Cardiologist Martha Gulati, from the American Society for Preventive Cardiology, offers insight on the key findings in diabetes and heart disease presented at the 2022 annual meeting of the American College of Cardiology.  

First, Dr Gulati shares updates from the SCORED trial, which looked at SGLT2 inhibitors and cardiovascular and renal event reduction in patients with type 2 diabetes and chronic kidney disease.  

Next, she shares insight on CHAP, an important study about chronic hypertension in pregnancy. Researchers found that more aggressive blood pressure control reduced adverse pregnancy outcomes.  

She then discusses the SuperWIN trial, which looked at various types of educational interventions regarding heart-healthy diet provided in supermarkets. The goal of this study was to assess adherence to the DASH diet.  

Dr Gulati closes her report with the PROMPT-HF trial, which aimed at improving the use of guideline-directed medical therapy in outpatients with heart failure. 

--

President, American Society for Preventive Cardiology, Jacksonville, Florida 

Martha Gulati, MD, has disclosed no relevant financial relationships. 

Cardiologist Martha Gulati, from the American Society for Preventive Cardiology, offers insight on the key findings in diabetes and heart disease presented at the 2022 annual meeting of the American College of Cardiology.  

First, Dr Gulati shares updates from the SCORED trial, which looked at SGLT2 inhibitors and cardiovascular and renal event reduction in patients with type 2 diabetes and chronic kidney disease.  

Next, she shares insight on CHAP, an important study about chronic hypertension in pregnancy. Researchers found that more aggressive blood pressure control reduced adverse pregnancy outcomes.  

She then discusses the SuperWIN trial, which looked at various types of educational interventions regarding heart-healthy diet provided in supermarkets. The goal of this study was to assess adherence to the DASH diet.  

Dr Gulati closes her report with the PROMPT-HF trial, which aimed at improving the use of guideline-directed medical therapy in outpatients with heart failure. 

--

President, American Society for Preventive Cardiology, Jacksonville, Florida 

Martha Gulati, MD, has disclosed no relevant financial relationships. 

Cardiologist Martha Gulati, from the American Society for Preventive Cardiology, offers insight on the key findings in diabetes and heart disease presented at the 2022 annual meeting of the American College of Cardiology.  

First, Dr Gulati shares updates from the SCORED trial, which looked at SGLT2 inhibitors and cardiovascular and renal event reduction in patients with type 2 diabetes and chronic kidney disease.  

Next, she shares insight on CHAP, an important study about chronic hypertension in pregnancy. Researchers found that more aggressive blood pressure control reduced adverse pregnancy outcomes.  

She then discusses the SuperWIN trial, which looked at various types of educational interventions regarding heart-healthy diet provided in supermarkets. The goal of this study was to assess adherence to the DASH diet.  

Dr Gulati closes her report with the PROMPT-HF trial, which aimed at improving the use of guideline-directed medical therapy in outpatients with heart failure. 

--

President, American Society for Preventive Cardiology, Jacksonville, Florida 

Martha Gulati, MD, has disclosed no relevant financial relationships. 

Pregnancy termination for medical reasons had been part of the fabric of everyday health care in the United States since the Supreme Court’s 1973 Roe v. Wade decision, which the current high court overturned in a ruling announced on June 24.

That means many clinicians across specialties are entering uncharted territory with the country’s new patchwork of abortion legality. Some specialties, cardiology among them, may feel the impact more than others.

javi_indy/ Thinkstock

“Unfortunately,” Dr. Haythe said, “many of the states that are going to make or have made abortion illegal are not providing that kind of preconception counseling or good prenatal care to women.”

Cardiologists can provide such counseling to their female patients of childbearing age who have high-risk cardiac conditions, “but not everybody knows that they have a heart problem when they get pregnant, and not everybody is getting screened for heart problems when they’re of childbearing age,” Dr. Haythe said.

“Sometimes it’s not clear whether the problems could have been picked up until a woman is pregnant and has started to have symptoms.” For example, “a lot of women with poor access to health care have rheumatic heart disease. They may have no idea that they have severe aortic stenosis, and it’s not until their second trimester that they start to feel really short of breath.” Often that can be treated in the cath lab, “but again, that’s putting the woman and the baby at risk.”

Cardiologists in states where abortion is illegal will still present the option to their patients with high-risk pregnancies, noted Dr. Haythe. But the conversation may sound something like, “you are at very high risk, termination of the pregnancy takes that risk away, but you’ll have to find a state where it’s legal to do that.”

Dr. Park said such a situation, when abortion is recommended but locally unavailable, is much like any other in cardiology for which the patient may want a second opinion. If a center “doesn’t have the capability or the technology to offer a certain treatment, the patient can opt to seek another opinion at another center,” she said. “Patients will often travel out of state to get the care they need.”

A requirement for out-of-state travel to obtain abortions is likely to worsen socioeconomic disparities in health care, Dr. Bond observed, “because we know that those who are low-income won’t be able to afford that travel.”

Dr. Bond is cosignatory on a statement from the Association of Black Cardiologists (ABC) responding to the high court’s ruling in Dobbs v. Jackson. “This decision will isolate the poor, socioeconomically disadvantaged, and minority populations specifically, widening the already large gaps in health care for our most vulnerable communities,” it states.

“The loss of broad protections supporting the medical and often lifesaving procedure of abortions is likely to have a real impact on the maternal mortality rate, especially in those with congenital and/or acquired cardiovascular conditions where evidence-based guidelines advise at times on termination of such high-risk pregnancies.”

The ABC, it states, “believes that every woman, and every person, should be afforded the right to safe, accessible, legal, timely, patient-centered, equitable, and affordable health care.”

The American College of Cardiology (ACC) released a statement on the matter June 24, signed by its president, Edward T.A. Fry, MD, along with five former ACC presidents. “While the ACC has no official policy on abortion, clinical practice guidelines and other clinical guidance tools address the dangers of pregnancy in certain patient populations at higher risk of death or serious cardiac events.”

The college, it states, is “deeply concerned about the potential implications of the Supreme Court decision regarding Roe vs. Wade on the ability of patients and clinicians to engage in important shared discussions about maternal health, or to remove previously available health care options.”

Dr. Bond proposed that a “vocal stance” from medical societies involved in women’s health, “perhaps even a collective stance from our cardiovascular societies and our obstetrics societies,” would also perhaps reach “the masses of doctors in private practice who are dealing with these patients.”

A version of this article first appeared on Medscape.com.

Pregnancy termination for medical reasons had been part of the fabric of everyday health care in the United States since the Supreme Court’s 1973 Roe v. Wade decision, which the current high court overturned in a ruling announced on June 24.

That means many clinicians across specialties are entering uncharted territory with the country’s new patchwork of abortion legality. Some specialties, cardiology among them, may feel the impact more than others.

javi_indy/ Thinkstock

“Unfortunately,” Dr. Haythe said, “many of the states that are going to make or have made abortion illegal are not providing that kind of preconception counseling or good prenatal care to women.”

Cardiologists can provide such counseling to their female patients of childbearing age who have high-risk cardiac conditions, “but not everybody knows that they have a heart problem when they get pregnant, and not everybody is getting screened for heart problems when they’re of childbearing age,” Dr. Haythe said.

“Sometimes it’s not clear whether the problems could have been picked up until a woman is pregnant and has started to have symptoms.” For example, “a lot of women with poor access to health care have rheumatic heart disease. They may have no idea that they have severe aortic stenosis, and it’s not until their second trimester that they start to feel really short of breath.” Often that can be treated in the cath lab, “but again, that’s putting the woman and the baby at risk.”

Cardiologists in states where abortion is illegal will still present the option to their patients with high-risk pregnancies, noted Dr. Haythe. But the conversation may sound something like, “you are at very high risk, termination of the pregnancy takes that risk away, but you’ll have to find a state where it’s legal to do that.”

Dr. Park said such a situation, when abortion is recommended but locally unavailable, is much like any other in cardiology for which the patient may want a second opinion. If a center “doesn’t have the capability or the technology to offer a certain treatment, the patient can opt to seek another opinion at another center,” she said. “Patients will often travel out of state to get the care they need.”

A requirement for out-of-state travel to obtain abortions is likely to worsen socioeconomic disparities in health care, Dr. Bond observed, “because we know that those who are low-income won’t be able to afford that travel.”

Dr. Bond is cosignatory on a statement from the Association of Black Cardiologists (ABC) responding to the high court’s ruling in Dobbs v. Jackson. “This decision will isolate the poor, socioeconomically disadvantaged, and minority populations specifically, widening the already large gaps in health care for our most vulnerable communities,” it states.

“The loss of broad protections supporting the medical and often lifesaving procedure of abortions is likely to have a real impact on the maternal mortality rate, especially in those with congenital and/or acquired cardiovascular conditions where evidence-based guidelines advise at times on termination of such high-risk pregnancies.”

The ABC, it states, “believes that every woman, and every person, should be afforded the right to safe, accessible, legal, timely, patient-centered, equitable, and affordable health care.”

The American College of Cardiology (ACC) released a statement on the matter June 24, signed by its president, Edward T.A. Fry, MD, along with five former ACC presidents. “While the ACC has no official policy on abortion, clinical practice guidelines and other clinical guidance tools address the dangers of pregnancy in certain patient populations at higher risk of death or serious cardiac events.”

The college, it states, is “deeply concerned about the potential implications of the Supreme Court decision regarding Roe vs. Wade on the ability of patients and clinicians to engage in important shared discussions about maternal health, or to remove previously available health care options.”

Dr. Bond proposed that a “vocal stance” from medical societies involved in women’s health, “perhaps even a collective stance from our cardiovascular societies and our obstetrics societies,” would also perhaps reach “the masses of doctors in private practice who are dealing with these patients.”

A version of this article first appeared on Medscape.com.

Pregnancy termination for medical reasons had been part of the fabric of everyday health care in the United States since the Supreme Court’s 1973 Roe v. Wade decision, which the current high court overturned in a ruling announced on June 24.

That means many clinicians across specialties are entering uncharted territory with the country’s new patchwork of abortion legality. Some specialties, cardiology among them, may feel the impact more than others.

javi_indy/ Thinkstock

“Unfortunately,” Dr. Haythe said, “many of the states that are going to make or have made abortion illegal are not providing that kind of preconception counseling or good prenatal care to women.”

Cardiologists can provide such counseling to their female patients of childbearing age who have high-risk cardiac conditions, “but not everybody knows that they have a heart problem when they get pregnant, and not everybody is getting screened for heart problems when they’re of childbearing age,” Dr. Haythe said.

“Sometimes it’s not clear whether the problems could have been picked up until a woman is pregnant and has started to have symptoms.” For example, “a lot of women with poor access to health care have rheumatic heart disease. They may have no idea that they have severe aortic stenosis, and it’s not until their second trimester that they start to feel really short of breath.” Often that can be treated in the cath lab, “but again, that’s putting the woman and the baby at risk.”

Cardiologists in states where abortion is illegal will still present the option to their patients with high-risk pregnancies, noted Dr. Haythe. But the conversation may sound something like, “you are at very high risk, termination of the pregnancy takes that risk away, but you’ll have to find a state where it’s legal to do that.”

Dr. Park said such a situation, when abortion is recommended but locally unavailable, is much like any other in cardiology for which the patient may want a second opinion. If a center “doesn’t have the capability or the technology to offer a certain treatment, the patient can opt to seek another opinion at another center,” she said. “Patients will often travel out of state to get the care they need.”

A requirement for out-of-state travel to obtain abortions is likely to worsen socioeconomic disparities in health care, Dr. Bond observed, “because we know that those who are low-income won’t be able to afford that travel.”

Dr. Bond is cosignatory on a statement from the Association of Black Cardiologists (ABC) responding to the high court’s ruling in Dobbs v. Jackson. “This decision will isolate the poor, socioeconomically disadvantaged, and minority populations specifically, widening the already large gaps in health care for our most vulnerable communities,” it states.

“The loss of broad protections supporting the medical and often lifesaving procedure of abortions is likely to have a real impact on the maternal mortality rate, especially in those with congenital and/or acquired cardiovascular conditions where evidence-based guidelines advise at times on termination of such high-risk pregnancies.”

The ABC, it states, “believes that every woman, and every person, should be afforded the right to safe, accessible, legal, timely, patient-centered, equitable, and affordable health care.”

The American College of Cardiology (ACC) released a statement on the matter June 24, signed by its president, Edward T.A. Fry, MD, along with five former ACC presidents. “While the ACC has no official policy on abortion, clinical practice guidelines and other clinical guidance tools address the dangers of pregnancy in certain patient populations at higher risk of death or serious cardiac events.”

The college, it states, is “deeply concerned about the potential implications of the Supreme Court decision regarding Roe vs. Wade on the ability of patients and clinicians to engage in important shared discussions about maternal health, or to remove previously available health care options.”

Dr. Bond proposed that a “vocal stance” from medical societies involved in women’s health, “perhaps even a collective stance from our cardiovascular societies and our obstetrics societies,” would also perhaps reach “the masses of doctors in private practice who are dealing with these patients.”

A version of this article first appeared on Medscape.com.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

Upadacitinib may soon be used for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA) after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave it its stamp of approval.

AbbVie, the drug’s manufacturer, announced on June 27 that the committee approved the use on June 23. The recommendation to approve market authorization for upadacitinib for nr-axSpA now goes to the European Commission, which is expected to make a decision by the third quarter of 2022.

“The CHMP’s recommendation to approve upadacitinib for patients with nr-axSpA is an important milestone in providing a new treatment option to patients in need,” said Neil Gallagher, MD, vice president of development and chief medical officer of AbbVie. He noted that currently, there are few options to treat symptoms such as inflammation, back pain, and stiffness for these patients.

Officially, the new indication for upadacitinib (Rinvoq) 15 mg once daily is for the treatment of active nr-axSpA in adult patients with objective signs of inflammation, as indicated by elevated C-reactive protein and/or MRI, whose condition has responded inadequately to NSAIDs.

Upadacitinib is a selective Janus kinase (JAK) inhibitor that in human cellular assays preferentially inhibits signaling by JAK1 or JAK1/3.

In the European Union, upadacitinib is currently approved for use in patients with moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, and moderate to severe atopic dermatitis. In addition to these indications, it is approved in the United States for ulcerative colitis but not for nr-axSpA.

The committee based its decision on the results of the nr-axSpA study within the SELECT-AXIS-2 trial, recently reported at the European Alliance of Associations for Rheumatology (EULAR) 2022 annual meeting.

The nr-axSpA study met the primary endpoint of a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) and the first 12 of 14 ranked secondary endpoints, according to AbbVie.

The most commonly reported adverse reactions with upadacitinib 15 mg were upper respiratory tract infections, elevated blood creatine phosphokinase levels, elevated alanine transaminase levels, bronchitis, nausea, cough, elevated aspartate transaminase levels, and hypercholesterolemia. These occurred in 2% or more of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in clinical trials.

The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications, AbbVie said.

A version of this article first appeared on Medscape.com.

Upadacitinib may soon be used for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA) after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave it its stamp of approval.

AbbVie, the drug’s manufacturer, announced on June 27 that the committee approved the use on June 23. The recommendation to approve market authorization for upadacitinib for nr-axSpA now goes to the European Commission, which is expected to make a decision by the third quarter of 2022.

“The CHMP’s recommendation to approve upadacitinib for patients with nr-axSpA is an important milestone in providing a new treatment option to patients in need,” said Neil Gallagher, MD, vice president of development and chief medical officer of AbbVie. He noted that currently, there are few options to treat symptoms such as inflammation, back pain, and stiffness for these patients.

Officially, the new indication for upadacitinib (Rinvoq) 15 mg once daily is for the treatment of active nr-axSpA in adult patients with objective signs of inflammation, as indicated by elevated C-reactive protein and/or MRI, whose condition has responded inadequately to NSAIDs.

Upadacitinib is a selective Janus kinase (JAK) inhibitor that in human cellular assays preferentially inhibits signaling by JAK1 or JAK1/3.

In the European Union, upadacitinib is currently approved for use in patients with moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, and moderate to severe atopic dermatitis. In addition to these indications, it is approved in the United States for ulcerative colitis but not for nr-axSpA.

The committee based its decision on the results of the nr-axSpA study within the SELECT-AXIS-2 trial, recently reported at the European Alliance of Associations for Rheumatology (EULAR) 2022 annual meeting.

The nr-axSpA study met the primary endpoint of a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) and the first 12 of 14 ranked secondary endpoints, according to AbbVie.

The most commonly reported adverse reactions with upadacitinib 15 mg were upper respiratory tract infections, elevated blood creatine phosphokinase levels, elevated alanine transaminase levels, bronchitis, nausea, cough, elevated aspartate transaminase levels, and hypercholesterolemia. These occurred in 2% or more of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in clinical trials.

The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications, AbbVie said.

A version of this article first appeared on Medscape.com.

Upadacitinib may soon be used for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA) after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave it its stamp of approval.

AbbVie, the drug’s manufacturer, announced on June 27 that the committee approved the use on June 23. The recommendation to approve market authorization for upadacitinib for nr-axSpA now goes to the European Commission, which is expected to make a decision by the third quarter of 2022.

“The CHMP’s recommendation to approve upadacitinib for patients with nr-axSpA is an important milestone in providing a new treatment option to patients in need,” said Neil Gallagher, MD, vice president of development and chief medical officer of AbbVie. He noted that currently, there are few options to treat symptoms such as inflammation, back pain, and stiffness for these patients.

Officially, the new indication for upadacitinib (Rinvoq) 15 mg once daily is for the treatment of active nr-axSpA in adult patients with objective signs of inflammation, as indicated by elevated C-reactive protein and/or MRI, whose condition has responded inadequately to NSAIDs.

Upadacitinib is a selective Janus kinase (JAK) inhibitor that in human cellular assays preferentially inhibits signaling by JAK1 or JAK1/3.

In the European Union, upadacitinib is currently approved for use in patients with moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, and moderate to severe atopic dermatitis. In addition to these indications, it is approved in the United States for ulcerative colitis but not for nr-axSpA.

The committee based its decision on the results of the nr-axSpA study within the SELECT-AXIS-2 trial, recently reported at the European Alliance of Associations for Rheumatology (EULAR) 2022 annual meeting.

The nr-axSpA study met the primary endpoint of a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) and the first 12 of 14 ranked secondary endpoints, according to AbbVie.

The most commonly reported adverse reactions with upadacitinib 15 mg were upper respiratory tract infections, elevated blood creatine phosphokinase levels, elevated alanine transaminase levels, bronchitis, nausea, cough, elevated aspartate transaminase levels, and hypercholesterolemia. These occurred in 2% or more of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in clinical trials.

The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications, AbbVie said.

A version of this article first appeared on Medscape.com.

New cases of COVID-19 continue to drop among children, but the vaccination effort in those under age 5 years began with something less than a bang.

Data are available only for the first 2 weekdays after the final approval on Saturday, June 18, but they show that just 1,245 children aged 4 years and younger received the COVID vaccine on June 20 and June 21. In the first 2 days after their respective approvals, almost 99,000 children aged 5-11 years and over 675,000 children aged 12-15 were vaccinated, according to data from the Centers for Disease Control and Prevention. Children aged 0-4 years represent almost 6% of the overall population, compared with 8.7% for the 5- to 11-year-olds and 5.1% for those aged 12-15.

The recent decline in new cases over the past 4 weeks and the substantial decline since the Omicron surge could be a factor in the lack of response, but it is worth noting that the almost 68,000 new child cases reported in the past week, June 17-23, are “far higher than 1 year ago, June 24, 2021, when 8,400 child cases were reported,” the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report.

That total for June 17-23 was 19% lower than the previous week and down by 40% since new cases hit a spring peak of 112,000 in late May. Regionally, new cases were down in the Midwest, the South, and the West, the AAP/CHA report showed, but the Northeast saw a small increase, which could be a signal of things to come for the summer.

The decline in new cases, however, has not been accompanied by decreases in hospitalizations or emergency department visits. New admissions of children aged 0-17 with confirmed COVID were at 0.31 per 100,000 population on June 24 after reaching that level on June 15, so no drop-off has occurred yet but there are signs of leveling off, based on CDC data.

The ED visit rates have been fairly steady through June, although COVID-related visits were up to 3.4% of all ED visits on June 22 for children aged 0-11 years, after being below 3% for the first 2 weeks of the month. The rate for children aged 12-15 has been between 1.6% and 1.9% for the past 3 weeks and the rate for 16- and 17-year-olds has been hovering between 1.7% and 2.2% for most of June, after going as high as 2.7% in late May, the CDC said on its COVID Data Tracker.

[email protected]

New cases of COVID-19 continue to drop among children, but the vaccination effort in those under age 5 years began with something less than a bang.

Data are available only for the first 2 weekdays after the final approval on Saturday, June 18, but they show that just 1,245 children aged 4 years and younger received the COVID vaccine on June 20 and June 21. In the first 2 days after their respective approvals, almost 99,000 children aged 5-11 years and over 675,000 children aged 12-15 were vaccinated, according to data from the Centers for Disease Control and Prevention. Children aged 0-4 years represent almost 6% of the overall population, compared with 8.7% for the 5- to 11-year-olds and 5.1% for those aged 12-15.

The recent decline in new cases over the past 4 weeks and the substantial decline since the Omicron surge could be a factor in the lack of response, but it is worth noting that the almost 68,000 new child cases reported in the past week, June 17-23, are “far higher than 1 year ago, June 24, 2021, when 8,400 child cases were reported,” the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report.

That total for June 17-23 was 19% lower than the previous week and down by 40% since new cases hit a spring peak of 112,000 in late May. Regionally, new cases were down in the Midwest, the South, and the West, the AAP/CHA report showed, but the Northeast saw a small increase, which could be a signal of things to come for the summer.

The decline in new cases, however, has not been accompanied by decreases in hospitalizations or emergency department visits. New admissions of children aged 0-17 with confirmed COVID were at 0.31 per 100,000 population on June 24 after reaching that level on June 15, so no drop-off has occurred yet but there are signs of leveling off, based on CDC data.

The ED visit rates have been fairly steady through June, although COVID-related visits were up to 3.4% of all ED visits on June 22 for children aged 0-11 years, after being below 3% for the first 2 weeks of the month. The rate for children aged 12-15 has been between 1.6% and 1.9% for the past 3 weeks and the rate for 16- and 17-year-olds has been hovering between 1.7% and 2.2% for most of June, after going as high as 2.7% in late May, the CDC said on its COVID Data Tracker.

[email protected]

New cases of COVID-19 continue to drop among children, but the vaccination effort in those under age 5 years began with something less than a bang.

Data are available only for the first 2 weekdays after the final approval on Saturday, June 18, but they show that just 1,245 children aged 4 years and younger received the COVID vaccine on June 20 and June 21. In the first 2 days after their respective approvals, almost 99,000 children aged 5-11 years and over 675,000 children aged 12-15 were vaccinated, according to data from the Centers for Disease Control and Prevention. Children aged 0-4 years represent almost 6% of the overall population, compared with 8.7% for the 5- to 11-year-olds and 5.1% for those aged 12-15.

The recent decline in new cases over the past 4 weeks and the substantial decline since the Omicron surge could be a factor in the lack of response, but it is worth noting that the almost 68,000 new child cases reported in the past week, June 17-23, are “far higher than 1 year ago, June 24, 2021, when 8,400 child cases were reported,” the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report.

That total for June 17-23 was 19% lower than the previous week and down by 40% since new cases hit a spring peak of 112,000 in late May. Regionally, new cases were down in the Midwest, the South, and the West, the AAP/CHA report showed, but the Northeast saw a small increase, which could be a signal of things to come for the summer.

The decline in new cases, however, has not been accompanied by decreases in hospitalizations or emergency department visits. New admissions of children aged 0-17 with confirmed COVID were at 0.31 per 100,000 population on June 24 after reaching that level on June 15, so no drop-off has occurred yet but there are signs of leveling off, based on CDC data.

The ED visit rates have been fairly steady through June, although COVID-related visits were up to 3.4% of all ED visits on June 22 for children aged 0-11 years, after being below 3% for the first 2 weeks of the month. The rate for children aged 12-15 has been between 1.6% and 1.9% for the past 3 weeks and the rate for 16- and 17-year-olds has been hovering between 1.7% and 2.2% for most of June, after going as high as 2.7% in late May, the CDC said on its COVID Data Tracker.

[email protected]

The U.S. Food and Drug Administration has approved a supplemental indication for the combination phentermine and topiramate extended-release capsules (Qsymia, Vivus) in patients aged 12 years and older with obesity.

The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a supplemental indication for the combination phentermine and topiramate extended-release capsules (Qsymia, Vivus) in patients aged 12 years and older with obesity.

The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a supplemental indication for the combination phentermine and topiramate extended-release capsules (Qsymia, Vivus) in patients aged 12 years and older with obesity.

The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.

A version of this article first appeared on Medscape.com.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

New research shows that the metastatic spread of breast cancer occurs predominantly during sleep, a discovery the investigators called “striking and unexpected.”

“This has not been shown before [and] we were surprised, indeed,” Nicola Aceto, PhD, professor of molecular oncology, Swiss Federal Institute of Technology Zürich, said in an interview.

The findings carry potential implications for the timing of biopsy and treatment of metastasis-prone cancers, the authors said.

The study was published online in Nature. 

Circulating tumor cells (CTCs) are generally believed to shed constantly or following particular events such as surgery or physical activity; however, the processes that regulate tumor cell metastasis and how circadian rhythms may play into tumorigenesis remain unclear.

To better understand these processes, Dr. Aceto and colleagues collected blood samples from 30 women with breast cancer at 4:00 a.m. and 10:00 a.m. – times representing the body’s resting and active phases, respectively.

The researchers observed that more than 78% of all CTCs obtained were from samples taken during the resting phase.

This finding is astounding, Harrison Ball, a PhD candidate, and Sunitha Nagrath, PhD, with the University of Michigan, Ann Arbor, wrote in Nature News & Views .

Dr. Aceto and colleagues also found that CTCs generated at night divide more quickly and therefore have a higher potential to metastasize, compared with those generated during the day, which “are devoid of metastatic ability,” according to the authors, who obtained similar results in a series of mouse models.

The team also observed that key circadian rhythm hormones (such as melatonin, testosterone, and glucocorticoids) regulate CTC generation, and insulin promotes tumor cell proliferation in a time-dependent manner, suggesting a “need for time-controlled approaches for the characterization and treatment of breast cancer,” the authors wrote.
 

Practice changing?

Dr. Ball and Dr. Nagrath said the time-dependent nature of CTC dynamics could very well transform how cancer patients are assessed and treated.

“The data pointing to CTC proliferation and release during the rest phase suggest that doctors might need to become more conscious of when to administer specific treatments,” they wrote.

Both cautioned, however, that large clinical trials would be needed before any consideration of circadian rhythms is incorporated into standard practice. It’s also unclear whether these results in breast cancer hold true for other tumor types.

Mariana G. Figueiro, PhD, who was not involved in the research, agreed that, if studies confirm more metastatic spread at night, “there is an opportunity to treat patients at strategic times.”

Dr. Figueiro, of the Icahn School of Medicine at Mount Sinai, New York, also saw a potential impact on the timing of blood draws. “I think tightening up on how people do biopsies and bloodwork based on circadian time is important.”

Marleen Meyers, MD, agreed that these findings could have many clinical implications.

“The most obvious is that the time of day [that] treatment is administered may influence efficacy,” said Dr. Meyers, clinical professor of medicine at New York University Langone’s Perlmutter Cancer Center.

But, Dr. Meyers noted, the benefits of treating someone at night would need to be weighed against the downsides of interrupting a person’s normal sleep-wake cycle. “If this finding is clinically important it will be a challenge incorporating this into clinical care,” she said.

The study had no funding reported. Dr. Aceto is a cofounder and member of the board of PAGE Therapeutics, listed as an inventor in patent applications related to circulating tumor cells, a paid consultant for several companies, and a Novartis shareholder. One coauthor is a cofounder of PAGE Therapeutics. All other authors declare no competing interests. Dr. Meyers and Dr. Figueiro reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research shows that the metastatic spread of breast cancer occurs predominantly during sleep, a discovery the investigators called “striking and unexpected.”

“This has not been shown before [and] we were surprised, indeed,” Nicola Aceto, PhD, professor of molecular oncology, Swiss Federal Institute of Technology Zürich, said in an interview.

The findings carry potential implications for the timing of biopsy and treatment of metastasis-prone cancers, the authors said.

The study was published online in Nature. 

Circulating tumor cells (CTCs) are generally believed to shed constantly or following particular events such as surgery or physical activity; however, the processes that regulate tumor cell metastasis and how circadian rhythms may play into tumorigenesis remain unclear.

To better understand these processes, Dr. Aceto and colleagues collected blood samples from 30 women with breast cancer at 4:00 a.m. and 10:00 a.m. – times representing the body’s resting and active phases, respectively.

The researchers observed that more than 78% of all CTCs obtained were from samples taken during the resting phase.

This finding is astounding, Harrison Ball, a PhD candidate, and Sunitha Nagrath, PhD, with the University of Michigan, Ann Arbor, wrote in Nature News & Views .

Dr. Aceto and colleagues also found that CTCs generated at night divide more quickly and therefore have a higher potential to metastasize, compared with those generated during the day, which “are devoid of metastatic ability,” according to the authors, who obtained similar results in a series of mouse models.

The team also observed that key circadian rhythm hormones (such as melatonin, testosterone, and glucocorticoids) regulate CTC generation, and insulin promotes tumor cell proliferation in a time-dependent manner, suggesting a “need for time-controlled approaches for the characterization and treatment of breast cancer,” the authors wrote.
 

Practice changing?

Dr. Ball and Dr. Nagrath said the time-dependent nature of CTC dynamics could very well transform how cancer patients are assessed and treated.

“The data pointing to CTC proliferation and release during the rest phase suggest that doctors might need to become more conscious of when to administer specific treatments,” they wrote.

Both cautioned, however, that large clinical trials would be needed before any consideration of circadian rhythms is incorporated into standard practice. It’s also unclear whether these results in breast cancer hold true for other tumor types.

Mariana G. Figueiro, PhD, who was not involved in the research, agreed that, if studies confirm more metastatic spread at night, “there is an opportunity to treat patients at strategic times.”

Dr. Figueiro, of the Icahn School of Medicine at Mount Sinai, New York, also saw a potential impact on the timing of blood draws. “I think tightening up on how people do biopsies and bloodwork based on circadian time is important.”

Marleen Meyers, MD, agreed that these findings could have many clinical implications.

“The most obvious is that the time of day [that] treatment is administered may influence efficacy,” said Dr. Meyers, clinical professor of medicine at New York University Langone’s Perlmutter Cancer Center.

But, Dr. Meyers noted, the benefits of treating someone at night would need to be weighed against the downsides of interrupting a person’s normal sleep-wake cycle. “If this finding is clinically important it will be a challenge incorporating this into clinical care,” she said.

The study had no funding reported. Dr. Aceto is a cofounder and member of the board of PAGE Therapeutics, listed as an inventor in patent applications related to circulating tumor cells, a paid consultant for several companies, and a Novartis shareholder. One coauthor is a cofounder of PAGE Therapeutics. All other authors declare no competing interests. Dr. Meyers and Dr. Figueiro reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

New research shows that the metastatic spread of breast cancer occurs predominantly during sleep, a discovery the investigators called “striking and unexpected.”

“This has not been shown before [and] we were surprised, indeed,” Nicola Aceto, PhD, professor of molecular oncology, Swiss Federal Institute of Technology Zürich, said in an interview.

The findings carry potential implications for the timing of biopsy and treatment of metastasis-prone cancers, the authors said.

The study was published online in Nature. 

Circulating tumor cells (CTCs) are generally believed to shed constantly or following particular events such as surgery or physical activity; however, the processes that regulate tumor cell metastasis and how circadian rhythms may play into tumorigenesis remain unclear.

To better understand these processes, Dr. Aceto and colleagues collected blood samples from 30 women with breast cancer at 4:00 a.m. and 10:00 a.m. – times representing the body’s resting and active phases, respectively.

The researchers observed that more than 78% of all CTCs obtained were from samples taken during the resting phase.

This finding is astounding, Harrison Ball, a PhD candidate, and Sunitha Nagrath, PhD, with the University of Michigan, Ann Arbor, wrote in Nature News & Views .

Dr. Aceto and colleagues also found that CTCs generated at night divide more quickly and therefore have a higher potential to metastasize, compared with those generated during the day, which “are devoid of metastatic ability,” according to the authors, who obtained similar results in a series of mouse models.

The team also observed that key circadian rhythm hormones (such as melatonin, testosterone, and glucocorticoids) regulate CTC generation, and insulin promotes tumor cell proliferation in a time-dependent manner, suggesting a “need for time-controlled approaches for the characterization and treatment of breast cancer,” the authors wrote.
 

Practice changing?

Dr. Ball and Dr. Nagrath said the time-dependent nature of CTC dynamics could very well transform how cancer patients are assessed and treated.

“The data pointing to CTC proliferation and release during the rest phase suggest that doctors might need to become more conscious of when to administer specific treatments,” they wrote.

Both cautioned, however, that large clinical trials would be needed before any consideration of circadian rhythms is incorporated into standard practice. It’s also unclear whether these results in breast cancer hold true for other tumor types.

Mariana G. Figueiro, PhD, who was not involved in the research, agreed that, if studies confirm more metastatic spread at night, “there is an opportunity to treat patients at strategic times.”

Dr. Figueiro, of the Icahn School of Medicine at Mount Sinai, New York, also saw a potential impact on the timing of blood draws. “I think tightening up on how people do biopsies and bloodwork based on circadian time is important.”

Marleen Meyers, MD, agreed that these findings could have many clinical implications.

“The most obvious is that the time of day [that] treatment is administered may influence efficacy,” said Dr. Meyers, clinical professor of medicine at New York University Langone’s Perlmutter Cancer Center.

But, Dr. Meyers noted, the benefits of treating someone at night would need to be weighed against the downsides of interrupting a person’s normal sleep-wake cycle. “If this finding is clinically important it will be a challenge incorporating this into clinical care,” she said.

The study had no funding reported. Dr. Aceto is a cofounder and member of the board of PAGE Therapeutics, listed as an inventor in patent applications related to circulating tumor cells, a paid consultant for several companies, and a Novartis shareholder. One coauthor is a cofounder of PAGE Therapeutics. All other authors declare no competing interests. Dr. Meyers and Dr. Figueiro reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Hydroxychloroquine should be initiated with caution in older patients with rheumatoid arthritis who also have heart failure or are at risk for it, say the authors of a study suggesting that the drug could increase their risk for major adverse cardiovascular events (MACE), compared with methotrexate.

A cohort study published online in the Journal of the American College of Cardiology looked at outcomes in 54,462 patients with RA aged 65 years or older and not previously treated with disease-modifying antirheumatic drugs. Half were initiated on methotrexate and half on hydroxychloroquine, making 27,231 propensity-matched pairs.

Across the entire cohort, hydroxychloroquine was not associated with a higher risk for sudden cardiac arrest, ventricular arrhythmia, or MACE, compared with methotrexate. When broken down into individual cardiovascular events, the data suggested a statistically significant 17% increase in the risk for cardiovascular mortality and 10% increase in all-cause mortality with hydroxychloroquine, although there were no differences in the risks for myocardial infarction or stroke.

However, a subgroup analysis revealed a significant 30% increase in the risk for MACE among patients starting hydroxychloroquine who also had a history of heart failure, compared with patients taking methotrexate. The researchers found no difference between the two drugs in patients without a history of heart failure. The study also suggested an overall 41% increase in the risk for hospitalization with heart failure with hydroxychloroquine, regardless of heart failure history.

Hydroxychloroquine was also associated with a 34% increase in the risk for cardiovascular mortality, a 22% increase in the risk for all-cause mortality, and a 74% increase in the risk for MI.

The lead author of the study, Elvira D’Andrea, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, said that hydroxychloroquine is used as a first-line treatment for RA, but there was limited evidence on its cardiovascular risks. The pandemic in particular shined a spotlight on these concerns and prompted the researchers to extend their original prepandemic study to encompass additional cardiovascular outcomes.

“The emerging concerns on its cardiovascular safety in early 2020 has led the rheumatological community, and patients regularly taking hydroxychloroquine for rheumatoid arthritis, to confusion,” Dr. D’Andrea said in an interview.

She advised that clinicians be cautious when initiating hydroxychloroquine in older patients with existing heart failure or who have risk factors for it. “Although heart failure is a known concern for hydroxychloroquine use, these findings helped to clarify the relationship between the use of hydroxychloroquine or methotrexate and heart failure. Clinicians should pay careful attention to clinical manifestations of cardiomyopathy or heart failure in older patients with rheumatoid arthritis treated with hydroxychloroquine.”

Hydroxychloroquine is associated with cardiotoxicity, particularly cardiomyopathy, which may help precipitate MACE or heart failure exacerbations in patients who already have deterioration of their cardiac tissue, the authors suggested.

Short follow-up period leaves risk attribution under question

In an accompanying editorial, Elizabeth Blair Solow, MD, and Bonnie L. Bermas, MD, of the University of Texas Southwestern Medical Center, Dallas, commented that the lack of an increased risk for arrhythmic events or MACE in the overall cohort taking hydroxychloroquine was reassuring. They also suggested the subgroup analysis findings among patients with preexisting heart failure were still “exploratory and hypothesis-generating” and should be interpreted with caution.

They noted that the follow-up time of the study was relatively short – a median of 209 days – given that hydroxychloroquine does not reach a steady-state level for 6 months.

“Evidence to date suggests cardiomyopathy from HCQ [hydroxychloroquine] takes years to develop, many months beyond the exposures described here, bringing into question as to whether HCQ itself increased HF hospitalizations,” the editorialists wrote.

The editorial also raised the question of whether the association observed in the study was related to a possible cardioprotective effect of methotrexate, given that previous studies have suggested this effect in older patients with RA.

The study authors did an exploratory analysis comparing hydroxychloroquine with sulfasalazine, which appeared to support their main findings of a possible cardiovascular effect of hydroxychloroquine. However, they qualified this by pointing out that the analysis involved small numbers of patients.

Senior investigator Seoyoung C. Kim, MD, ScD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, also noted that the study only looked at outcomes in patients aged 65 years and older.

“It would be clinically important to further examine the cardiovascular safety of hydroxychloroquine versus methotrexate in a younger population with rheumatic conditions,” she said.

The study was supported by the National Institutes of Health, Brigham and Women’s Hospital, and Harvard Medical School. Four authors declared unrelated research grants from the pharmaceutical sector, with one also declaring stock options and consulting work with the pharmaceutical sector. No other conflicts of interest were declared.

A version of this article first appeared on Medscape.com.

Hydroxychloroquine should be initiated with caution in older patients with rheumatoid arthritis who also have heart failure or are at risk for it, say the authors of a study suggesting that the drug could increase their risk for major adverse cardiovascular events (MACE), compared with methotrexate.

A cohort study published online in the Journal of the American College of Cardiology looked at outcomes in 54,462 patients with RA aged 65 years or older and not previously treated with disease-modifying antirheumatic drugs. Half were initiated on methotrexate and half on hydroxychloroquine, making 27,231 propensity-matched pairs.

Across the entire cohort, hydroxychloroquine was not associated with a higher risk for sudden cardiac arrest, ventricular arrhythmia, or MACE, compared with methotrexate. When broken down into individual cardiovascular events, the data suggested a statistically significant 17% increase in the risk for cardiovascular mortality and 10% increase in all-cause mortality with hydroxychloroquine, although there were no differences in the risks for myocardial infarction or stroke.

However, a subgroup analysis revealed a significant 30% increase in the risk for MACE among patients starting hydroxychloroquine who also had a history of heart failure, compared with patients taking methotrexate. The researchers found no difference between the two drugs in patients without a history of heart failure. The study also suggested an overall 41% increase in the risk for hospitalization with heart failure with hydroxychloroquine, regardless of heart failure history.

Hydroxychloroquine was also associated with a 34% increase in the risk for cardiovascular mortality, a 22% increase in the risk for all-cause mortality, and a 74% increase in the risk for MI.

The lead author of the study, Elvira D’Andrea, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, said that hydroxychloroquine is used as a first-line treatment for RA, but there was limited evidence on its cardiovascular risks. The pandemic in particular shined a spotlight on these concerns and prompted the researchers to extend their original prepandemic study to encompass additional cardiovascular outcomes.

“The emerging concerns on its cardiovascular safety in early 2020 has led the rheumatological community, and patients regularly taking hydroxychloroquine for rheumatoid arthritis, to confusion,” Dr. D’Andrea said in an interview.

She advised that clinicians be cautious when initiating hydroxychloroquine in older patients with existing heart failure or who have risk factors for it. “Although heart failure is a known concern for hydroxychloroquine use, these findings helped to clarify the relationship between the use of hydroxychloroquine or methotrexate and heart failure. Clinicians should pay careful attention to clinical manifestations of cardiomyopathy or heart failure in older patients with rheumatoid arthritis treated with hydroxychloroquine.”

Hydroxychloroquine is associated with cardiotoxicity, particularly cardiomyopathy, which may help precipitate MACE or heart failure exacerbations in patients who already have deterioration of their cardiac tissue, the authors suggested.

Short follow-up period leaves risk attribution under question

In an accompanying editorial, Elizabeth Blair Solow, MD, and Bonnie L. Bermas, MD, of the University of Texas Southwestern Medical Center, Dallas, commented that the lack of an increased risk for arrhythmic events or MACE in the overall cohort taking hydroxychloroquine was reassuring. They also suggested the subgroup analysis findings among patients with preexisting heart failure were still “exploratory and hypothesis-generating” and should be interpreted with caution.

They noted that the follow-up time of the study was relatively short – a median of 209 days – given that hydroxychloroquine does not reach a steady-state level for 6 months.

“Evidence to date suggests cardiomyopathy from HCQ [hydroxychloroquine] takes years to develop, many months beyond the exposures described here, bringing into question as to whether HCQ itself increased HF hospitalizations,” the editorialists wrote.

The editorial also raised the question of whether the association observed in the study was related to a possible cardioprotective effect of methotrexate, given that previous studies have suggested this effect in older patients with RA.

The study authors did an exploratory analysis comparing hydroxychloroquine with sulfasalazine, which appeared to support their main findings of a possible cardiovascular effect of hydroxychloroquine. However, they qualified this by pointing out that the analysis involved small numbers of patients.

Senior investigator Seoyoung C. Kim, MD, ScD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, also noted that the study only looked at outcomes in patients aged 65 years and older.

“It would be clinically important to further examine the cardiovascular safety of hydroxychloroquine versus methotrexate in a younger population with rheumatic conditions,” she said.

The study was supported by the National Institutes of Health, Brigham and Women’s Hospital, and Harvard Medical School. Four authors declared unrelated research grants from the pharmaceutical sector, with one also declaring stock options and consulting work with the pharmaceutical sector. No other conflicts of interest were declared.

A version of this article first appeared on Medscape.com.

Hydroxychloroquine should be initiated with caution in older patients with rheumatoid arthritis who also have heart failure or are at risk for it, say the authors of a study suggesting that the drug could increase their risk for major adverse cardiovascular events (MACE), compared with methotrexate.

A cohort study published online in the Journal of the American College of Cardiology looked at outcomes in 54,462 patients with RA aged 65 years or older and not previously treated with disease-modifying antirheumatic drugs. Half were initiated on methotrexate and half on hydroxychloroquine, making 27,231 propensity-matched pairs.

Across the entire cohort, hydroxychloroquine was not associated with a higher risk for sudden cardiac arrest, ventricular arrhythmia, or MACE, compared with methotrexate. When broken down into individual cardiovascular events, the data suggested a statistically significant 17% increase in the risk for cardiovascular mortality and 10% increase in all-cause mortality with hydroxychloroquine, although there were no differences in the risks for myocardial infarction or stroke.

However, a subgroup analysis revealed a significant 30% increase in the risk for MACE among patients starting hydroxychloroquine who also had a history of heart failure, compared with patients taking methotrexate. The researchers found no difference between the two drugs in patients without a history of heart failure. The study also suggested an overall 41% increase in the risk for hospitalization with heart failure with hydroxychloroquine, regardless of heart failure history.

Hydroxychloroquine was also associated with a 34% increase in the risk for cardiovascular mortality, a 22% increase in the risk for all-cause mortality, and a 74% increase in the risk for MI.

The lead author of the study, Elvira D’Andrea, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, said that hydroxychloroquine is used as a first-line treatment for RA, but there was limited evidence on its cardiovascular risks. The pandemic in particular shined a spotlight on these concerns and prompted the researchers to extend their original prepandemic study to encompass additional cardiovascular outcomes.

“The emerging concerns on its cardiovascular safety in early 2020 has led the rheumatological community, and patients regularly taking hydroxychloroquine for rheumatoid arthritis, to confusion,” Dr. D’Andrea said in an interview.

She advised that clinicians be cautious when initiating hydroxychloroquine in older patients with existing heart failure or who have risk factors for it. “Although heart failure is a known concern for hydroxychloroquine use, these findings helped to clarify the relationship between the use of hydroxychloroquine or methotrexate and heart failure. Clinicians should pay careful attention to clinical manifestations of cardiomyopathy or heart failure in older patients with rheumatoid arthritis treated with hydroxychloroquine.”

Hydroxychloroquine is associated with cardiotoxicity, particularly cardiomyopathy, which may help precipitate MACE or heart failure exacerbations in patients who already have deterioration of their cardiac tissue, the authors suggested.

Short follow-up period leaves risk attribution under question

In an accompanying editorial, Elizabeth Blair Solow, MD, and Bonnie L. Bermas, MD, of the University of Texas Southwestern Medical Center, Dallas, commented that the lack of an increased risk for arrhythmic events or MACE in the overall cohort taking hydroxychloroquine was reassuring. They also suggested the subgroup analysis findings among patients with preexisting heart failure were still “exploratory and hypothesis-generating” and should be interpreted with caution.

They noted that the follow-up time of the study was relatively short – a median of 209 days – given that hydroxychloroquine does not reach a steady-state level for 6 months.

“Evidence to date suggests cardiomyopathy from HCQ [hydroxychloroquine] takes years to develop, many months beyond the exposures described here, bringing into question as to whether HCQ itself increased HF hospitalizations,” the editorialists wrote.

The editorial also raised the question of whether the association observed in the study was related to a possible cardioprotective effect of methotrexate, given that previous studies have suggested this effect in older patients with RA.

The study authors did an exploratory analysis comparing hydroxychloroquine with sulfasalazine, which appeared to support their main findings of a possible cardiovascular effect of hydroxychloroquine. However, they qualified this by pointing out that the analysis involved small numbers of patients.

Senior investigator Seoyoung C. Kim, MD, ScD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, also noted that the study only looked at outcomes in patients aged 65 years and older.

“It would be clinically important to further examine the cardiovascular safety of hydroxychloroquine versus methotrexate in a younger population with rheumatic conditions,” she said.

The study was supported by the National Institutes of Health, Brigham and Women’s Hospital, and Harvard Medical School. Four authors declared unrelated research grants from the pharmaceutical sector, with one also declaring stock options and consulting work with the pharmaceutical sector. No other conflicts of interest were declared.

A version of this article first appeared on Medscape.com.

“I’m happy to contribute, but can you keep it anonymous? It’s a safety concern for me.”

On the day that the Supreme Court of the United States voted to strike down Roe v. Wade, I reached out to ob.gyn.s across the country, wanting to hear their reactions. My own response, like that of many doctors and women, was a visceral mix of anger, fear, and grief. I could only begin to imagine what the real experts on reproductive health care were going through.

When the first ob.gyn. responded to my request by expressing concerns around anonymity and personal safety, I was shocked – but I shouldn’t have been. For starters, there is already a storied history in this country of deadly attacks on abortion providers. David Gunn, MD; Barnett Slepian, MD; and George Tiller, MD, were all tragically murdered by antiabortion extremists. Then, there’s the existence of websites that keep logs of abortion providers and sometimes include photos, office contact information, or even home addresses.

The idea that any reproductive health care provider should have to think twice before offering their uniquely qualified opinion is profoundly disturbing, nearly as disturbing as the Supreme Court’s decision itself. But it’s more critical than ever for ob.gyn. voices to be amplified. This is the time for the healthcare community to rally around women’s health providers, to learn from them, to support them.

I asked ob.gyns. around the country to tell me what they were thinking and feeling on the day that Roe v. Wade was overturned. We agreed to keep the responses anonymous, given that several people expressed very understandable safety concerns.

Here’s what they had to say.
 

Tennessee ob.gyn.

“Today is an emotionally charged day for many people in this country, yet as I type this, with my ob.gyn. practice continuing around me, with my own almost 10-week pregnancy growing inside me, I feel quite blunted. I feel powerless to answer questions that are variations on ‘what next?’ or ‘how do we fight back?’ All I can think of is, I am so glad I do not have anyone on my schedule right now who does not want to be pregnant. But what will happen when that eventually changes? What about my colleagues who do have these patients on their schedules today? On a personal level, what if my prenatal genetic testing comes back abnormal? How can we so blatantly disregard a separation of church and state in this country? What ways will our government interfere with my practice next? My head is spinning, but I have to go see my next patient. She is a 25-year-old who is here to have an IUD placed, and that seems like the most important thing I can do today.”

South Carolina ob.gyn.

“I’m really scared. For my patients and for myself. I don’t know how to be a good ob.gyn. if my ability to offer safe and accessible abortion care is being threatened.”

Massachusetts ob.gyn.

“Livid and devastated and sad and terrified.” 

California family planning specialist

“The fact is that about one in four people with uteruses have had an abortion. I can’t tell you how many abortions I’ve provided for people who say that they don’t ‘believe’ in them or that they thought they’d never be in this situation. ... The fact is that pregnancy is a life-threatening condition in and of itself. I am an ob.gyn., a medical doctor, and an abortion provider. I will not stop providing abortions or helping people access them. I will dedicate my life to ensuring this right to bodily autonomy. Today I am devastated by the Supreme Court’s decision to force parenthood that will result in increased maternal mortality. I am broken, but I have never been more proud to be an abortion provider.”

New York ob.gyn.

“Grateful to live in a state and work for a hospital where I can provide abortions but feel terrible for so many people less fortunate and underserved.”

Illinois maternal-fetal medicine specialist

“As a maternal-fetal medicine specialist, I fear for my patients who are at the highest risk of pregnancy complications having their freedom taken away. For the tragic ultrasound findings that make a pregnant person carry a baby who will never live. For the patients who cannot use most forms of contraception because of their medical comorbidities. For the patients who are victims of intimate partner violence or under the influence of their culture, to continue having children regardless of their desires or their health. ... The freedom to prevent or end a pregnancy has enabled women to become independent and productive members of society on their own terms, with or without children. My heart breaks for the children and adolescents and adults who are being told they are second-class citizens, not worthy of making their own decisions. Politicians and Supreme Court justices are not in the clinic room, ultrasound suite, operating room, or delivery room when we have these intense conversations and pregnancy outcomes. They have no idea that of which they speak, and it’s unconscionable that they can determine what healthcare decisions my patients can make for their own lives. Nobody knows a body better than the patient themselves.”

Texas ob.gyn.

“In the area where I live and practice, it feels like guns and the people who use them have more legal rights than people with uteruses in desperate or life-threatening situations. I’m afraid for my personal safety as a women’s health practitioner in this political climate. I feel helpless, but I’m supposed to be able to help my patients.”

Missouri family planning specialist

“Abortion is an essential part of healthcare, and the only people that should get a say in it are the patient and their doctor. Period. The fact that some far-off court without any medical expertise can insert itself into individual medical decisions is oppressive and unethical.”

Georgia ob.gyn.

“I can’t even think straight right now. I feel sick. Honestly, I’ve been thinking about moving for a long time now. Somewhere where I would actually be able to offer good, comprehensive care.”

New York ob.gyn.

“I graduated from my ob.gyn. residency hours after the Roe v. Wade news broke. It was so emotional for me. I’ve dedicated my life to caring for people with uteruses and I will not let this heartbreaking news change that. I feel more committed than ever to women’s health. I fully plan to continue delivering babies, providing contraception, and performing abortions. I will be there to help women with desired pregnancies who received unspeakably bad news about fetal anomalies. I will be there to help women with life-threatening pregnancy complications before fetal viability. I will be there to help women with ectopic pregnancies. I will be there to help women who were raped or otherwise forced into pregnancy. I will always be there to help women.”

Dr. Croll is a neurovascular fellow at New York University Langone Health. She disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

“I’m happy to contribute, but can you keep it anonymous? It’s a safety concern for me.”

On the day that the Supreme Court of the United States voted to strike down Roe v. Wade, I reached out to ob.gyn.s across the country, wanting to hear their reactions. My own response, like that of many doctors and women, was a visceral mix of anger, fear, and grief. I could only begin to imagine what the real experts on reproductive health care were going through.

When the first ob.gyn. responded to my request by expressing concerns around anonymity and personal safety, I was shocked – but I shouldn’t have been. For starters, there is already a storied history in this country of deadly attacks on abortion providers. David Gunn, MD; Barnett Slepian, MD; and George Tiller, MD, were all tragically murdered by antiabortion extremists. Then, there’s the existence of websites that keep logs of abortion providers and sometimes include photos, office contact information, or even home addresses.

The idea that any reproductive health care provider should have to think twice before offering their uniquely qualified opinion is profoundly disturbing, nearly as disturbing as the Supreme Court’s decision itself. But it’s more critical than ever for ob.gyn. voices to be amplified. This is the time for the healthcare community to rally around women’s health providers, to learn from them, to support them.

I asked ob.gyns. around the country to tell me what they were thinking and feeling on the day that Roe v. Wade was overturned. We agreed to keep the responses anonymous, given that several people expressed very understandable safety concerns.

Here’s what they had to say.
 

Tennessee ob.gyn.

“Today is an emotionally charged day for many people in this country, yet as I type this, with my ob.gyn. practice continuing around me, with my own almost 10-week pregnancy growing inside me, I feel quite blunted. I feel powerless to answer questions that are variations on ‘what next?’ or ‘how do we fight back?’ All I can think of is, I am so glad I do not have anyone on my schedule right now who does not want to be pregnant. But what will happen when that eventually changes? What about my colleagues who do have these patients on their schedules today? On a personal level, what if my prenatal genetic testing comes back abnormal? How can we so blatantly disregard a separation of church and state in this country? What ways will our government interfere with my practice next? My head is spinning, but I have to go see my next patient. She is a 25-year-old who is here to have an IUD placed, and that seems like the most important thing I can do today.”

South Carolina ob.gyn.

“I’m really scared. For my patients and for myself. I don’t know how to be a good ob.gyn. if my ability to offer safe and accessible abortion care is being threatened.”

Massachusetts ob.gyn.

“Livid and devastated and sad and terrified.” 

California family planning specialist

“The fact is that about one in four people with uteruses have had an abortion. I can’t tell you how many abortions I’ve provided for people who say that they don’t ‘believe’ in them or that they thought they’d never be in this situation. ... The fact is that pregnancy is a life-threatening condition in and of itself. I am an ob.gyn., a medical doctor, and an abortion provider. I will not stop providing abortions or helping people access them. I will dedicate my life to ensuring this right to bodily autonomy. Today I am devastated by the Supreme Court’s decision to force parenthood that will result in increased maternal mortality. I am broken, but I have never been more proud to be an abortion provider.”

New York ob.gyn.

“Grateful to live in a state and work for a hospital where I can provide abortions but feel terrible for so many people less fortunate and underserved.”

Illinois maternal-fetal medicine specialist

“As a maternal-fetal medicine specialist, I fear for my patients who are at the highest risk of pregnancy complications having their freedom taken away. For the tragic ultrasound findings that make a pregnant person carry a baby who will never live. For the patients who cannot use most forms of contraception because of their medical comorbidities. For the patients who are victims of intimate partner violence or under the influence of their culture, to continue having children regardless of their desires or their health. ... The freedom to prevent or end a pregnancy has enabled women to become independent and productive members of society on their own terms, with or without children. My heart breaks for the children and adolescents and adults who are being told they are second-class citizens, not worthy of making their own decisions. Politicians and Supreme Court justices are not in the clinic room, ultrasound suite, operating room, or delivery room when we have these intense conversations and pregnancy outcomes. They have no idea that of which they speak, and it’s unconscionable that they can determine what healthcare decisions my patients can make for their own lives. Nobody knows a body better than the patient themselves.”

Texas ob.gyn.

“In the area where I live and practice, it feels like guns and the people who use them have more legal rights than people with uteruses in desperate or life-threatening situations. I’m afraid for my personal safety as a women’s health practitioner in this political climate. I feel helpless, but I’m supposed to be able to help my patients.”

Missouri family planning specialist

“Abortion is an essential part of healthcare, and the only people that should get a say in it are the patient and their doctor. Period. The fact that some far-off court without any medical expertise can insert itself into individual medical decisions is oppressive and unethical.”

Georgia ob.gyn.

“I can’t even think straight right now. I feel sick. Honestly, I’ve been thinking about moving for a long time now. Somewhere where I would actually be able to offer good, comprehensive care.”

New York ob.gyn.

“I graduated from my ob.gyn. residency hours after the Roe v. Wade news broke. It was so emotional for me. I’ve dedicated my life to caring for people with uteruses and I will not let this heartbreaking news change that. I feel more committed than ever to women’s health. I fully plan to continue delivering babies, providing contraception, and performing abortions. I will be there to help women with desired pregnancies who received unspeakably bad news about fetal anomalies. I will be there to help women with life-threatening pregnancy complications before fetal viability. I will be there to help women with ectopic pregnancies. I will be there to help women who were raped or otherwise forced into pregnancy. I will always be there to help women.”

Dr. Croll is a neurovascular fellow at New York University Langone Health. She disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

“I’m happy to contribute, but can you keep it anonymous? It’s a safety concern for me.”

On the day that the Supreme Court of the United States voted to strike down Roe v. Wade, I reached out to ob.gyn.s across the country, wanting to hear their reactions. My own response, like that of many doctors and women, was a visceral mix of anger, fear, and grief. I could only begin to imagine what the real experts on reproductive health care were going through.

When the first ob.gyn. responded to my request by expressing concerns around anonymity and personal safety, I was shocked – but I shouldn’t have been. For starters, there is already a storied history in this country of deadly attacks on abortion providers. David Gunn, MD; Barnett Slepian, MD; and George Tiller, MD, were all tragically murdered by antiabortion extremists. Then, there’s the existence of websites that keep logs of abortion providers and sometimes include photos, office contact information, or even home addresses.

The idea that any reproductive health care provider should have to think twice before offering their uniquely qualified opinion is profoundly disturbing, nearly as disturbing as the Supreme Court’s decision itself. But it’s more critical than ever for ob.gyn. voices to be amplified. This is the time for the healthcare community to rally around women’s health providers, to learn from them, to support them.

I asked ob.gyns. around the country to tell me what they were thinking and feeling on the day that Roe v. Wade was overturned. We agreed to keep the responses anonymous, given that several people expressed very understandable safety concerns.

Here’s what they had to say.
 

Tennessee ob.gyn.

“Today is an emotionally charged day for many people in this country, yet as I type this, with my ob.gyn. practice continuing around me, with my own almost 10-week pregnancy growing inside me, I feel quite blunted. I feel powerless to answer questions that are variations on ‘what next?’ or ‘how do we fight back?’ All I can think of is, I am so glad I do not have anyone on my schedule right now who does not want to be pregnant. But what will happen when that eventually changes? What about my colleagues who do have these patients on their schedules today? On a personal level, what if my prenatal genetic testing comes back abnormal? How can we so blatantly disregard a separation of church and state in this country? What ways will our government interfere with my practice next? My head is spinning, but I have to go see my next patient. She is a 25-year-old who is here to have an IUD placed, and that seems like the most important thing I can do today.”

South Carolina ob.gyn.

“I’m really scared. For my patients and for myself. I don’t know how to be a good ob.gyn. if my ability to offer safe and accessible abortion care is being threatened.”

Massachusetts ob.gyn.

“Livid and devastated and sad and terrified.” 

California family planning specialist

“The fact is that about one in four people with uteruses have had an abortion. I can’t tell you how many abortions I’ve provided for people who say that they don’t ‘believe’ in them or that they thought they’d never be in this situation. ... The fact is that pregnancy is a life-threatening condition in and of itself. I am an ob.gyn., a medical doctor, and an abortion provider. I will not stop providing abortions or helping people access them. I will dedicate my life to ensuring this right to bodily autonomy. Today I am devastated by the Supreme Court’s decision to force parenthood that will result in increased maternal mortality. I am broken, but I have never been more proud to be an abortion provider.”

New York ob.gyn.

“Grateful to live in a state and work for a hospital where I can provide abortions but feel terrible for so many people less fortunate and underserved.”

Illinois maternal-fetal medicine specialist

“As a maternal-fetal medicine specialist, I fear for my patients who are at the highest risk of pregnancy complications having their freedom taken away. For the tragic ultrasound findings that make a pregnant person carry a baby who will never live. For the patients who cannot use most forms of contraception because of their medical comorbidities. For the patients who are victims of intimate partner violence or under the influence of their culture, to continue having children regardless of their desires or their health. ... The freedom to prevent or end a pregnancy has enabled women to become independent and productive members of society on their own terms, with or without children. My heart breaks for the children and adolescents and adults who are being told they are second-class citizens, not worthy of making their own decisions. Politicians and Supreme Court justices are not in the clinic room, ultrasound suite, operating room, or delivery room when we have these intense conversations and pregnancy outcomes. They have no idea that of which they speak, and it’s unconscionable that they can determine what healthcare decisions my patients can make for their own lives. Nobody knows a body better than the patient themselves.”

Texas ob.gyn.

“In the area where I live and practice, it feels like guns and the people who use them have more legal rights than people with uteruses in desperate or life-threatening situations. I’m afraid for my personal safety as a women’s health practitioner in this political climate. I feel helpless, but I’m supposed to be able to help my patients.”

Missouri family planning specialist

“Abortion is an essential part of healthcare, and the only people that should get a say in it are the patient and their doctor. Period. The fact that some far-off court without any medical expertise can insert itself into individual medical decisions is oppressive and unethical.”

Georgia ob.gyn.

“I can’t even think straight right now. I feel sick. Honestly, I’ve been thinking about moving for a long time now. Somewhere where I would actually be able to offer good, comprehensive care.”

New York ob.gyn.

“I graduated from my ob.gyn. residency hours after the Roe v. Wade news broke. It was so emotional for me. I’ve dedicated my life to caring for people with uteruses and I will not let this heartbreaking news change that. I feel more committed than ever to women’s health. I fully plan to continue delivering babies, providing contraception, and performing abortions. I will be there to help women with desired pregnancies who received unspeakably bad news about fetal anomalies. I will be there to help women with life-threatening pregnancy complications before fetal viability. I will be there to help women with ectopic pregnancies. I will be there to help women who were raped or otherwise forced into pregnancy. I will always be there to help women.”

Dr. Croll is a neurovascular fellow at New York University Langone Health. She disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.