in Canada between February 2019 and January 2021. They analyzed data from more than 27,000 patients admitted to the ICU for 48 hours or longer. ICUs were randomly assigned to switch from standard-volume tubes to small-volume tubes for lab testing. The research team primarily assessed RBC transfusion in units per patient per ICU stay, as well as hemoglobin decrease during ICU stay, length of stay in the ICU and hospital, mortality in the ICU and hospital, and specimen tubes with insufficient volume for testing.
In a primary analysis of 21,201 patients, which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference between tube-volume groups in RBC units per patient per ICU stay (relative risk [RR], 0.91). However, there was an absolute reduction of 7.24 RBC units per 100 patients per ICU stay in the small-volume group.
In addition, in a prespecified secondary analysis of 27,411 patients, RBC units per patient per ICU stay significantly decreased (RR, 0.88) after the switch to small-volume tubes, and there was an absolute reduction of 9.84 RBC units per 100 patients per ICU stay.
Overall, the median decrease in transfusion-adjusted hemoglobin wasn’t significantly different in the primary analysis but was lower in the secondary analysis. The frequency of specimens with insufficient volume for testing was low (≤0.03%) before and after the transition to small-volume tubes.
About 36,000 units of blood were given to ICU patients during the study period. The use of small-volume tubes may have saved about 1500 RBC units, the authors estimated.
“This could be an important way to help preserve the supply of blood products for patients who need them, including those undergoing cancer treatment, surgery, trauma, or other medical illnesses,” Siegal said. “The other great aspect is that this was implemented by people on the ground in the ICUs, and it’s still in use in most of those hospitals today.”
The investigators noted the need to study the switch in other patient populations, such as non-ICU hospitalized patients or outpatient settings. For instance, ICU patients often have central venous or arterial catheters for blood draws, but small-volume tubes can be used with venipuncture and could lead to additional benefits there as well.
Implementing Change
Commenting on the findings for this article, Lisa Hicks, MD, a hematologist at St. Michael’s Hospital and associate professor of medicine at the University of Toronto, said, “Routinely collecting smaller volumes of blood for diagnostic testing appears to be feasible and does not cause problems with inadequate sampling. Whether this strategy decreases transfusion is more complicated.” Hicks did not participate in the study.
“At the end of the day, we still don’t know with certainty whether reduced-volume blood collection tubes decrease transfusion burden in ICU patients — it’s possible that there are so many other factors driving down hemoglobin in this population that the impact of blood collection volume is modest to negligible,” she said. “On the other hand, it’s also possible that there is an important impact that was masked by the relatively short ICU stays in the included population.”
Hicks has researched ways to reduce unnecessary diagnostic phlebotomy in ICUs. She and colleagues found that targeting clinicians’ test ordering behavior can decrease blood draws and RBC transfusions.
“What we now know, thanks to Siegal et al, is that we don’t need to collect nearly as much blood from our ICU patients as we do, raising the question of which strategy should really be standard,” she said. “My vote goes for more blood in the patient and less in the bin.”
The study was funded by a peer-reviewed grant from the Academic Health Sciences Centers AFP Innovation Fund/Hamilton Academic Health Sciences Organization and the Hamilton Health Sciences Research Institute through the Population Health Research Institute. Siegal, who is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease, reported honoraria for presentations paid indirectly to her institution from BMS-Pfizer, AstraZeneca, Servier, and Roche outside of the submitted work. Hicks reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM JAMA
Underdiagnosed: Iron deficiency anemia during pregnancy
Jerome J. Federspiel, MD, often cares for patients who are about to deliver a baby but who have untreated iron deficiency anemia (IDA). Often, these patients require a blood transfusion after giving birth.
“I am sad to hear commonly from patients we treat that they have had iron-deficient anemia symptoms for many years. Correcting these conditions makes birth safer and, oftentimes, makes people feel much better – sometimes better than they have in years,” Dr. Federspiel, maternal-fetal medicine physician and assistant professor of obstetrics and gynecology and population health sciences at Duke University, Durham, N.C., said.
Even patients he is able to diagnose earlier “will have difficulties catching up during pregnancy.”
The condition is the most common type of anemia among people who are pregnant. IDA increases a patient’s risk of delivering preterm and developing postpartum depression and puts their infants at a risk for perinatal mortality. Without proper treatment of IDA throughout pregnancy, the condition can also lead to low birth weights in infants or failing to meet weight goals later on.
But of all women with a new diagnosis of IDA from 2021 to 2022, 10% were pregnant, according to an analysis by Komodo Health, a health care analytics company.
While estimates of the prevalence of IDA vary, research from 2021 found 6.5% of nearly 1,500 patients who were pregnant during the first trimester had the condition, a figure the researchers said might underrepresent the problem.
“In severe cases [fetal outcomes can include] abnormal fetal oxygenation, nonreassuring fetal heart rate patterns, reduced amniotic fluid volume, fetal cerebral vasodilation, and fetal death,” Alianne S. Tilley, NP, family nurse practitioner at Women’s Care of Lake Cumberland, Somerset, Ky., said.
Research has shown that adequate levels of iron are an integral component in the development of the fetal brain. Some studies have reported that IDA during pregnancy increases an infant’s risk for poor neurodevelopmental outcomes.
Lack of screening protocol
Discrepancies in guidance for testing patients who are pregnant for IDA may add to late diagnosis and low treatment, according to Katelin Zahn, MD, assistant professor of general obstetrics, gynecology, and midwifery at University of North Carolina at Chapel Hill.
“There’s no consistency, which leads to a lot of variation in individual practice, which creates variation in outcomes, too,” Dr. Zahn said. “You can only do so much as one independent physician, and you need to be able to create change in a system that functions and provides standard of care even when you aren’t there.”
The American College of Obstetricians and Gynecologists recommends screening all patients who are pregnant with a complete blood count in the first trimester and again between 24 and 27 weeks of gestation.
Patients who meet criteria for IDA based on hematocrit levels less than 33% in the first and third trimesters, and less than 32% in the second trimester, should be evaluated to determine the cause. Those with IDA should be treated with supplemental iron, in addition to prenatal vitamins, ACOG says.
But the U.S. Preventive Services Task Force in 2015 found insufficient evidence to recommend for or against screening patients without symptoms or signs of the condition. The organization is in the process of updating the recommendation.
Prevention as best practice
The most effective way to address IDA in patients who are pregnant is prevention, according to Dr. Federspiel.
“Having a systematic approach to screening and treatment is really important, and this starts before pregnancy,” Dr. Federspiel said. “On average, a typical pregnancy requires an additional 1 g of iron.”
Dr. Federspiel recommends clinicians discuss the causes and the effects of IDA with patients who are planning to or could become pregnant. Clinicians might recommend iron- and folate-rich foods and vitamins B12 and C and ask patients if they face any barriers to access.
“Prenatal vitamins with iron are the gold standard in preventing IDA in the pregnant population,” Ms. Tilley said. “Education on the significant risk factors associated with IDA in early pregnancy is key.”
A version of this article first appeared on Medscape.com.
Jerome J. Federspiel, MD, often cares for patients who are about to deliver a baby but who have untreated iron deficiency anemia (IDA). Often, these patients require a blood transfusion after giving birth.
“I am sad to hear commonly from patients we treat that they have had iron-deficient anemia symptoms for many years. Correcting these conditions makes birth safer and, oftentimes, makes people feel much better – sometimes better than they have in years,” Dr. Federspiel, maternal-fetal medicine physician and assistant professor of obstetrics and gynecology and population health sciences at Duke University, Durham, N.C., said.
Even patients he is able to diagnose earlier “will have difficulties catching up during pregnancy.”
The condition is the most common type of anemia among people who are pregnant. IDA increases a patient’s risk of delivering preterm and developing postpartum depression and puts their infants at a risk for perinatal mortality. Without proper treatment of IDA throughout pregnancy, the condition can also lead to low birth weights in infants or failing to meet weight goals later on.
But of all women with a new diagnosis of IDA from 2021 to 2022, 10% were pregnant, according to an analysis by Komodo Health, a health care analytics company.
While estimates of the prevalence of IDA vary, research from 2021 found 6.5% of nearly 1,500 patients who were pregnant during the first trimester had the condition, a figure the researchers said might underrepresent the problem.
“In severe cases [fetal outcomes can include] abnormal fetal oxygenation, nonreassuring fetal heart rate patterns, reduced amniotic fluid volume, fetal cerebral vasodilation, and fetal death,” Alianne S. Tilley, NP, family nurse practitioner at Women’s Care of Lake Cumberland, Somerset, Ky., said.
Research has shown that adequate levels of iron are an integral component in the development of the fetal brain. Some studies have reported that IDA during pregnancy increases an infant’s risk for poor neurodevelopmental outcomes.
Lack of screening protocol
Discrepancies in guidance for testing patients who are pregnant for IDA may add to late diagnosis and low treatment, according to Katelin Zahn, MD, assistant professor of general obstetrics, gynecology, and midwifery at University of North Carolina at Chapel Hill.
“There’s no consistency, which leads to a lot of variation in individual practice, which creates variation in outcomes, too,” Dr. Zahn said. “You can only do so much as one independent physician, and you need to be able to create change in a system that functions and provides standard of care even when you aren’t there.”
The American College of Obstetricians and Gynecologists recommends screening all patients who are pregnant with a complete blood count in the first trimester and again between 24 and 27 weeks of gestation.
Patients who meet criteria for IDA based on hematocrit levels less than 33% in the first and third trimesters, and less than 32% in the second trimester, should be evaluated to determine the cause. Those with IDA should be treated with supplemental iron, in addition to prenatal vitamins, ACOG says.
But the U.S. Preventive Services Task Force in 2015 found insufficient evidence to recommend for or against screening patients without symptoms or signs of the condition. The organization is in the process of updating the recommendation.
Prevention as best practice
The most effective way to address IDA in patients who are pregnant is prevention, according to Dr. Federspiel.
“Having a systematic approach to screening and treatment is really important, and this starts before pregnancy,” Dr. Federspiel said. “On average, a typical pregnancy requires an additional 1 g of iron.”
Dr. Federspiel recommends clinicians discuss the causes and the effects of IDA with patients who are planning to or could become pregnant. Clinicians might recommend iron- and folate-rich foods and vitamins B12 and C and ask patients if they face any barriers to access.
“Prenatal vitamins with iron are the gold standard in preventing IDA in the pregnant population,” Ms. Tilley said. “Education on the significant risk factors associated with IDA in early pregnancy is key.”
A version of this article first appeared on Medscape.com.
Jerome J. Federspiel, MD, often cares for patients who are about to deliver a baby but who have untreated iron deficiency anemia (IDA). Often, these patients require a blood transfusion after giving birth.
“I am sad to hear commonly from patients we treat that they have had iron-deficient anemia symptoms for many years. Correcting these conditions makes birth safer and, oftentimes, makes people feel much better – sometimes better than they have in years,” Dr. Federspiel, maternal-fetal medicine physician and assistant professor of obstetrics and gynecology and population health sciences at Duke University, Durham, N.C., said.
Even patients he is able to diagnose earlier “will have difficulties catching up during pregnancy.”
The condition is the most common type of anemia among people who are pregnant. IDA increases a patient’s risk of delivering preterm and developing postpartum depression and puts their infants at a risk for perinatal mortality. Without proper treatment of IDA throughout pregnancy, the condition can also lead to low birth weights in infants or failing to meet weight goals later on.
But of all women with a new diagnosis of IDA from 2021 to 2022, 10% were pregnant, according to an analysis by Komodo Health, a health care analytics company.
While estimates of the prevalence of IDA vary, research from 2021 found 6.5% of nearly 1,500 patients who were pregnant during the first trimester had the condition, a figure the researchers said might underrepresent the problem.
“In severe cases [fetal outcomes can include] abnormal fetal oxygenation, nonreassuring fetal heart rate patterns, reduced amniotic fluid volume, fetal cerebral vasodilation, and fetal death,” Alianne S. Tilley, NP, family nurse practitioner at Women’s Care of Lake Cumberland, Somerset, Ky., said.
Research has shown that adequate levels of iron are an integral component in the development of the fetal brain. Some studies have reported that IDA during pregnancy increases an infant’s risk for poor neurodevelopmental outcomes.
Lack of screening protocol
Discrepancies in guidance for testing patients who are pregnant for IDA may add to late diagnosis and low treatment, according to Katelin Zahn, MD, assistant professor of general obstetrics, gynecology, and midwifery at University of North Carolina at Chapel Hill.
“There’s no consistency, which leads to a lot of variation in individual practice, which creates variation in outcomes, too,” Dr. Zahn said. “You can only do so much as one independent physician, and you need to be able to create change in a system that functions and provides standard of care even when you aren’t there.”
The American College of Obstetricians and Gynecologists recommends screening all patients who are pregnant with a complete blood count in the first trimester and again between 24 and 27 weeks of gestation.
Patients who meet criteria for IDA based on hematocrit levels less than 33% in the first and third trimesters, and less than 32% in the second trimester, should be evaluated to determine the cause. Those with IDA should be treated with supplemental iron, in addition to prenatal vitamins, ACOG says.
But the U.S. Preventive Services Task Force in 2015 found insufficient evidence to recommend for or against screening patients without symptoms or signs of the condition. The organization is in the process of updating the recommendation.
Prevention as best practice
The most effective way to address IDA in patients who are pregnant is prevention, according to Dr. Federspiel.
“Having a systematic approach to screening and treatment is really important, and this starts before pregnancy,” Dr. Federspiel said. “On average, a typical pregnancy requires an additional 1 g of iron.”
Dr. Federspiel recommends clinicians discuss the causes and the effects of IDA with patients who are planning to or could become pregnant. Clinicians might recommend iron- and folate-rich foods and vitamins B12 and C and ask patients if they face any barriers to access.
“Prenatal vitamins with iron are the gold standard in preventing IDA in the pregnant population,” Ms. Tilley said. “Education on the significant risk factors associated with IDA in early pregnancy is key.”
A version of this article first appeared on Medscape.com.
Time to stop routine maintenance therapy in myeloma?
For more than 10 years, ongoing treatment with lenalidomide following autologous hematopoietic stem cell transplantation (ASCT) has been the unchallenged gold standard.
The new findings were from the MASTER study, published in The Lancet Haematology, along with an invited commentary by Dr. Derman. In MASTER, patients who showed no evidence of disease after transplantation and two phases of consolidation therapy had the opportunity to avoid lenalidomide maintenance.
In the lenalidomide-free group, just 9% of patients without high-risk chromosome abnormalities or just one HRCA progressed within 2 years. About 47% of patients with two or more HRCAs progressed within 2 years.
The MASTER authors concluded that modern regimens of induction plus ASCT/consolidation might be good enough for many patients. Avoiding maintenance therapy “lead to most patients with newly diagnosed multiple myeloma reaching an MRD [minimal residual disease]-free, treatment-free state with a low risk of disease progression.” They also cautioned that the approach was “not optimal” for high-risk patients.
“We have been indoctrinated into continuous therapy,” said lead author Luciano Costa, MD, professor of medicine at the University of Alabama at Birmingham. “This was a reasonable approach at the time when [induction and consolidation] therapy was not as effective.”
Lenalidomide for post-ASCT maintenance became a guideline standard following a pivotal study published in the New England Journal of Medicine in 2012. The study showed that lenalidomide maintenance after transplantation almost doubled the time to progression (P < .001) and improved survival (P = .03).
Shaji Kumar, MD, is chair of the National Comprehensive Cancer Network Multiple Myeloma Guidelines and professor of medicine at the Mayo Clinic in Rochester, Minn.
Dr. Kumar said that the MASTER results alone are not sufficient to change current guidelines because the study was a single-arm, uncontrolled, phase 2 trial. However, there are “multiple reasons why we would like to stop treatment at some point in time,” Dr. Kumar said.
“Quality of life, the financial cost, and the toxicity are three main reasons why we would like to discontinue the maintenance or give maintenance only for the amount of time that a patient needs it,” Dr. Kumar added. “So then the question comes up, how do we identify the people who need long term treatment versus the people who don’t?”
“Response” in MM is conventionally classified by criteria laid down by the International Myeloma Working Group. However, the MASTER trial made use of a different measure: MRD negativity, in which myeloma cells can no longer be detected in bone-marrow aspirate at a level of 1 in 100,000 (10–5) or, in some studies, 1 in 1 million (10–6).
MRD is a rare bird in oncology: A surrogate endpoint that provides answers faster than progression-free survival or overall survival but is a reliable guide to both. In 2020 a team headed by Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, published a large meta-analysis showing that a negative MRD in a patient with MM was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001).
In an interview from 2022, Dr. Munshi explained that patients with MRD negativity are not necessarily “cured”: “Simply, physiologically, it means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
In MASTER, which was based at five U.S. academic medical centers, 81% of participants (96/118) achieved MRD negativity at the 10–5 cutoff. Eighty-four people (71%) had two consecutive MRD-negative results and did not go on to lenalidomide maintenance. Instead, they were monitored with lab tests every 8 weeks for the first 24 weeks and every 16 weeks thereafter and assessed for any changes in MRD after 6 months and 18 months.
The median age in MASTER was 61 years, 43% were women, and 20% were non-Hispanic Black. About 20% of participants had two or more HRCAs, 37% had one HRCA, and 43% had no HRCAs. All participants had four 28-day cycles of induction with Dara-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone). This was followed by ASCT and up to two phases of consolidation with Dara-KRd.
MASTER is not the only study to show that MRD-guided discontinuation of lenalidomide seems feasible in some patients. In November 2023, Spanish researchers published a study in Blood testing a combination of lenalidomide, dexamethasone, and ixazomib. The trial allowed MRD-negative patients to stop therapy after 2 years. Progression was 17.2% over the following 4 years in the group that dropped maintenance, which included high-risk patients. The authors concluded that their results “support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years.”
These two trials are conspicuous by their rarity.
Said Dr. Derman: “We haven’t done a great job until recently of designing trials that look into discontinuation.”
Both Dr. Derman and Dr. Costa raised the elephant in the room: industry funding.
“Maintenance therapy is big business,” said Dr. Derman. He added that he had experienced problems in the past obtaining industry funding for research that involved stopping therapy.
Dr. Costa, coauthor of the MASTER trial, agreed in part: “Most pharmaceutical companies do not embark on trials like this because they’re primarily doing registration trials.” MASTER garnered some industry funding, however, and Dr. Costa found that encouraging.
How much money is at stake? In other words, what are the financial savings if patients with zero to one HRCAs who are MRD negative start to take treatment holidays from lenalidomide maintenance?
In the United States in 2019 approximately 6,410 patients received ASCT. The MASTER publication stated that “around 85%” of newly diagnosed MM patients have zero to one HRCAs and that 73% of these patients were able to stop therapy in the trial. This suggests that, each year, approximately 4,000 new patients might be eligible to avoid lenalidomide after ASCT.
The price tag of lenalidomide is approximately $20,000 per month in the United States, according to Dr. Derman. A cohort of 4,000 patients avoiding lenalidomide each year represents lost revenue of $80 million per month or almost $1 billion per year. And this does not take into account patients already on lenalidomide from previous years – or sales outside the United States. The MM multiple research pipeline reflects a lack of enthusiasm for paring down maintenance.
There are currently 229 interventional clinical studies in MM taking place nationwide. Of these, just three trials are testing what happens when patients stop therapy in the post-ASCT setting and none of the three is sponsored by industry (NCT04108624, NCT05091372, and NCT04071457). (All data from clinicaltrials.gov; search covered phase 2, 3, or 4 studies still accruing data; descriptions hand-checked; search terms: maintenance/consolidation/post-ASCT.)
Dr. Derman said that it is “incumbent on investigators” to carry out the studies to identify who is eligible to stop therapy because industry is “probably always going to err on the side of treating more.”
Sergio Giralt, MD, head of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, New York, was an author of the key 2012 study that enshrined lenalidomide maintenance in the guidelines. Dr. Giralt expressed concerns about the single-arm design of MASTER and said he would like to see a randomized study where some patients continued treatment and others stopped.
Dr. Giralt cautioned: “If you’re MRD negative, the chances of having to deal with your disease in the next 5 years is one in five.” Physicians could certainly “have a conversation” with patients who are MRD negative about stopping therapy, but this would need to be weighed against the need for bone-marrow biopsies every 3-6 months to check progress. (In MASTER, MRD was checked at 6 and 18 months.)
Dr. Kumar believes that “we need to pursue the concept of decreasing the duration of treatment.” However, newer immunotherapies may be the answer: “Who knows? That may be the future, that we will do more of this hit-and-run approach rather than trying to keep them persistently on something.”
Dr. Derman said: “I personally think that the data is already there ... [MASTER] shows that perhaps this notion of indefinite maintenance therapy is one that really has to go by the wayside ... patients should have the option to consider with their physician [the chance to] potentially discontinue treatment.”
For 15 years, relentless lenalidomide maintenance has “quite rightly been the strongest pillar of therapy”, said Dr. Costa. “But for patients, this is not something that they easily embrace – it’s not ideal that you are going to have to take therapy for the rest of your life.”
Dr. Costa concluded: “I don’t think we had a single patient who was reluctant to stop therapy.”
Dr. Munshi reported relationships with Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Pfizer, and he is the scientific founder of Oncopep and DCT. Dr. Derman disclosed ties with Janssen, Cota, and BMS. Dr. Costa reported ties with Amgen, Cota, Janssen, BMS, AbbVie, Ionis, Genentech, Sanofi, Karyopharm, AstraZeneca, Adaptive Biotechnologies, Takeda, and Pfizer. Dr. Kumar declared relationships with AbbVie, Amgen, BMS, GlaxoSmithKline, Karyopharm, Regeneron, Roche, Sanofi, Takeda, and BeiGene. Dr. Giralt reported ties with Amgen, CSL Behring, Caladrius, Celgene, Ceramedix, ExpertConnect, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharmaceuticals, Magnolia Innovation, Novartis, Omeros, Pfizer, Physicians’ Education Resource, Sanofi, TRM Oncology, and Xcenda.
For more than 10 years, ongoing treatment with lenalidomide following autologous hematopoietic stem cell transplantation (ASCT) has been the unchallenged gold standard.
The new findings were from the MASTER study, published in The Lancet Haematology, along with an invited commentary by Dr. Derman. In MASTER, patients who showed no evidence of disease after transplantation and two phases of consolidation therapy had the opportunity to avoid lenalidomide maintenance.
In the lenalidomide-free group, just 9% of patients without high-risk chromosome abnormalities or just one HRCA progressed within 2 years. About 47% of patients with two or more HRCAs progressed within 2 years.
The MASTER authors concluded that modern regimens of induction plus ASCT/consolidation might be good enough for many patients. Avoiding maintenance therapy “lead to most patients with newly diagnosed multiple myeloma reaching an MRD [minimal residual disease]-free, treatment-free state with a low risk of disease progression.” They also cautioned that the approach was “not optimal” for high-risk patients.
“We have been indoctrinated into continuous therapy,” said lead author Luciano Costa, MD, professor of medicine at the University of Alabama at Birmingham. “This was a reasonable approach at the time when [induction and consolidation] therapy was not as effective.”
Lenalidomide for post-ASCT maintenance became a guideline standard following a pivotal study published in the New England Journal of Medicine in 2012. The study showed that lenalidomide maintenance after transplantation almost doubled the time to progression (P < .001) and improved survival (P = .03).
Shaji Kumar, MD, is chair of the National Comprehensive Cancer Network Multiple Myeloma Guidelines and professor of medicine at the Mayo Clinic in Rochester, Minn.
Dr. Kumar said that the MASTER results alone are not sufficient to change current guidelines because the study was a single-arm, uncontrolled, phase 2 trial. However, there are “multiple reasons why we would like to stop treatment at some point in time,” Dr. Kumar said.
“Quality of life, the financial cost, and the toxicity are three main reasons why we would like to discontinue the maintenance or give maintenance only for the amount of time that a patient needs it,” Dr. Kumar added. “So then the question comes up, how do we identify the people who need long term treatment versus the people who don’t?”
“Response” in MM is conventionally classified by criteria laid down by the International Myeloma Working Group. However, the MASTER trial made use of a different measure: MRD negativity, in which myeloma cells can no longer be detected in bone-marrow aspirate at a level of 1 in 100,000 (10–5) or, in some studies, 1 in 1 million (10–6).
MRD is a rare bird in oncology: A surrogate endpoint that provides answers faster than progression-free survival or overall survival but is a reliable guide to both. In 2020 a team headed by Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, published a large meta-analysis showing that a negative MRD in a patient with MM was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001).
In an interview from 2022, Dr. Munshi explained that patients with MRD negativity are not necessarily “cured”: “Simply, physiologically, it means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
In MASTER, which was based at five U.S. academic medical centers, 81% of participants (96/118) achieved MRD negativity at the 10–5 cutoff. Eighty-four people (71%) had two consecutive MRD-negative results and did not go on to lenalidomide maintenance. Instead, they were monitored with lab tests every 8 weeks for the first 24 weeks and every 16 weeks thereafter and assessed for any changes in MRD after 6 months and 18 months.
The median age in MASTER was 61 years, 43% were women, and 20% were non-Hispanic Black. About 20% of participants had two or more HRCAs, 37% had one HRCA, and 43% had no HRCAs. All participants had four 28-day cycles of induction with Dara-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone). This was followed by ASCT and up to two phases of consolidation with Dara-KRd.
MASTER is not the only study to show that MRD-guided discontinuation of lenalidomide seems feasible in some patients. In November 2023, Spanish researchers published a study in Blood testing a combination of lenalidomide, dexamethasone, and ixazomib. The trial allowed MRD-negative patients to stop therapy after 2 years. Progression was 17.2% over the following 4 years in the group that dropped maintenance, which included high-risk patients. The authors concluded that their results “support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years.”
These two trials are conspicuous by their rarity.
Said Dr. Derman: “We haven’t done a great job until recently of designing trials that look into discontinuation.”
Both Dr. Derman and Dr. Costa raised the elephant in the room: industry funding.
“Maintenance therapy is big business,” said Dr. Derman. He added that he had experienced problems in the past obtaining industry funding for research that involved stopping therapy.
Dr. Costa, coauthor of the MASTER trial, agreed in part: “Most pharmaceutical companies do not embark on trials like this because they’re primarily doing registration trials.” MASTER garnered some industry funding, however, and Dr. Costa found that encouraging.
How much money is at stake? In other words, what are the financial savings if patients with zero to one HRCAs who are MRD negative start to take treatment holidays from lenalidomide maintenance?
In the United States in 2019 approximately 6,410 patients received ASCT. The MASTER publication stated that “around 85%” of newly diagnosed MM patients have zero to one HRCAs and that 73% of these patients were able to stop therapy in the trial. This suggests that, each year, approximately 4,000 new patients might be eligible to avoid lenalidomide after ASCT.
The price tag of lenalidomide is approximately $20,000 per month in the United States, according to Dr. Derman. A cohort of 4,000 patients avoiding lenalidomide each year represents lost revenue of $80 million per month or almost $1 billion per year. And this does not take into account patients already on lenalidomide from previous years – or sales outside the United States. The MM multiple research pipeline reflects a lack of enthusiasm for paring down maintenance.
There are currently 229 interventional clinical studies in MM taking place nationwide. Of these, just three trials are testing what happens when patients stop therapy in the post-ASCT setting and none of the three is sponsored by industry (NCT04108624, NCT05091372, and NCT04071457). (All data from clinicaltrials.gov; search covered phase 2, 3, or 4 studies still accruing data; descriptions hand-checked; search terms: maintenance/consolidation/post-ASCT.)
Dr. Derman said that it is “incumbent on investigators” to carry out the studies to identify who is eligible to stop therapy because industry is “probably always going to err on the side of treating more.”
Sergio Giralt, MD, head of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, New York, was an author of the key 2012 study that enshrined lenalidomide maintenance in the guidelines. Dr. Giralt expressed concerns about the single-arm design of MASTER and said he would like to see a randomized study where some patients continued treatment and others stopped.
Dr. Giralt cautioned: “If you’re MRD negative, the chances of having to deal with your disease in the next 5 years is one in five.” Physicians could certainly “have a conversation” with patients who are MRD negative about stopping therapy, but this would need to be weighed against the need for bone-marrow biopsies every 3-6 months to check progress. (In MASTER, MRD was checked at 6 and 18 months.)
Dr. Kumar believes that “we need to pursue the concept of decreasing the duration of treatment.” However, newer immunotherapies may be the answer: “Who knows? That may be the future, that we will do more of this hit-and-run approach rather than trying to keep them persistently on something.”
Dr. Derman said: “I personally think that the data is already there ... [MASTER] shows that perhaps this notion of indefinite maintenance therapy is one that really has to go by the wayside ... patients should have the option to consider with their physician [the chance to] potentially discontinue treatment.”
For 15 years, relentless lenalidomide maintenance has “quite rightly been the strongest pillar of therapy”, said Dr. Costa. “But for patients, this is not something that they easily embrace – it’s not ideal that you are going to have to take therapy for the rest of your life.”
Dr. Costa concluded: “I don’t think we had a single patient who was reluctant to stop therapy.”
Dr. Munshi reported relationships with Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Pfizer, and he is the scientific founder of Oncopep and DCT. Dr. Derman disclosed ties with Janssen, Cota, and BMS. Dr. Costa reported ties with Amgen, Cota, Janssen, BMS, AbbVie, Ionis, Genentech, Sanofi, Karyopharm, AstraZeneca, Adaptive Biotechnologies, Takeda, and Pfizer. Dr. Kumar declared relationships with AbbVie, Amgen, BMS, GlaxoSmithKline, Karyopharm, Regeneron, Roche, Sanofi, Takeda, and BeiGene. Dr. Giralt reported ties with Amgen, CSL Behring, Caladrius, Celgene, Ceramedix, ExpertConnect, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharmaceuticals, Magnolia Innovation, Novartis, Omeros, Pfizer, Physicians’ Education Resource, Sanofi, TRM Oncology, and Xcenda.
For more than 10 years, ongoing treatment with lenalidomide following autologous hematopoietic stem cell transplantation (ASCT) has been the unchallenged gold standard.
The new findings were from the MASTER study, published in The Lancet Haematology, along with an invited commentary by Dr. Derman. In MASTER, patients who showed no evidence of disease after transplantation and two phases of consolidation therapy had the opportunity to avoid lenalidomide maintenance.
In the lenalidomide-free group, just 9% of patients without high-risk chromosome abnormalities or just one HRCA progressed within 2 years. About 47% of patients with two or more HRCAs progressed within 2 years.
The MASTER authors concluded that modern regimens of induction plus ASCT/consolidation might be good enough for many patients. Avoiding maintenance therapy “lead to most patients with newly diagnosed multiple myeloma reaching an MRD [minimal residual disease]-free, treatment-free state with a low risk of disease progression.” They also cautioned that the approach was “not optimal” for high-risk patients.
“We have been indoctrinated into continuous therapy,” said lead author Luciano Costa, MD, professor of medicine at the University of Alabama at Birmingham. “This was a reasonable approach at the time when [induction and consolidation] therapy was not as effective.”
Lenalidomide for post-ASCT maintenance became a guideline standard following a pivotal study published in the New England Journal of Medicine in 2012. The study showed that lenalidomide maintenance after transplantation almost doubled the time to progression (P < .001) and improved survival (P = .03).
Shaji Kumar, MD, is chair of the National Comprehensive Cancer Network Multiple Myeloma Guidelines and professor of medicine at the Mayo Clinic in Rochester, Minn.
Dr. Kumar said that the MASTER results alone are not sufficient to change current guidelines because the study was a single-arm, uncontrolled, phase 2 trial. However, there are “multiple reasons why we would like to stop treatment at some point in time,” Dr. Kumar said.
“Quality of life, the financial cost, and the toxicity are three main reasons why we would like to discontinue the maintenance or give maintenance only for the amount of time that a patient needs it,” Dr. Kumar added. “So then the question comes up, how do we identify the people who need long term treatment versus the people who don’t?”
“Response” in MM is conventionally classified by criteria laid down by the International Myeloma Working Group. However, the MASTER trial made use of a different measure: MRD negativity, in which myeloma cells can no longer be detected in bone-marrow aspirate at a level of 1 in 100,000 (10–5) or, in some studies, 1 in 1 million (10–6).
MRD is a rare bird in oncology: A surrogate endpoint that provides answers faster than progression-free survival or overall survival but is a reliable guide to both. In 2020 a team headed by Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, published a large meta-analysis showing that a negative MRD in a patient with MM was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001).
In an interview from 2022, Dr. Munshi explained that patients with MRD negativity are not necessarily “cured”: “Simply, physiologically, it means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
In MASTER, which was based at five U.S. academic medical centers, 81% of participants (96/118) achieved MRD negativity at the 10–5 cutoff. Eighty-four people (71%) had two consecutive MRD-negative results and did not go on to lenalidomide maintenance. Instead, they were monitored with lab tests every 8 weeks for the first 24 weeks and every 16 weeks thereafter and assessed for any changes in MRD after 6 months and 18 months.
The median age in MASTER was 61 years, 43% were women, and 20% were non-Hispanic Black. About 20% of participants had two or more HRCAs, 37% had one HRCA, and 43% had no HRCAs. All participants had four 28-day cycles of induction with Dara-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone). This was followed by ASCT and up to two phases of consolidation with Dara-KRd.
MASTER is not the only study to show that MRD-guided discontinuation of lenalidomide seems feasible in some patients. In November 2023, Spanish researchers published a study in Blood testing a combination of lenalidomide, dexamethasone, and ixazomib. The trial allowed MRD-negative patients to stop therapy after 2 years. Progression was 17.2% over the following 4 years in the group that dropped maintenance, which included high-risk patients. The authors concluded that their results “support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years.”
These two trials are conspicuous by their rarity.
Said Dr. Derman: “We haven’t done a great job until recently of designing trials that look into discontinuation.”
Both Dr. Derman and Dr. Costa raised the elephant in the room: industry funding.
“Maintenance therapy is big business,” said Dr. Derman. He added that he had experienced problems in the past obtaining industry funding for research that involved stopping therapy.
Dr. Costa, coauthor of the MASTER trial, agreed in part: “Most pharmaceutical companies do not embark on trials like this because they’re primarily doing registration trials.” MASTER garnered some industry funding, however, and Dr. Costa found that encouraging.
How much money is at stake? In other words, what are the financial savings if patients with zero to one HRCAs who are MRD negative start to take treatment holidays from lenalidomide maintenance?
In the United States in 2019 approximately 6,410 patients received ASCT. The MASTER publication stated that “around 85%” of newly diagnosed MM patients have zero to one HRCAs and that 73% of these patients were able to stop therapy in the trial. This suggests that, each year, approximately 4,000 new patients might be eligible to avoid lenalidomide after ASCT.
The price tag of lenalidomide is approximately $20,000 per month in the United States, according to Dr. Derman. A cohort of 4,000 patients avoiding lenalidomide each year represents lost revenue of $80 million per month or almost $1 billion per year. And this does not take into account patients already on lenalidomide from previous years – or sales outside the United States. The MM multiple research pipeline reflects a lack of enthusiasm for paring down maintenance.
There are currently 229 interventional clinical studies in MM taking place nationwide. Of these, just three trials are testing what happens when patients stop therapy in the post-ASCT setting and none of the three is sponsored by industry (NCT04108624, NCT05091372, and NCT04071457). (All data from clinicaltrials.gov; search covered phase 2, 3, or 4 studies still accruing data; descriptions hand-checked; search terms: maintenance/consolidation/post-ASCT.)
Dr. Derman said that it is “incumbent on investigators” to carry out the studies to identify who is eligible to stop therapy because industry is “probably always going to err on the side of treating more.”
Sergio Giralt, MD, head of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, New York, was an author of the key 2012 study that enshrined lenalidomide maintenance in the guidelines. Dr. Giralt expressed concerns about the single-arm design of MASTER and said he would like to see a randomized study where some patients continued treatment and others stopped.
Dr. Giralt cautioned: “If you’re MRD negative, the chances of having to deal with your disease in the next 5 years is one in five.” Physicians could certainly “have a conversation” with patients who are MRD negative about stopping therapy, but this would need to be weighed against the need for bone-marrow biopsies every 3-6 months to check progress. (In MASTER, MRD was checked at 6 and 18 months.)
Dr. Kumar believes that “we need to pursue the concept of decreasing the duration of treatment.” However, newer immunotherapies may be the answer: “Who knows? That may be the future, that we will do more of this hit-and-run approach rather than trying to keep them persistently on something.”
Dr. Derman said: “I personally think that the data is already there ... [MASTER] shows that perhaps this notion of indefinite maintenance therapy is one that really has to go by the wayside ... patients should have the option to consider with their physician [the chance to] potentially discontinue treatment.”
For 15 years, relentless lenalidomide maintenance has “quite rightly been the strongest pillar of therapy”, said Dr. Costa. “But for patients, this is not something that they easily embrace – it’s not ideal that you are going to have to take therapy for the rest of your life.”
Dr. Costa concluded: “I don’t think we had a single patient who was reluctant to stop therapy.”
Dr. Munshi reported relationships with Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Pfizer, and he is the scientific founder of Oncopep and DCT. Dr. Derman disclosed ties with Janssen, Cota, and BMS. Dr. Costa reported ties with Amgen, Cota, Janssen, BMS, AbbVie, Ionis, Genentech, Sanofi, Karyopharm, AstraZeneca, Adaptive Biotechnologies, Takeda, and Pfizer. Dr. Kumar declared relationships with AbbVie, Amgen, BMS, GlaxoSmithKline, Karyopharm, Regeneron, Roche, Sanofi, Takeda, and BeiGene. Dr. Giralt reported ties with Amgen, CSL Behring, Caladrius, Celgene, Ceramedix, ExpertConnect, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharmaceuticals, Magnolia Innovation, Novartis, Omeros, Pfizer, Physicians’ Education Resource, Sanofi, TRM Oncology, and Xcenda.
FDA OKs new agent to block chemotherapy-induced neutropenia
Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.
The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.
The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.
The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.
During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.
The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.
The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.
A version of this article first appeared on Medscape.com.
Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.
The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.
The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.
The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.
During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.
The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.
The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.
A version of this article first appeared on Medscape.com.
Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.
The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.
The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.
The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.
During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.
The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.
The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.
A version of this article first appeared on Medscape.com.
FDA investigates secondary cancers from CAR T-cell therapies
Secondary cancers are a known risk for this class of immunotherapies, known as B-cell maturation antigen (BCMA)–directed or CD19-directed autologous CAR T-cell therapies, and are included in the prescribing information for these drugs. However, the FDA has received 19 reports of secondary cancers, including CAR-positive lymphoma, since 2017, when the first CAR T-cell treatments were approved, according to Endpoints News.
Most of these reports came from the FDA’s postmarketing adverse event system and others from clinical trial data.
Although the overall benefits of these products continue to outweigh their potential risks, “FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” the agency said in a press release.
Currently approved products in this class include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).
“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the FDA added.
Suspected adverse events, including T-cell cancers, should be reported by contacting the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
A version of this article first appeared on Medscape.com.
Secondary cancers are a known risk for this class of immunotherapies, known as B-cell maturation antigen (BCMA)–directed or CD19-directed autologous CAR T-cell therapies, and are included in the prescribing information for these drugs. However, the FDA has received 19 reports of secondary cancers, including CAR-positive lymphoma, since 2017, when the first CAR T-cell treatments were approved, according to Endpoints News.
Most of these reports came from the FDA’s postmarketing adverse event system and others from clinical trial data.
Although the overall benefits of these products continue to outweigh their potential risks, “FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” the agency said in a press release.
Currently approved products in this class include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).
“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the FDA added.
Suspected adverse events, including T-cell cancers, should be reported by contacting the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
A version of this article first appeared on Medscape.com.
Secondary cancers are a known risk for this class of immunotherapies, known as B-cell maturation antigen (BCMA)–directed or CD19-directed autologous CAR T-cell therapies, and are included in the prescribing information for these drugs. However, the FDA has received 19 reports of secondary cancers, including CAR-positive lymphoma, since 2017, when the first CAR T-cell treatments were approved, according to Endpoints News.
Most of these reports came from the FDA’s postmarketing adverse event system and others from clinical trial data.
Although the overall benefits of these products continue to outweigh their potential risks, “FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” the agency said in a press release.
Currently approved products in this class include idecabtagene vicleucel (Abecma), lisocabtagene maraleucel (Breyanzi), ciltacabtagene autoleucel (Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).
“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the FDA added.
Suspected adverse events, including T-cell cancers, should be reported by contacting the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
A version of this article first appeared on Medscape.com.
Redispensing unused cancer meds cuts waste, saves money
TOPLINE:
to save money and reduce waste, a Dutch study has found.
METHODOLOGY:
- Ongoing drug shortages and growing drug prices contribute to access issues in oncology.
- Researchers compared the reduction in drug waste and cost savings from redispensing oral anticancer drugs versus the standard practice of disposing of them.
- Outpatient pharmacies at four Dutch hospitals participated. A total of 1,071 patients with cancer receiving oral anticancer drugs for at-home use were given special packaging for returning unused medication to the pharmacy.
- The pharmacy ensured the quality of returned drugs based on authenticity, appearance, remaining shelf-life, and adequate storage temperature.
TAKEAWAY:
- A total of 13,069 oral anticancer drug packages, containing an average of 27 daily doses per package, were dispensed during the study period.
- Overall, 16% of patients (n = 171) returned 335 (2.6%) unused oral anticancer drug packages, of which 68% were redispensed after passing quality control.
- Redispensing unused oral anticancer drugs reduced waste by 68%, compared with disposing of them, and provided a mean net annual cost savings of €576 (U.S. $682) per patient per year.
- When just those patients who took targeted oral anticancer drugs for up to 24 months were looked at, the mean net annual cost savings associated with the quality check protocol increased to €934 (U.S. $1,019) per patient or of only the visual quality check was €1,348 (U.S. $1,474) per patient.
IN PRACTICE:
“New strategies targeting waste are required to improve financial and ecologic sustainability of expensive therapies, such as oral anticancer drugs, that frequently remain unused by patients,” the authors write. “These findings provide a waste-minimizing strategy to contribute to sustainable and affordable access to drugs.”
SOURCE:
The study, by Elisabeth M. Smale, PharmD, of Radboud University Medical Center, the Netherlands, and colleagues, was published online in JAMA Oncology.
LIMITATIONS:
Novel drugs are substantially more expensive in the United States, and the Dutch findings might underestimate potential cost savings generated through redispensing programs in the United States. Participants were prompted to return unused oral anticancer drugs through reminders at the pharmacy, but all such drugs may not have been returned.
DISCLOSURES:
The study was funded by ZonMw, the Dutch national organization for health research and development. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
to save money and reduce waste, a Dutch study has found.
METHODOLOGY:
- Ongoing drug shortages and growing drug prices contribute to access issues in oncology.
- Researchers compared the reduction in drug waste and cost savings from redispensing oral anticancer drugs versus the standard practice of disposing of them.
- Outpatient pharmacies at four Dutch hospitals participated. A total of 1,071 patients with cancer receiving oral anticancer drugs for at-home use were given special packaging for returning unused medication to the pharmacy.
- The pharmacy ensured the quality of returned drugs based on authenticity, appearance, remaining shelf-life, and adequate storage temperature.
TAKEAWAY:
- A total of 13,069 oral anticancer drug packages, containing an average of 27 daily doses per package, were dispensed during the study period.
- Overall, 16% of patients (n = 171) returned 335 (2.6%) unused oral anticancer drug packages, of which 68% were redispensed after passing quality control.
- Redispensing unused oral anticancer drugs reduced waste by 68%, compared with disposing of them, and provided a mean net annual cost savings of €576 (U.S. $682) per patient per year.
- When just those patients who took targeted oral anticancer drugs for up to 24 months were looked at, the mean net annual cost savings associated with the quality check protocol increased to €934 (U.S. $1,019) per patient or of only the visual quality check was €1,348 (U.S. $1,474) per patient.
IN PRACTICE:
“New strategies targeting waste are required to improve financial and ecologic sustainability of expensive therapies, such as oral anticancer drugs, that frequently remain unused by patients,” the authors write. “These findings provide a waste-minimizing strategy to contribute to sustainable and affordable access to drugs.”
SOURCE:
The study, by Elisabeth M. Smale, PharmD, of Radboud University Medical Center, the Netherlands, and colleagues, was published online in JAMA Oncology.
LIMITATIONS:
Novel drugs are substantially more expensive in the United States, and the Dutch findings might underestimate potential cost savings generated through redispensing programs in the United States. Participants were prompted to return unused oral anticancer drugs through reminders at the pharmacy, but all such drugs may not have been returned.
DISCLOSURES:
The study was funded by ZonMw, the Dutch national organization for health research and development. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
to save money and reduce waste, a Dutch study has found.
METHODOLOGY:
- Ongoing drug shortages and growing drug prices contribute to access issues in oncology.
- Researchers compared the reduction in drug waste and cost savings from redispensing oral anticancer drugs versus the standard practice of disposing of them.
- Outpatient pharmacies at four Dutch hospitals participated. A total of 1,071 patients with cancer receiving oral anticancer drugs for at-home use were given special packaging for returning unused medication to the pharmacy.
- The pharmacy ensured the quality of returned drugs based on authenticity, appearance, remaining shelf-life, and adequate storage temperature.
TAKEAWAY:
- A total of 13,069 oral anticancer drug packages, containing an average of 27 daily doses per package, were dispensed during the study period.
- Overall, 16% of patients (n = 171) returned 335 (2.6%) unused oral anticancer drug packages, of which 68% were redispensed after passing quality control.
- Redispensing unused oral anticancer drugs reduced waste by 68%, compared with disposing of them, and provided a mean net annual cost savings of €576 (U.S. $682) per patient per year.
- When just those patients who took targeted oral anticancer drugs for up to 24 months were looked at, the mean net annual cost savings associated with the quality check protocol increased to €934 (U.S. $1,019) per patient or of only the visual quality check was €1,348 (U.S. $1,474) per patient.
IN PRACTICE:
“New strategies targeting waste are required to improve financial and ecologic sustainability of expensive therapies, such as oral anticancer drugs, that frequently remain unused by patients,” the authors write. “These findings provide a waste-minimizing strategy to contribute to sustainable and affordable access to drugs.”
SOURCE:
The study, by Elisabeth M. Smale, PharmD, of Radboud University Medical Center, the Netherlands, and colleagues, was published online in JAMA Oncology.
LIMITATIONS:
Novel drugs are substantially more expensive in the United States, and the Dutch findings might underestimate potential cost savings generated through redispensing programs in the United States. Participants were prompted to return unused oral anticancer drugs through reminders at the pharmacy, but all such drugs may not have been returned.
DISCLOSURES:
The study was funded by ZonMw, the Dutch national organization for health research and development. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Before signing an offer letter: Read this
You’ve just received an offer letter from that job you interviewed for. Sometimes you want to let the employer know right away how interested you are. The verbiage says the letter isn’t “binding.” So you eagerly sign on the dotted line. Everything looks great ... until it isn’t.
Attorney Ericka Adler, JD, LLM, a partner at Roetzel & Andress, a Chicago-based law firm that represents physicians and health care professionals nationwide, described her client who was in this predicament. The physician, a dermatologist, left a practice where she had been employed because she had received an “amazing” offer letter that included promises about her new work location, staffing, equipment, and hours. She signed and immediately gave notice to her previous employer.
“When she received the actual employment contract, none of those details from the offer letter – which is also called a letter of intent [LOI] – were included,” Ms. Adler told this news organization. The physician wanted to have the details from the LOI formally spelled out in the contract, but the employer refused.
“Basically, they said, ‘This is our standard contract and you’ll just have to trust us that we’ll keep our word. We meant what we said in the LOI, but we cannot include those details in the actual agreement because everyone has the same form of agreement.’ “ The physician decided to sign the contract and accept the position.
She contacted Ms. Adler after she had been at her new position for a month. “She had received none of the things they had promised her in the LOI,” Ms. Adler reported. “She lacked the NP and PA support, she lacked the equipment, she didn’t have enough exam rooms. As soon as she started, someone with whom she was sharing call coverage left, and she was expected to take over. The LOI had a cap on the amount of call she would be required to take, but that verbiage didn’t make it into the contract.”
Ms. Adler tried to address this issue with the employer. “We couldn’t say they had literally breached the agreement, but we did list the things that were mentioned in the LOI but on which they hadn’t delivered. We asked them to fix the issue within 10 days.”
The employer argued “that they didn’t have to fulfill anything that wasn’t spelled out in the contract, even if it was in the LOI. In fact, the contract specified clearly that the signed employment agreement was the only agreement and replaced any previous written or oral agreements between the parties.”
The dermatologist ultimately left the new position. “She might have been able to have a legal claim against the employer for breach or perhaps ‘detrimental reliance’ – meaning, she might have argued that she had been financially harmed due to the false promises made to her. But it would have been difficult and expensive for her to litigate the issue,” said Ms. Adler.
“It also didn’t seem like the physician could remain in the job and develop a positive work relationship with the employer, given that she felt betrayed and misled, and didn’t like the terms of employment, which didn’t match her needs or expectations,” said Ms. Adler.
She added that “most employers are not as unscrupulous and dishonest as this one was. But some employers do play on the fact that younger doctors – especially residents and fellows – tend to be trusting or feel they don’t have negotiation power. They’re often excited to get an offer and sign it without a second thought.”
That’s why she advises physicians to “review the terms of the LOI carefully and make sure you’re comfortable with them before signing it; but know that the real contract to negotiate will be the actual Employment Agreement.”
She also advises physicians not to give notice at their current place of employment until they’ve signed the final contract with the new employer.
On the same page?
Anu Murthy, JD, an attorney and associate contract review specialist at Contract Diagnostics, explained that the LOI is a document that the candidate receives after an interview but before a full contract. Sometimes, the LOI is preceded by a verbal or e-mailed offer, which is less formal.
“An LOI is sometimes called a Term Sheet or Memorandum of Understanding,“ Ms. Murthy told this news organization. “Typically, it lays out key provisions, such as compensation, initial term of the contract, location, and recruitment incentives.” Sometimes it includes mention of staffing, call schedule, malpractice, noncompete covenants, and other components of the position.
Justin Nabity, founder and CEO of Physicians Thrive, a physician financial advisory group, said that LOIs are “a way for employers to gauge a prospective employee’s level of interest.”
The employer “doesn’t want to send a contract with a lot of details before determining whether the candidate is really serious about the position, so the offer letter doesn’t show the whole picture,” Mr. Nabity told this news organization.
Dennis Hursh, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, agreed.
“Another way of putting it is that the employer wants to see whether the prospective employee is on the same page. The LOI will typically include some key components that will later appear in a more complete and formal contract, together with other topics and details. Agreeing to those key components signals that indeed you and the employer are in accord,” said Mr. Hursh.
But are you really on the same page with your prospective employer? And if you seem to be on the same page, and you sign the LOI, is that a guarantee that the employer will honor its terms?
Not necessarily, according to the experts. In fact, many LOIs contain some verbiage stating that the letter isn’t binding, which can be confusing. Others suggest that it is binding, but the candidate doesn’t realize that the letter isn’t a formal contract and that the contract may contain details not included in the LOI or may omit details mentioned in the LOI, as happened to Ms. Adler’s unfortunate client.
“One of the pitfalls I see is that doctors sign the LOI without recognizing whether it’s binding or nonbinding,” Ms. Murthy said. “If it’s binding, it creates a legal obligation on your part and could preclude you from further negotiation once you see the contract and feel you’d like to negotiate some of its terms.”
Binding letters are typically offered to candidates after some back-and-forth between the parties, and important terms have been agreed to, which can happen either verbally or via e-mail. Once these agreements have been reached, they’re summarized in a “binding” letter before being extended into a full contract.
“But even if you’ve agreed on the terms verbally, it’s still important to have someone more experienced review the offer letter before signing it,” Ms. Murthy said. “It’s important to understand the ‘legalese’ and what your rights and obligations are before agreeing to anything.”
And certainly, if you receive a binding LOI, you shouldn’t sign anything until you’re sure you’re comfortable with its contents and have more details.
Are “nonbinding” LOIs really not binding?
Even if the LOI is nonbinding, that doesn’t necessarily mean you can sign it and expect to negotiate later. “I see people tripped up when they sign the LOI, thinking they’ll negotiate later,” said Mr. Hursh. “They may not like the terms – for example, they think the compensation is too low – and they figure they’ll work it out at the contract stage, because the LOI is ‘not legally binding.’ “
But because the candidate signed the LOI, “the employer is under the impression that the compensation was acceptable, so now you’ve tied your hands – and the hands of any attorney you may consult down the road – to negotiate those terms.”
Mr. Hursh said he is often consulted by physicians who signed the contract “to get the ball rolling,” thinking that the LOI was “just a meaningless bureaucratic paper.” They need to understand “that the employer wants to make sure they’re in agreement on the basic points before getting into the details,” he said. “Large hospitals with in-house counsel may not want to use their legal department’s valuable time in redrafting terms they thought were acceptable to the candidate, and most practices don’t want to pay a lawyer to draft an LOI and then come back and say, ‘Actually, the physician wants more compensation.’ “
Mr. Nabity summarized: “The LOI is essentially a negotiation tactic to take some of the cards out of the hands of the doctor and commit him or her to something they’re not ready to commit to.” Employers may be playing on the sense of pressure and candidate’s fear that the job will slip through their fingers if they wait too long to sign. “But it’s better to wait longer at this stage before signing even a nonbinding LOI,” he said.
What to do before signing
So how should physicians relate to the LOI? Mr. Nabity advises “working through the details of the offer letter first, going through it carefully and identifying areas of concern, bearing in mind that employers never begin with their best offer.”
He pointed out that physicians “rarely know their value and usually don’t know how to work through the dynamics of compensation, call schedules, additional incentives, bonuses, and productivity,” so they need to be informed about these areas before signing anything.
Ms. Murthy recommended “going back and saying [to the prospective employer], ‘Thank you, but I need time to consider and evaluate this offer.’ Then, do some due diligence.”
At that point, you can hire an attorney to go over the offer, educate yourself about compensation benchmarks and what your worth actually is, or consult another trained professional or more experienced individual who can review the LOI before you sign it.
That’s what Dominique Cleveland, MD, a Texas-based ob.gyn., did when she received an LOI 5 years ago.
“The offer letter from the group practice contained a statement that the group wanted me to come on board, what the salary would be, and the time frame that would be covered in the contract,” she told this news organization. “It mentioned benefits and incentives and relocation, but it was only a short document – maybe one or two pages long.”
At the time that she received her LOI, Dr. Cleveland was completing her residency. She consulted experienced faculty members from her institution to find out whether the terms laid out in the LOI “were the norm and were reasonable.” She was “fairly certain” that the salary was low and this was confirmed by the faculty members she talked to. “So I felt comfortable asking for more [compensation],” she said.
The employer was receptive to her proposed changes, which were included in the more detailed contract that followed. “I can’t say there were any surprises per se in the contract because I had negotiated my salary after receiving the offer letter,” she said. She accepted the position and has been working there ever since.
Dr. Cleveland advises physicians “not to make a decision without speaking to someone who’s experienced and can help you compare what’s out there.”
She also encourages physicians to ask for what they want, whether it’s compensation or something else, such as call schedule or vacation time, without being afraid. “I’m a firm believer that you won’t know what you can get if you don’t ask for it,” she said.
Negotiation tips
Mr. Nabity recommended not agreeing to any terms until you are ready to enter into negotiation, recognizing that negotiation is an “art” that requires skill and training. “Either get trained in negotiation, perhaps taking courses to advocate for yourself – which is rare, and most doctors aren’t likely to do this – or go to a trained advocate, such as a lawyer, who can do so on your behalf.”
You might share your concerns with the person who interviewed you, with the person whose name is on the LOI, or with the recruiter who can advocate on your behalf, Ms. Murthy said. “You can reach out to the recruiter and say, ‘I really appreciate the opportunity, but there are some things in the offer letter I’d like to continue discussing.’ “
When you’re ready to negotiate, be sure to assemble all of your “asks” in a single document rather than going back to the prospective employer with “multiple individual questions multiple times,” Ms. Murthy advised. It’s more efficient and the employer or recruiter will appreciate that.
She also advised couching your request in language that expresses your appreciation for the offer and stating that you would like the agreement to serve the best interests of both parties. “Use open-ended language like that, and ask if it’s all right for you to send back some questions, ask for clarification, or share concerns.”
Most employers “will be fine with that,” Ms. Murthy said. “Most won’t say, ‘This is it, take it or leave it.’ If they do, that’s a red flag for you to reconsider whether you really want to work for this particular employer.”
Mr. Hursh suggested that if you choose to sign the LOI immediately, so as to rapidly let the prospective employer know of your interest, “you should add some type of qualification such as, ‘I’m signing this to express my interest, but accepting the position will be dependent upon a more thorough review of compensation benchmarks,’ for example.”
Mr. Nabity agreed: “You can add a handwritten note to the signed LOI expressing that you’re eager to move forward and proceed with the position, but it shouldn’t be construed as accepting the terms of the LOI until you’ve seen the full contract.
“Remember, health care can’t exist without doctors,” Mr. Nabity said. “Doctors are the star players and should go into the negotiation process recognizing their true worth.”
A version of this article appeared on Medscape.com.
You’ve just received an offer letter from that job you interviewed for. Sometimes you want to let the employer know right away how interested you are. The verbiage says the letter isn’t “binding.” So you eagerly sign on the dotted line. Everything looks great ... until it isn’t.
Attorney Ericka Adler, JD, LLM, a partner at Roetzel & Andress, a Chicago-based law firm that represents physicians and health care professionals nationwide, described her client who was in this predicament. The physician, a dermatologist, left a practice where she had been employed because she had received an “amazing” offer letter that included promises about her new work location, staffing, equipment, and hours. She signed and immediately gave notice to her previous employer.
“When she received the actual employment contract, none of those details from the offer letter – which is also called a letter of intent [LOI] – were included,” Ms. Adler told this news organization. The physician wanted to have the details from the LOI formally spelled out in the contract, but the employer refused.
“Basically, they said, ‘This is our standard contract and you’ll just have to trust us that we’ll keep our word. We meant what we said in the LOI, but we cannot include those details in the actual agreement because everyone has the same form of agreement.’ “ The physician decided to sign the contract and accept the position.
She contacted Ms. Adler after she had been at her new position for a month. “She had received none of the things they had promised her in the LOI,” Ms. Adler reported. “She lacked the NP and PA support, she lacked the equipment, she didn’t have enough exam rooms. As soon as she started, someone with whom she was sharing call coverage left, and she was expected to take over. The LOI had a cap on the amount of call she would be required to take, but that verbiage didn’t make it into the contract.”
Ms. Adler tried to address this issue with the employer. “We couldn’t say they had literally breached the agreement, but we did list the things that were mentioned in the LOI but on which they hadn’t delivered. We asked them to fix the issue within 10 days.”
The employer argued “that they didn’t have to fulfill anything that wasn’t spelled out in the contract, even if it was in the LOI. In fact, the contract specified clearly that the signed employment agreement was the only agreement and replaced any previous written or oral agreements between the parties.”
The dermatologist ultimately left the new position. “She might have been able to have a legal claim against the employer for breach or perhaps ‘detrimental reliance’ – meaning, she might have argued that she had been financially harmed due to the false promises made to her. But it would have been difficult and expensive for her to litigate the issue,” said Ms. Adler.
“It also didn’t seem like the physician could remain in the job and develop a positive work relationship with the employer, given that she felt betrayed and misled, and didn’t like the terms of employment, which didn’t match her needs or expectations,” said Ms. Adler.
She added that “most employers are not as unscrupulous and dishonest as this one was. But some employers do play on the fact that younger doctors – especially residents and fellows – tend to be trusting or feel they don’t have negotiation power. They’re often excited to get an offer and sign it without a second thought.”
That’s why she advises physicians to “review the terms of the LOI carefully and make sure you’re comfortable with them before signing it; but know that the real contract to negotiate will be the actual Employment Agreement.”
She also advises physicians not to give notice at their current place of employment until they’ve signed the final contract with the new employer.
On the same page?
Anu Murthy, JD, an attorney and associate contract review specialist at Contract Diagnostics, explained that the LOI is a document that the candidate receives after an interview but before a full contract. Sometimes, the LOI is preceded by a verbal or e-mailed offer, which is less formal.
“An LOI is sometimes called a Term Sheet or Memorandum of Understanding,“ Ms. Murthy told this news organization. “Typically, it lays out key provisions, such as compensation, initial term of the contract, location, and recruitment incentives.” Sometimes it includes mention of staffing, call schedule, malpractice, noncompete covenants, and other components of the position.
Justin Nabity, founder and CEO of Physicians Thrive, a physician financial advisory group, said that LOIs are “a way for employers to gauge a prospective employee’s level of interest.”
The employer “doesn’t want to send a contract with a lot of details before determining whether the candidate is really serious about the position, so the offer letter doesn’t show the whole picture,” Mr. Nabity told this news organization.
Dennis Hursh, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, agreed.
“Another way of putting it is that the employer wants to see whether the prospective employee is on the same page. The LOI will typically include some key components that will later appear in a more complete and formal contract, together with other topics and details. Agreeing to those key components signals that indeed you and the employer are in accord,” said Mr. Hursh.
But are you really on the same page with your prospective employer? And if you seem to be on the same page, and you sign the LOI, is that a guarantee that the employer will honor its terms?
Not necessarily, according to the experts. In fact, many LOIs contain some verbiage stating that the letter isn’t binding, which can be confusing. Others suggest that it is binding, but the candidate doesn’t realize that the letter isn’t a formal contract and that the contract may contain details not included in the LOI or may omit details mentioned in the LOI, as happened to Ms. Adler’s unfortunate client.
“One of the pitfalls I see is that doctors sign the LOI without recognizing whether it’s binding or nonbinding,” Ms. Murthy said. “If it’s binding, it creates a legal obligation on your part and could preclude you from further negotiation once you see the contract and feel you’d like to negotiate some of its terms.”
Binding letters are typically offered to candidates after some back-and-forth between the parties, and important terms have been agreed to, which can happen either verbally or via e-mail. Once these agreements have been reached, they’re summarized in a “binding” letter before being extended into a full contract.
“But even if you’ve agreed on the terms verbally, it’s still important to have someone more experienced review the offer letter before signing it,” Ms. Murthy said. “It’s important to understand the ‘legalese’ and what your rights and obligations are before agreeing to anything.”
And certainly, if you receive a binding LOI, you shouldn’t sign anything until you’re sure you’re comfortable with its contents and have more details.
Are “nonbinding” LOIs really not binding?
Even if the LOI is nonbinding, that doesn’t necessarily mean you can sign it and expect to negotiate later. “I see people tripped up when they sign the LOI, thinking they’ll negotiate later,” said Mr. Hursh. “They may not like the terms – for example, they think the compensation is too low – and they figure they’ll work it out at the contract stage, because the LOI is ‘not legally binding.’ “
But because the candidate signed the LOI, “the employer is under the impression that the compensation was acceptable, so now you’ve tied your hands – and the hands of any attorney you may consult down the road – to negotiate those terms.”
Mr. Hursh said he is often consulted by physicians who signed the contract “to get the ball rolling,” thinking that the LOI was “just a meaningless bureaucratic paper.” They need to understand “that the employer wants to make sure they’re in agreement on the basic points before getting into the details,” he said. “Large hospitals with in-house counsel may not want to use their legal department’s valuable time in redrafting terms they thought were acceptable to the candidate, and most practices don’t want to pay a lawyer to draft an LOI and then come back and say, ‘Actually, the physician wants more compensation.’ “
Mr. Nabity summarized: “The LOI is essentially a negotiation tactic to take some of the cards out of the hands of the doctor and commit him or her to something they’re not ready to commit to.” Employers may be playing on the sense of pressure and candidate’s fear that the job will slip through their fingers if they wait too long to sign. “But it’s better to wait longer at this stage before signing even a nonbinding LOI,” he said.
What to do before signing
So how should physicians relate to the LOI? Mr. Nabity advises “working through the details of the offer letter first, going through it carefully and identifying areas of concern, bearing in mind that employers never begin with their best offer.”
He pointed out that physicians “rarely know their value and usually don’t know how to work through the dynamics of compensation, call schedules, additional incentives, bonuses, and productivity,” so they need to be informed about these areas before signing anything.
Ms. Murthy recommended “going back and saying [to the prospective employer], ‘Thank you, but I need time to consider and evaluate this offer.’ Then, do some due diligence.”
At that point, you can hire an attorney to go over the offer, educate yourself about compensation benchmarks and what your worth actually is, or consult another trained professional or more experienced individual who can review the LOI before you sign it.
That’s what Dominique Cleveland, MD, a Texas-based ob.gyn., did when she received an LOI 5 years ago.
“The offer letter from the group practice contained a statement that the group wanted me to come on board, what the salary would be, and the time frame that would be covered in the contract,” she told this news organization. “It mentioned benefits and incentives and relocation, but it was only a short document – maybe one or two pages long.”
At the time that she received her LOI, Dr. Cleveland was completing her residency. She consulted experienced faculty members from her institution to find out whether the terms laid out in the LOI “were the norm and were reasonable.” She was “fairly certain” that the salary was low and this was confirmed by the faculty members she talked to. “So I felt comfortable asking for more [compensation],” she said.
The employer was receptive to her proposed changes, which were included in the more detailed contract that followed. “I can’t say there were any surprises per se in the contract because I had negotiated my salary after receiving the offer letter,” she said. She accepted the position and has been working there ever since.
Dr. Cleveland advises physicians “not to make a decision without speaking to someone who’s experienced and can help you compare what’s out there.”
She also encourages physicians to ask for what they want, whether it’s compensation or something else, such as call schedule or vacation time, without being afraid. “I’m a firm believer that you won’t know what you can get if you don’t ask for it,” she said.
Negotiation tips
Mr. Nabity recommended not agreeing to any terms until you are ready to enter into negotiation, recognizing that negotiation is an “art” that requires skill and training. “Either get trained in negotiation, perhaps taking courses to advocate for yourself – which is rare, and most doctors aren’t likely to do this – or go to a trained advocate, such as a lawyer, who can do so on your behalf.”
You might share your concerns with the person who interviewed you, with the person whose name is on the LOI, or with the recruiter who can advocate on your behalf, Ms. Murthy said. “You can reach out to the recruiter and say, ‘I really appreciate the opportunity, but there are some things in the offer letter I’d like to continue discussing.’ “
When you’re ready to negotiate, be sure to assemble all of your “asks” in a single document rather than going back to the prospective employer with “multiple individual questions multiple times,” Ms. Murthy advised. It’s more efficient and the employer or recruiter will appreciate that.
She also advised couching your request in language that expresses your appreciation for the offer and stating that you would like the agreement to serve the best interests of both parties. “Use open-ended language like that, and ask if it’s all right for you to send back some questions, ask for clarification, or share concerns.”
Most employers “will be fine with that,” Ms. Murthy said. “Most won’t say, ‘This is it, take it or leave it.’ If they do, that’s a red flag for you to reconsider whether you really want to work for this particular employer.”
Mr. Hursh suggested that if you choose to sign the LOI immediately, so as to rapidly let the prospective employer know of your interest, “you should add some type of qualification such as, ‘I’m signing this to express my interest, but accepting the position will be dependent upon a more thorough review of compensation benchmarks,’ for example.”
Mr. Nabity agreed: “You can add a handwritten note to the signed LOI expressing that you’re eager to move forward and proceed with the position, but it shouldn’t be construed as accepting the terms of the LOI until you’ve seen the full contract.
“Remember, health care can’t exist without doctors,” Mr. Nabity said. “Doctors are the star players and should go into the negotiation process recognizing their true worth.”
A version of this article appeared on Medscape.com.
You’ve just received an offer letter from that job you interviewed for. Sometimes you want to let the employer know right away how interested you are. The verbiage says the letter isn’t “binding.” So you eagerly sign on the dotted line. Everything looks great ... until it isn’t.
Attorney Ericka Adler, JD, LLM, a partner at Roetzel & Andress, a Chicago-based law firm that represents physicians and health care professionals nationwide, described her client who was in this predicament. The physician, a dermatologist, left a practice where she had been employed because she had received an “amazing” offer letter that included promises about her new work location, staffing, equipment, and hours. She signed and immediately gave notice to her previous employer.
“When she received the actual employment contract, none of those details from the offer letter – which is also called a letter of intent [LOI] – were included,” Ms. Adler told this news organization. The physician wanted to have the details from the LOI formally spelled out in the contract, but the employer refused.
“Basically, they said, ‘This is our standard contract and you’ll just have to trust us that we’ll keep our word. We meant what we said in the LOI, but we cannot include those details in the actual agreement because everyone has the same form of agreement.’ “ The physician decided to sign the contract and accept the position.
She contacted Ms. Adler after she had been at her new position for a month. “She had received none of the things they had promised her in the LOI,” Ms. Adler reported. “She lacked the NP and PA support, she lacked the equipment, she didn’t have enough exam rooms. As soon as she started, someone with whom she was sharing call coverage left, and she was expected to take over. The LOI had a cap on the amount of call she would be required to take, but that verbiage didn’t make it into the contract.”
Ms. Adler tried to address this issue with the employer. “We couldn’t say they had literally breached the agreement, but we did list the things that were mentioned in the LOI but on which they hadn’t delivered. We asked them to fix the issue within 10 days.”
The employer argued “that they didn’t have to fulfill anything that wasn’t spelled out in the contract, even if it was in the LOI. In fact, the contract specified clearly that the signed employment agreement was the only agreement and replaced any previous written or oral agreements between the parties.”
The dermatologist ultimately left the new position. “She might have been able to have a legal claim against the employer for breach or perhaps ‘detrimental reliance’ – meaning, she might have argued that she had been financially harmed due to the false promises made to her. But it would have been difficult and expensive for her to litigate the issue,” said Ms. Adler.
“It also didn’t seem like the physician could remain in the job and develop a positive work relationship with the employer, given that she felt betrayed and misled, and didn’t like the terms of employment, which didn’t match her needs or expectations,” said Ms. Adler.
She added that “most employers are not as unscrupulous and dishonest as this one was. But some employers do play on the fact that younger doctors – especially residents and fellows – tend to be trusting or feel they don’t have negotiation power. They’re often excited to get an offer and sign it without a second thought.”
That’s why she advises physicians to “review the terms of the LOI carefully and make sure you’re comfortable with them before signing it; but know that the real contract to negotiate will be the actual Employment Agreement.”
She also advises physicians not to give notice at their current place of employment until they’ve signed the final contract with the new employer.
On the same page?
Anu Murthy, JD, an attorney and associate contract review specialist at Contract Diagnostics, explained that the LOI is a document that the candidate receives after an interview but before a full contract. Sometimes, the LOI is preceded by a verbal or e-mailed offer, which is less formal.
“An LOI is sometimes called a Term Sheet or Memorandum of Understanding,“ Ms. Murthy told this news organization. “Typically, it lays out key provisions, such as compensation, initial term of the contract, location, and recruitment incentives.” Sometimes it includes mention of staffing, call schedule, malpractice, noncompete covenants, and other components of the position.
Justin Nabity, founder and CEO of Physicians Thrive, a physician financial advisory group, said that LOIs are “a way for employers to gauge a prospective employee’s level of interest.”
The employer “doesn’t want to send a contract with a lot of details before determining whether the candidate is really serious about the position, so the offer letter doesn’t show the whole picture,” Mr. Nabity told this news organization.
Dennis Hursh, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, agreed.
“Another way of putting it is that the employer wants to see whether the prospective employee is on the same page. The LOI will typically include some key components that will later appear in a more complete and formal contract, together with other topics and details. Agreeing to those key components signals that indeed you and the employer are in accord,” said Mr. Hursh.
But are you really on the same page with your prospective employer? And if you seem to be on the same page, and you sign the LOI, is that a guarantee that the employer will honor its terms?
Not necessarily, according to the experts. In fact, many LOIs contain some verbiage stating that the letter isn’t binding, which can be confusing. Others suggest that it is binding, but the candidate doesn’t realize that the letter isn’t a formal contract and that the contract may contain details not included in the LOI or may omit details mentioned in the LOI, as happened to Ms. Adler’s unfortunate client.
“One of the pitfalls I see is that doctors sign the LOI without recognizing whether it’s binding or nonbinding,” Ms. Murthy said. “If it’s binding, it creates a legal obligation on your part and could preclude you from further negotiation once you see the contract and feel you’d like to negotiate some of its terms.”
Binding letters are typically offered to candidates after some back-and-forth between the parties, and important terms have been agreed to, which can happen either verbally or via e-mail. Once these agreements have been reached, they’re summarized in a “binding” letter before being extended into a full contract.
“But even if you’ve agreed on the terms verbally, it’s still important to have someone more experienced review the offer letter before signing it,” Ms. Murthy said. “It’s important to understand the ‘legalese’ and what your rights and obligations are before agreeing to anything.”
And certainly, if you receive a binding LOI, you shouldn’t sign anything until you’re sure you’re comfortable with its contents and have more details.
Are “nonbinding” LOIs really not binding?
Even if the LOI is nonbinding, that doesn’t necessarily mean you can sign it and expect to negotiate later. “I see people tripped up when they sign the LOI, thinking they’ll negotiate later,” said Mr. Hursh. “They may not like the terms – for example, they think the compensation is too low – and they figure they’ll work it out at the contract stage, because the LOI is ‘not legally binding.’ “
But because the candidate signed the LOI, “the employer is under the impression that the compensation was acceptable, so now you’ve tied your hands – and the hands of any attorney you may consult down the road – to negotiate those terms.”
Mr. Hursh said he is often consulted by physicians who signed the contract “to get the ball rolling,” thinking that the LOI was “just a meaningless bureaucratic paper.” They need to understand “that the employer wants to make sure they’re in agreement on the basic points before getting into the details,” he said. “Large hospitals with in-house counsel may not want to use their legal department’s valuable time in redrafting terms they thought were acceptable to the candidate, and most practices don’t want to pay a lawyer to draft an LOI and then come back and say, ‘Actually, the physician wants more compensation.’ “
Mr. Nabity summarized: “The LOI is essentially a negotiation tactic to take some of the cards out of the hands of the doctor and commit him or her to something they’re not ready to commit to.” Employers may be playing on the sense of pressure and candidate’s fear that the job will slip through their fingers if they wait too long to sign. “But it’s better to wait longer at this stage before signing even a nonbinding LOI,” he said.
What to do before signing
So how should physicians relate to the LOI? Mr. Nabity advises “working through the details of the offer letter first, going through it carefully and identifying areas of concern, bearing in mind that employers never begin with their best offer.”
He pointed out that physicians “rarely know their value and usually don’t know how to work through the dynamics of compensation, call schedules, additional incentives, bonuses, and productivity,” so they need to be informed about these areas before signing anything.
Ms. Murthy recommended “going back and saying [to the prospective employer], ‘Thank you, but I need time to consider and evaluate this offer.’ Then, do some due diligence.”
At that point, you can hire an attorney to go over the offer, educate yourself about compensation benchmarks and what your worth actually is, or consult another trained professional or more experienced individual who can review the LOI before you sign it.
That’s what Dominique Cleveland, MD, a Texas-based ob.gyn., did when she received an LOI 5 years ago.
“The offer letter from the group practice contained a statement that the group wanted me to come on board, what the salary would be, and the time frame that would be covered in the contract,” she told this news organization. “It mentioned benefits and incentives and relocation, but it was only a short document – maybe one or two pages long.”
At the time that she received her LOI, Dr. Cleveland was completing her residency. She consulted experienced faculty members from her institution to find out whether the terms laid out in the LOI “were the norm and were reasonable.” She was “fairly certain” that the salary was low and this was confirmed by the faculty members she talked to. “So I felt comfortable asking for more [compensation],” she said.
The employer was receptive to her proposed changes, which were included in the more detailed contract that followed. “I can’t say there were any surprises per se in the contract because I had negotiated my salary after receiving the offer letter,” she said. She accepted the position and has been working there ever since.
Dr. Cleveland advises physicians “not to make a decision without speaking to someone who’s experienced and can help you compare what’s out there.”
She also encourages physicians to ask for what they want, whether it’s compensation or something else, such as call schedule or vacation time, without being afraid. “I’m a firm believer that you won’t know what you can get if you don’t ask for it,” she said.
Negotiation tips
Mr. Nabity recommended not agreeing to any terms until you are ready to enter into negotiation, recognizing that negotiation is an “art” that requires skill and training. “Either get trained in negotiation, perhaps taking courses to advocate for yourself – which is rare, and most doctors aren’t likely to do this – or go to a trained advocate, such as a lawyer, who can do so on your behalf.”
You might share your concerns with the person who interviewed you, with the person whose name is on the LOI, or with the recruiter who can advocate on your behalf, Ms. Murthy said. “You can reach out to the recruiter and say, ‘I really appreciate the opportunity, but there are some things in the offer letter I’d like to continue discussing.’ “
When you’re ready to negotiate, be sure to assemble all of your “asks” in a single document rather than going back to the prospective employer with “multiple individual questions multiple times,” Ms. Murthy advised. It’s more efficient and the employer or recruiter will appreciate that.
She also advised couching your request in language that expresses your appreciation for the offer and stating that you would like the agreement to serve the best interests of both parties. “Use open-ended language like that, and ask if it’s all right for you to send back some questions, ask for clarification, or share concerns.”
Most employers “will be fine with that,” Ms. Murthy said. “Most won’t say, ‘This is it, take it or leave it.’ If they do, that’s a red flag for you to reconsider whether you really want to work for this particular employer.”
Mr. Hursh suggested that if you choose to sign the LOI immediately, so as to rapidly let the prospective employer know of your interest, “you should add some type of qualification such as, ‘I’m signing this to express my interest, but accepting the position will be dependent upon a more thorough review of compensation benchmarks,’ for example.”
Mr. Nabity agreed: “You can add a handwritten note to the signed LOI expressing that you’re eager to move forward and proceed with the position, but it shouldn’t be construed as accepting the terms of the LOI until you’ve seen the full contract.
“Remember, health care can’t exist without doctors,” Mr. Nabity said. “Doctors are the star players and should go into the negotiation process recognizing their true worth.”
A version of this article appeared on Medscape.com.
Infographic: Careers that tempt doctors to leave medicine
In a recently published Medscape report, 26% of American physicians said they were considering a career away from practicing medicine, for various reasons. Becoming a teacher was one of the nonclinical careers that most enthused them. What were the others?
For more details, check out the Medscape Physicians and Nonclinical Careers Report 2023.
A version of this article first appeared on Medscape.com.
In a recently published Medscape report, 26% of American physicians said they were considering a career away from practicing medicine, for various reasons. Becoming a teacher was one of the nonclinical careers that most enthused them. What were the others?
For more details, check out the Medscape Physicians and Nonclinical Careers Report 2023.
A version of this article first appeared on Medscape.com.
In a recently published Medscape report, 26% of American physicians said they were considering a career away from practicing medicine, for various reasons. Becoming a teacher was one of the nonclinical careers that most enthused them. What were the others?
For more details, check out the Medscape Physicians and Nonclinical Careers Report 2023.
A version of this article first appeared on Medscape.com.
FDA panel voices concerns over 2 lymphoma accelerated approvals
At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.
“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.
Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.
The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.
Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.
Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.
The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.
The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.
For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.
At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.
“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
‘Dangerous precedent’
The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.
For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.
But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.
And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.
“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.
The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.
The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.
Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.
ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.
“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.
Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.
Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.
Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”
At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.
“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.
Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.
The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.
Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.
Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.
The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.
The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.
For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.
At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.
“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
‘Dangerous precedent’
The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.
For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.
But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.
And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.
“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.
The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.
The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.
Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.
ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.
“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.
Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.
Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.
Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”
At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.
“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.
Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.
The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.
Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.
Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.
The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.
The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.
For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.
At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.
“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
‘Dangerous precedent’
The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.
For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.
But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.
And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.
“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.
The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.
The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.
Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.
ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.
“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.
Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.
Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.
Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”