Hematology

After the American Academy of Pediatrics (AAP) began recommending vitamin K shots for newborns in 1961, infant bleeding as a result of vitamin K deficiency plummeted. The life-threatening disorder is so rare that some parents now question the need for injections to safeguard against it.

The situation amounts to “a failure of our success,” Ivan Hand, MD, a coauthor of a new AAP statement on vitamin K, told this news organization. Much like diseases that can be prevented with vaccines, vitamin K deficiency bleeding isn’t top of mind for parents. “It’s not something they’re aware of or afraid of,” he said.

In 2019, however, the AAP listed public education about the importance of the shots in its 10 most important priorities.

The policy update urges clinicians to bone up on the benefits and perceived risks of vitamin K deficiency, which is essential for clotting, and to “strongly advocate” for the shot in discussions with parents who may get competing messages from their social circles, the internet, and other health care professionals.

Dr. Hand, director of neonatology at NYC Health + Hospitals Kings County, Brooklyn, said clinicians walk a line between educating and alienating parents who favor natural birth processes. “We’re hoping that by talking to the families and answering their questions and explaining the risks, parents will accept vitamin K as a necessary treatment for their babies,” he said.

Vitamin K does not easily pass through the placenta and is not plentiful in breast milk, the preferred nutrition source for newborns. It takes months for babies to build their stores through food and gut bacteria.

Infants who do not receive vitamin K at birth are 81 times more likely to develop late-onset vitamin K deficiency bleeding, which occurs a week to 6 months after birth, according to the Centers for Disease Control and Prevention. One in five babies with the disorder dies, and about half have bleeding in the skull that can lead to brain damage.
 

New dosing for premature infants

The AAP’s new statement, published in the journal Pediatrics, reaffirms the administration of a 1-mg intramuscular dose for infants weighing more than 1,500 grams, or about 3 lb 5 oz, within 6 hours of birth. For premature infants who weigh less, the guidance recommends an intramuscular dose of 0.3 to 0.5 mg/kg.

The group notes that oral preparations of vitamin K have proven less effective because of malabsorption and challenges with adhering to dosing regimens.

The document also warns that breastfed babies can experience vitamin K deficiency bleeding even if they have received the shot, because concentration of vitamin K often wanes before a baby starts eating solid food. The disorder “should be considered when evaluating bleeding in the first 6 months of life, even in infants who received prophylaxis, and especially in exclusively breastfed infants,” it states.

Accounts of parental refusals date back to 2013, when the CDC reported four cases of deficiency bleeding in Tennessee. The infants’ parents said they declined vitamin K because they worried about increased risk of leukemia, thought the injection was unnecessary, or wanted to minimize the baby’s exposure to “toxins.” Leukemia concern stemmed from a 1992 report linking vitamin K to childhood cancer, an association that did not hold up in subsequent studies.

More recent research has documented parental concerns about preservatives and injection pain as well as distrust of medical and public health authorities. Some parents have been accused of neglect for refusing to allow their babies to receive the shots.  

Phoebe Danziger, MD, a pediatrician and writer in rural Michigan who has studied parental refusal of standard-of-care interventions, called the document a “welcome update” to the AAP’s last statement on the topic, in 2003. She told this news organization that lower dosing for premature infants may reassure some vitamin K–hesitant parents who worry about one-size-fits-all dosing.

But Dr. Danziger added that “evidence is lacking to support the claim that pediatricians can really move the needle on parental hesitancy and refusal simply through better listening and more persuasive counseling.” She said the AAP should do more to address “the broader social climate of mistrust and misinformation” that fuels refusal.

Dr. Hand and Dr. Danziger have disclosed no relevant financial relationships.

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

After the American Academy of Pediatrics (AAP) began recommending vitamin K shots for newborns in 1961, infant bleeding as a result of vitamin K deficiency plummeted. The life-threatening disorder is so rare that some parents now question the need for injections to safeguard against it.

The situation amounts to “a failure of our success,” Ivan Hand, MD, a coauthor of a new AAP statement on vitamin K, told this news organization. Much like diseases that can be prevented with vaccines, vitamin K deficiency bleeding isn’t top of mind for parents. “It’s not something they’re aware of or afraid of,” he said.

In 2019, however, the AAP listed public education about the importance of the shots in its 10 most important priorities.

The policy update urges clinicians to bone up on the benefits and perceived risks of vitamin K deficiency, which is essential for clotting, and to “strongly advocate” for the shot in discussions with parents who may get competing messages from their social circles, the internet, and other health care professionals.

Dr. Hand, director of neonatology at NYC Health + Hospitals Kings County, Brooklyn, said clinicians walk a line between educating and alienating parents who favor natural birth processes. “We’re hoping that by talking to the families and answering their questions and explaining the risks, parents will accept vitamin K as a necessary treatment for their babies,” he said.

Vitamin K does not easily pass through the placenta and is not plentiful in breast milk, the preferred nutrition source for newborns. It takes months for babies to build their stores through food and gut bacteria.

Infants who do not receive vitamin K at birth are 81 times more likely to develop late-onset vitamin K deficiency bleeding, which occurs a week to 6 months after birth, according to the Centers for Disease Control and Prevention. One in five babies with the disorder dies, and about half have bleeding in the skull that can lead to brain damage.
 

New dosing for premature infants

The AAP’s new statement, published in the journal Pediatrics, reaffirms the administration of a 1-mg intramuscular dose for infants weighing more than 1,500 grams, or about 3 lb 5 oz, within 6 hours of birth. For premature infants who weigh less, the guidance recommends an intramuscular dose of 0.3 to 0.5 mg/kg.

The group notes that oral preparations of vitamin K have proven less effective because of malabsorption and challenges with adhering to dosing regimens.

The document also warns that breastfed babies can experience vitamin K deficiency bleeding even if they have received the shot, because concentration of vitamin K often wanes before a baby starts eating solid food. The disorder “should be considered when evaluating bleeding in the first 6 months of life, even in infants who received prophylaxis, and especially in exclusively breastfed infants,” it states.

Accounts of parental refusals date back to 2013, when the CDC reported four cases of deficiency bleeding in Tennessee. The infants’ parents said they declined vitamin K because they worried about increased risk of leukemia, thought the injection was unnecessary, or wanted to minimize the baby’s exposure to “toxins.” Leukemia concern stemmed from a 1992 report linking vitamin K to childhood cancer, an association that did not hold up in subsequent studies.

More recent research has documented parental concerns about preservatives and injection pain as well as distrust of medical and public health authorities. Some parents have been accused of neglect for refusing to allow their babies to receive the shots.  

Phoebe Danziger, MD, a pediatrician and writer in rural Michigan who has studied parental refusal of standard-of-care interventions, called the document a “welcome update” to the AAP’s last statement on the topic, in 2003. She told this news organization that lower dosing for premature infants may reassure some vitamin K–hesitant parents who worry about one-size-fits-all dosing.

But Dr. Danziger added that “evidence is lacking to support the claim that pediatricians can really move the needle on parental hesitancy and refusal simply through better listening and more persuasive counseling.” She said the AAP should do more to address “the broader social climate of mistrust and misinformation” that fuels refusal.

Dr. Hand and Dr. Danziger have disclosed no relevant financial relationships.

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

After the American Academy of Pediatrics (AAP) began recommending vitamin K shots for newborns in 1961, infant bleeding as a result of vitamin K deficiency plummeted. The life-threatening disorder is so rare that some parents now question the need for injections to safeguard against it.

The situation amounts to “a failure of our success,” Ivan Hand, MD, a coauthor of a new AAP statement on vitamin K, told this news organization. Much like diseases that can be prevented with vaccines, vitamin K deficiency bleeding isn’t top of mind for parents. “It’s not something they’re aware of or afraid of,” he said.

In 2019, however, the AAP listed public education about the importance of the shots in its 10 most important priorities.

The policy update urges clinicians to bone up on the benefits and perceived risks of vitamin K deficiency, which is essential for clotting, and to “strongly advocate” for the shot in discussions with parents who may get competing messages from their social circles, the internet, and other health care professionals.

Dr. Hand, director of neonatology at NYC Health + Hospitals Kings County, Brooklyn, said clinicians walk a line between educating and alienating parents who favor natural birth processes. “We’re hoping that by talking to the families and answering their questions and explaining the risks, parents will accept vitamin K as a necessary treatment for their babies,” he said.

Vitamin K does not easily pass through the placenta and is not plentiful in breast milk, the preferred nutrition source for newborns. It takes months for babies to build their stores through food and gut bacteria.

Infants who do not receive vitamin K at birth are 81 times more likely to develop late-onset vitamin K deficiency bleeding, which occurs a week to 6 months after birth, according to the Centers for Disease Control and Prevention. One in five babies with the disorder dies, and about half have bleeding in the skull that can lead to brain damage.
 

New dosing for premature infants

The AAP’s new statement, published in the journal Pediatrics, reaffirms the administration of a 1-mg intramuscular dose for infants weighing more than 1,500 grams, or about 3 lb 5 oz, within 6 hours of birth. For premature infants who weigh less, the guidance recommends an intramuscular dose of 0.3 to 0.5 mg/kg.

The group notes that oral preparations of vitamin K have proven less effective because of malabsorption and challenges with adhering to dosing regimens.

The document also warns that breastfed babies can experience vitamin K deficiency bleeding even if they have received the shot, because concentration of vitamin K often wanes before a baby starts eating solid food. The disorder “should be considered when evaluating bleeding in the first 6 months of life, even in infants who received prophylaxis, and especially in exclusively breastfed infants,” it states.

Accounts of parental refusals date back to 2013, when the CDC reported four cases of deficiency bleeding in Tennessee. The infants’ parents said they declined vitamin K because they worried about increased risk of leukemia, thought the injection was unnecessary, or wanted to minimize the baby’s exposure to “toxins.” Leukemia concern stemmed from a 1992 report linking vitamin K to childhood cancer, an association that did not hold up in subsequent studies.

More recent research has documented parental concerns about preservatives and injection pain as well as distrust of medical and public health authorities. Some parents have been accused of neglect for refusing to allow their babies to receive the shots.  

Phoebe Danziger, MD, a pediatrician and writer in rural Michigan who has studied parental refusal of standard-of-care interventions, called the document a “welcome update” to the AAP’s last statement on the topic, in 2003. She told this news organization that lower dosing for premature infants may reassure some vitamin K–hesitant parents who worry about one-size-fits-all dosing.

But Dr. Danziger added that “evidence is lacking to support the claim that pediatricians can really move the needle on parental hesitancy and refusal simply through better listening and more persuasive counseling.” She said the AAP should do more to address “the broader social climate of mistrust and misinformation” that fuels refusal.

Dr. Hand and Dr. Danziger have disclosed no relevant financial relationships.

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

Four cases of acquired hemophilia A (AHA) identified after SARS-CoV-2 immunizations in a province in northern Italy caught the attention of researchers, who stressed that the cases are “unusual,” but not necessarily caused by vaccination.

“The overall number of cases observed does not allow ... any definitive conclusion over a possible causal relationship between SARS-CoV-2 vaccination and AHA, which would need more epidemiological and pharmacovigilance data about suspected vaccine-related adverse events,” Maria Cristina Leone, MD, of Azienda USL-IRCCS di Reggio Emilia (Italy), and colleagues reported online on Jan. 19, 2022, in a letter to the editors of Thrombosis Research.

The cases, observed in Reggio Emilia during the first 8 months of the vaccination campaign, occurred following receipt of mRNA BNT162b2 (Pfizer-BioNTech) vaccine. The AHA patients included two men and two women who ranged in age from 67 to 86 years.

During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine, the authors noted.

In the 5 years prior, from January 2016 to December 2020, only zero to two cases of AHA were observed each year, totaling five cases, or 1.9 cases per million people/year. These numbers are in line with the estimated incidence of the disease, the researchers noted, adding that “it should nonetheless be underlined that vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and stop the pandemic.”

However, they also wrote that the “unusual observation of four cases of a rare disease during the first months of the vaccination campaign in our province could be of interest and could sensitize health care personnel toward a possible complication of SARS-CoV-2 immunization.”

AHA is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation factor VIII. It is mainly associated with malignancy, autoimmune diseases, certain medications, and postnatal status.

“Sporadic AHA cases have been reported in association with infectious diseases or vaccinations,” the author noted, adding that associations between the BNT162b2 vaccine immune complications, including AHA, have also been reported by other authors.

Three of the four case patients in Reggio Emilia had “at least one common clinical association of AHA,” they found, suggesting that these associations could “reflect susceptibility to autoimmunity potentially triggered by vaccination.”

“Case four died due to complications from sepsis after being treated with steroid and rituximab, whereas the first three cases underwent clinical and laboratory remission after immunosuppressive therapy, and no relapse has been observed during follow-up, as in the other two cases reported: This could suggest a more favorable prognosis in respect to other non–vaccine-associated cases, but longer-term data are definitely needed,” they concluded.

The authors reported having no disclosures.

Four cases of acquired hemophilia A (AHA) identified after SARS-CoV-2 immunizations in a province in northern Italy caught the attention of researchers, who stressed that the cases are “unusual,” but not necessarily caused by vaccination.

“The overall number of cases observed does not allow ... any definitive conclusion over a possible causal relationship between SARS-CoV-2 vaccination and AHA, which would need more epidemiological and pharmacovigilance data about suspected vaccine-related adverse events,” Maria Cristina Leone, MD, of Azienda USL-IRCCS di Reggio Emilia (Italy), and colleagues reported online on Jan. 19, 2022, in a letter to the editors of Thrombosis Research.

The cases, observed in Reggio Emilia during the first 8 months of the vaccination campaign, occurred following receipt of mRNA BNT162b2 (Pfizer-BioNTech) vaccine. The AHA patients included two men and two women who ranged in age from 67 to 86 years.

During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine, the authors noted.

In the 5 years prior, from January 2016 to December 2020, only zero to two cases of AHA were observed each year, totaling five cases, or 1.9 cases per million people/year. These numbers are in line with the estimated incidence of the disease, the researchers noted, adding that “it should nonetheless be underlined that vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and stop the pandemic.”

However, they also wrote that the “unusual observation of four cases of a rare disease during the first months of the vaccination campaign in our province could be of interest and could sensitize health care personnel toward a possible complication of SARS-CoV-2 immunization.”

AHA is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation factor VIII. It is mainly associated with malignancy, autoimmune diseases, certain medications, and postnatal status.

“Sporadic AHA cases have been reported in association with infectious diseases or vaccinations,” the author noted, adding that associations between the BNT162b2 vaccine immune complications, including AHA, have also been reported by other authors.

Three of the four case patients in Reggio Emilia had “at least one common clinical association of AHA,” they found, suggesting that these associations could “reflect susceptibility to autoimmunity potentially triggered by vaccination.”

“Case four died due to complications from sepsis after being treated with steroid and rituximab, whereas the first three cases underwent clinical and laboratory remission after immunosuppressive therapy, and no relapse has been observed during follow-up, as in the other two cases reported: This could suggest a more favorable prognosis in respect to other non–vaccine-associated cases, but longer-term data are definitely needed,” they concluded.

The authors reported having no disclosures.

Four cases of acquired hemophilia A (AHA) identified after SARS-CoV-2 immunizations in a province in northern Italy caught the attention of researchers, who stressed that the cases are “unusual,” but not necessarily caused by vaccination.

“The overall number of cases observed does not allow ... any definitive conclusion over a possible causal relationship between SARS-CoV-2 vaccination and AHA, which would need more epidemiological and pharmacovigilance data about suspected vaccine-related adverse events,” Maria Cristina Leone, MD, of Azienda USL-IRCCS di Reggio Emilia (Italy), and colleagues reported online on Jan. 19, 2022, in a letter to the editors of Thrombosis Research.

The cases, observed in Reggio Emilia during the first 8 months of the vaccination campaign, occurred following receipt of mRNA BNT162b2 (Pfizer-BioNTech) vaccine. The AHA patients included two men and two women who ranged in age from 67 to 86 years.

During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine, the authors noted.

In the 5 years prior, from January 2016 to December 2020, only zero to two cases of AHA were observed each year, totaling five cases, or 1.9 cases per million people/year. These numbers are in line with the estimated incidence of the disease, the researchers noted, adding that “it should nonetheless be underlined that vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and stop the pandemic.”

However, they also wrote that the “unusual observation of four cases of a rare disease during the first months of the vaccination campaign in our province could be of interest and could sensitize health care personnel toward a possible complication of SARS-CoV-2 immunization.”

AHA is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation factor VIII. It is mainly associated with malignancy, autoimmune diseases, certain medications, and postnatal status.

“Sporadic AHA cases have been reported in association with infectious diseases or vaccinations,” the author noted, adding that associations between the BNT162b2 vaccine immune complications, including AHA, have also been reported by other authors.

Three of the four case patients in Reggio Emilia had “at least one common clinical association of AHA,” they found, suggesting that these associations could “reflect susceptibility to autoimmunity potentially triggered by vaccination.”

“Case four died due to complications from sepsis after being treated with steroid and rituximab, whereas the first three cases underwent clinical and laboratory remission after immunosuppressive therapy, and no relapse has been observed during follow-up, as in the other two cases reported: This could suggest a more favorable prognosis in respect to other non–vaccine-associated cases, but longer-term data are definitely needed,” they concluded.

The authors reported having no disclosures.

Researchers evaluating whether endometriosis is linked with preterm birth found no such association in a multicenter cohort study of more than 1300 women.

These new findings, which were published online in JAMA Network Open, suggest that changing monitoring strategies to prevent preterm birth for women with the disease may not be necessary.

The research team, led by Louis Marcellin, MD, PhD, with the department of obstetrics and gynecology at Université de Paris, also found that disease phenotype or whether the preterm birth was induced or spontaneous did not appear to alter the result.

Those results differ from previous research. Data on the phenotypes and their link with preterm birth have been scarce, but previous studies have shown the risk for preterm birth is more pronounced in women who have deep endometriosis than in women with ovarian endometriosis.

Dr. Marcellin said in an interview that “little is known about the impact of endometriosis on obstetric outcomes. In contrast to previous studies, we reported no differences in the risk for preterm delivery between women with endometriosis (34 of 470 [7.2%]) and those without endometriosis (53 of 881 [6.0%]), even when adjusted for multiple factors.”

The authors accounted for mother’s age, body mass index before pregnancy, birth country, number of times the woman had given birth, previous cesarean delivery, and history of preterm birth. After adjusting for potential confounders, endometriosis was not associated with preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.64-1.77).

The researchers found no differences among preterm births based on a mother’s endometriosis phenotype. Those phenotypes include Isolated superficial peritoneal endometriosis, ovarian endometrioma, and deep endometriosis.

“Monitoring pregnancy beyond the normal protocols or changing management strategies may not be warranted in cases of endometriosis,” Dr. Marcellin said.

More research on endometriosis’ potential link to birth outcomes is needed.

An expert not involved with the study said the new paper highlights important new avenues of research but should not be seen as the final word on the connection between endometriosis and preterm birth.

Of the 1,351 study participants (mean age, 32.9 years) who had a singleton delivery after 22 weeks’ gestation, 470 were assigned to the endometriosis group, and 881 were assigned to the control group.

The authors concluded that “pregnant women with endometriosis should not be considered to have an exceptionally high risk for preterm birth. However, further studies are needed to examine the potential for other adverse perinatal outcomes or specific but rare complications.”

Daniela Carusi, MD, said the difficulty with the study’s design is that “premature birth is not one problem or one disease.”

Many very different problems can all end with premature birth. Sometimes it’s an infection or inflammation or bleeding in the uterus or hypertension in the mother, for example, and all those things can lead to a preterm birth, she explained.

“This study inherently lumps all those things together,” said Dr. Carusi, who is director of surgical obstetrics and placental abnormalities in the department of obstetrics and gynecology at Brigham and Women’s Hospital, Boston. “It’s quite possible endometriosis can have a big impact in one of those areas and no impact in the other areas, but the study design wouldn’t be able to pick that up.”
 

Editorialists: Results challenge findings of previous studies

In an accompanying commentary, Liisu Saavalainen, MD, PhD, and Oskari Heikinheimo, MD, PhD, both with the department of obstetrics and gynecology, Helsinki University Hospital, wrote that several previous studies have suggested that women with endometriosis have a slightly higher risk for preterm birth.

Those studies were mostly retrospective and differed in the way they classified endometriosis and the way they selected patients, the editorialists write. Also, most women in these studies typically had subfertility, they added.

The study by Dr. Marcellin and colleagues differs from previous related research in that was prospective and assessed the risk for preterm delivery in women both with endometriosis and those without endometriosis from several maternity centers in France. The women with endometriosis were classified according to the severity of their disease.

The editorialists wrote: “The novel results by Marcellin et al. challenge the findings of most previous studies on this topic. These results are valuable and comforting. However, they are also likely to trigger new studies on the pregnancy risks associated with different types of endometriosis. That is good news.”

Dr. Carusi said the study was well done and included a notably large size. Further complimenting the research, she said it’s important to talk about this little-discussed pregnancy complication. There’s been much more focus for women with endometriosis and their physicians on getting pregnant and on talking about the length of their term.

The study leaves some things unanswered.

The study was funded by research grants from the French Ministry of Health and was sponsored by the Département de la Recherche Clinique et du Développement de l’Assistance Publique–Hôpitaux de Paris. Dr. Carusi reported no relevant financial relationships. One study coauthor reported receiving personal fees from Bioserinity and Ferring outside the submitted work. No other disclosures were reported.

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

Researchers evaluating whether endometriosis is linked with preterm birth found no such association in a multicenter cohort study of more than 1300 women.

These new findings, which were published online in JAMA Network Open, suggest that changing monitoring strategies to prevent preterm birth for women with the disease may not be necessary.

The research team, led by Louis Marcellin, MD, PhD, with the department of obstetrics and gynecology at Université de Paris, also found that disease phenotype or whether the preterm birth was induced or spontaneous did not appear to alter the result.

Those results differ from previous research. Data on the phenotypes and their link with preterm birth have been scarce, but previous studies have shown the risk for preterm birth is more pronounced in women who have deep endometriosis than in women with ovarian endometriosis.

Dr. Marcellin said in an interview that “little is known about the impact of endometriosis on obstetric outcomes. In contrast to previous studies, we reported no differences in the risk for preterm delivery between women with endometriosis (34 of 470 [7.2%]) and those without endometriosis (53 of 881 [6.0%]), even when adjusted for multiple factors.”

The authors accounted for mother’s age, body mass index before pregnancy, birth country, number of times the woman had given birth, previous cesarean delivery, and history of preterm birth. After adjusting for potential confounders, endometriosis was not associated with preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.64-1.77).

The researchers found no differences among preterm births based on a mother’s endometriosis phenotype. Those phenotypes include Isolated superficial peritoneal endometriosis, ovarian endometrioma, and deep endometriosis.

“Monitoring pregnancy beyond the normal protocols or changing management strategies may not be warranted in cases of endometriosis,” Dr. Marcellin said.

More research on endometriosis’ potential link to birth outcomes is needed.

An expert not involved with the study said the new paper highlights important new avenues of research but should not be seen as the final word on the connection between endometriosis and preterm birth.

Of the 1,351 study participants (mean age, 32.9 years) who had a singleton delivery after 22 weeks’ gestation, 470 were assigned to the endometriosis group, and 881 were assigned to the control group.

The authors concluded that “pregnant women with endometriosis should not be considered to have an exceptionally high risk for preterm birth. However, further studies are needed to examine the potential for other adverse perinatal outcomes or specific but rare complications.”

Daniela Carusi, MD, said the difficulty with the study’s design is that “premature birth is not one problem or one disease.”

Many very different problems can all end with premature birth. Sometimes it’s an infection or inflammation or bleeding in the uterus or hypertension in the mother, for example, and all those things can lead to a preterm birth, she explained.

“This study inherently lumps all those things together,” said Dr. Carusi, who is director of surgical obstetrics and placental abnormalities in the department of obstetrics and gynecology at Brigham and Women’s Hospital, Boston. “It’s quite possible endometriosis can have a big impact in one of those areas and no impact in the other areas, but the study design wouldn’t be able to pick that up.”
 

Editorialists: Results challenge findings of previous studies

In an accompanying commentary, Liisu Saavalainen, MD, PhD, and Oskari Heikinheimo, MD, PhD, both with the department of obstetrics and gynecology, Helsinki University Hospital, wrote that several previous studies have suggested that women with endometriosis have a slightly higher risk for preterm birth.

Those studies were mostly retrospective and differed in the way they classified endometriosis and the way they selected patients, the editorialists write. Also, most women in these studies typically had subfertility, they added.

The study by Dr. Marcellin and colleagues differs from previous related research in that was prospective and assessed the risk for preterm delivery in women both with endometriosis and those without endometriosis from several maternity centers in France. The women with endometriosis were classified according to the severity of their disease.

The editorialists wrote: “The novel results by Marcellin et al. challenge the findings of most previous studies on this topic. These results are valuable and comforting. However, they are also likely to trigger new studies on the pregnancy risks associated with different types of endometriosis. That is good news.”

Dr. Carusi said the study was well done and included a notably large size. Further complimenting the research, she said it’s important to talk about this little-discussed pregnancy complication. There’s been much more focus for women with endometriosis and their physicians on getting pregnant and on talking about the length of their term.

The study leaves some things unanswered.

The study was funded by research grants from the French Ministry of Health and was sponsored by the Département de la Recherche Clinique et du Développement de l’Assistance Publique–Hôpitaux de Paris. Dr. Carusi reported no relevant financial relationships. One study coauthor reported receiving personal fees from Bioserinity and Ferring outside the submitted work. No other disclosures were reported.

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

Researchers evaluating whether endometriosis is linked with preterm birth found no such association in a multicenter cohort study of more than 1300 women.

These new findings, which were published online in JAMA Network Open, suggest that changing monitoring strategies to prevent preterm birth for women with the disease may not be necessary.

The research team, led by Louis Marcellin, MD, PhD, with the department of obstetrics and gynecology at Université de Paris, also found that disease phenotype or whether the preterm birth was induced or spontaneous did not appear to alter the result.

Those results differ from previous research. Data on the phenotypes and their link with preterm birth have been scarce, but previous studies have shown the risk for preterm birth is more pronounced in women who have deep endometriosis than in women with ovarian endometriosis.

Dr. Marcellin said in an interview that “little is known about the impact of endometriosis on obstetric outcomes. In contrast to previous studies, we reported no differences in the risk for preterm delivery between women with endometriosis (34 of 470 [7.2%]) and those without endometriosis (53 of 881 [6.0%]), even when adjusted for multiple factors.”

The authors accounted for mother’s age, body mass index before pregnancy, birth country, number of times the woman had given birth, previous cesarean delivery, and history of preterm birth. After adjusting for potential confounders, endometriosis was not associated with preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.64-1.77).

The researchers found no differences among preterm births based on a mother’s endometriosis phenotype. Those phenotypes include Isolated superficial peritoneal endometriosis, ovarian endometrioma, and deep endometriosis.

“Monitoring pregnancy beyond the normal protocols or changing management strategies may not be warranted in cases of endometriosis,” Dr. Marcellin said.

More research on endometriosis’ potential link to birth outcomes is needed.

An expert not involved with the study said the new paper highlights important new avenues of research but should not be seen as the final word on the connection between endometriosis and preterm birth.

Of the 1,351 study participants (mean age, 32.9 years) who had a singleton delivery after 22 weeks’ gestation, 470 were assigned to the endometriosis group, and 881 were assigned to the control group.

The authors concluded that “pregnant women with endometriosis should not be considered to have an exceptionally high risk for preterm birth. However, further studies are needed to examine the potential for other adverse perinatal outcomes or specific but rare complications.”

Daniela Carusi, MD, said the difficulty with the study’s design is that “premature birth is not one problem or one disease.”

Many very different problems can all end with premature birth. Sometimes it’s an infection or inflammation or bleeding in the uterus or hypertension in the mother, for example, and all those things can lead to a preterm birth, she explained.

“This study inherently lumps all those things together,” said Dr. Carusi, who is director of surgical obstetrics and placental abnormalities in the department of obstetrics and gynecology at Brigham and Women’s Hospital, Boston. “It’s quite possible endometriosis can have a big impact in one of those areas and no impact in the other areas, but the study design wouldn’t be able to pick that up.”
 

Editorialists: Results challenge findings of previous studies

In an accompanying commentary, Liisu Saavalainen, MD, PhD, and Oskari Heikinheimo, MD, PhD, both with the department of obstetrics and gynecology, Helsinki University Hospital, wrote that several previous studies have suggested that women with endometriosis have a slightly higher risk for preterm birth.

Those studies were mostly retrospective and differed in the way they classified endometriosis and the way they selected patients, the editorialists write. Also, most women in these studies typically had subfertility, they added.

The study by Dr. Marcellin and colleagues differs from previous related research in that was prospective and assessed the risk for preterm delivery in women both with endometriosis and those without endometriosis from several maternity centers in France. The women with endometriosis were classified according to the severity of their disease.

The editorialists wrote: “The novel results by Marcellin et al. challenge the findings of most previous studies on this topic. These results are valuable and comforting. However, they are also likely to trigger new studies on the pregnancy risks associated with different types of endometriosis. That is good news.”

Dr. Carusi said the study was well done and included a notably large size. Further complimenting the research, she said it’s important to talk about this little-discussed pregnancy complication. There’s been much more focus for women with endometriosis and their physicians on getting pregnant and on talking about the length of their term.

The study leaves some things unanswered.

The study was funded by research grants from the French Ministry of Health and was sponsored by the Département de la Recherche Clinique et du Développement de l’Assistance Publique–Hôpitaux de Paris. Dr. Carusi reported no relevant financial relationships. One study coauthor reported receiving personal fees from Bioserinity and Ferring outside the submitted work. No other disclosures were reported.

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

Early, permanent discontinuation of venetoclax in the treatment of relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) is linked to shortened survival outcomes, but temporary interruption shows no impact on survival, underscoring the importance of preventing discontinuation.

“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.

Courtsey Memorial Sloan Kettering Cancer Center

“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.

Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.

Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).

The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).

Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).

Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).

The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.

However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.

“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.

“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.

Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”

The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.

Early, permanent discontinuation of venetoclax in the treatment of relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) is linked to shortened survival outcomes, but temporary interruption shows no impact on survival, underscoring the importance of preventing discontinuation.

“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.

Courtsey Memorial Sloan Kettering Cancer Center

“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.

Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.

Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).

The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).

Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).

Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).

The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.

However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.

“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.

“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.

Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”

The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.

Early, permanent discontinuation of venetoclax in the treatment of relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) is linked to shortened survival outcomes, but temporary interruption shows no impact on survival, underscoring the importance of preventing discontinuation.

“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.

Courtsey Memorial Sloan Kettering Cancer Center

“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.

Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.

Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).

The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).

Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).

Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).

The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.

However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.

“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.

“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.

Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”

The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.

Methylergonovine is often used to control severe bleeding immediately after cesarean deliveries. But a new study suggests that the ergot alkaloid agent could benefit these women if administered before delivery, researchers from the University of Iowa Hospitals, Iowa City, reported in the January edition of the American Journal of Obstetrics and Gynecology. The data were presented Feb. 4 at the 2022 virtual Pregnancy Meeting of the Society of Maternal-Fetal Medicine.

The findings have prompted the institution to begin administering prophylactic methylergonovine in addition to oxytocin at the time of cesarean deliveries, according to the researchers.

“The addition of prophylactic methylergonovine improved uterine tone, decreased the requirement of additional uterotonic agents, decreased the risk of postpartum hemorrhage, and decreased the need for blood transfusions,” lead author Nicole Masse, MD, assistant professor of maternal-fetal medicine at the University of Iowa, said in an interview.

Abnormal uterine tone is the leading cause of postpartum hemorrhage, Dr. Masse said. “Satisfactory uterine tone following delivery is essential. This study found a decreased need for blood transfusions in patients who received prophylactic methylergonovine. Given the risks of blood transfusions, which can include disease transmission and allergic reactions, transfusions should be avoided whenever possible.”

Conducted between June 2019 and February 2021, the single-center, randomized controlled trial of 160 women undergoing an intrapartum cesarean birth is the largest of its kind to date, Dr. Masse said. Women received either intravenous oxytocin at a dose of 300 mU per minute plus 1 mL of intramuscular normal saline (n = 80) or intravenous oxytocin at a dose of 300 mU per minute plus 0.2 mg (1 mL) of intramuscular methylergonovine (n = 80).

Women who received prophylactic methylergonovine required significantly less additional uterotonic agents than those who received oxytocin alone (20% vs. 55%; relative risk, 0.36; 95% confidence interval 0.22-0.59), according to the researchers. Those receiving methylergonovine were more likely to experience improved uterine tone (80% vs. 41.2%; RR, 1.94; 95% CI, 1.46-2.56), a lower incidence of postpartum hemorrhage (35% vs. 58.8%; RR, 0.6; 95% CI, 0.42-0.85), decreased need for a blood transfusion (5% vs. 22.5%; RR, 0.22; 95% CI, 0.08-0.63), and lower mean quantitative blood loss (996 mL vs. 1,315 mL; P = .004), they reported.      

“As the majority of postpartum hemorrhages are preventable, this study is clinically relevant and can serve to decrease the morbidity associated with postpartum hemorrhage,” Dr. Masse said.

Jennifer Choi, DO, clinical assistant professor of maternal-fetal medicine at Stony Brook University Hospital, New York, said the Iowa team’s results are contrary to prior studies showing no benefit with simultaneous use of oxytocin and ergot alkaloids.    

“It would be interesting to see long-term benefits across a diverse population,” she said. “But as methylergonovine is a known contraindication to hypertensive and cardiovascular disorders, including pre-eclampsia, patients would have to be carefully screened.”

Kecia Gaither, MD, MPH, associate professor of clinical obstetrics and gynecology at Weill Cornell Medicine, New York, called the study “a novel idea, but more research and higher numbers are needed for a substantive conclusion.”

Additional studies should look at variables such as the number of prior cesarean deliveries, body mass index, presence of uterine myomas, presence of abnormal placentation (placenta accreta, increta, percreta), and presence of multiple gestation, said Dr. Gaither, who also is director of perinatal services at NYC Health + Hospitals/Lincoln.

“Methergine [methylergonovine] use is contraindicated in women with hypertension/pre-eclampsia spectrum, mitral valve prolapse, history of coronary artery disease, and liver pathology,” she noted.

The researchers reported no relevant financial conflicts of interest.

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

Methylergonovine is often used to control severe bleeding immediately after cesarean deliveries. But a new study suggests that the ergot alkaloid agent could benefit these women if administered before delivery, researchers from the University of Iowa Hospitals, Iowa City, reported in the January edition of the American Journal of Obstetrics and Gynecology. The data were presented Feb. 4 at the 2022 virtual Pregnancy Meeting of the Society of Maternal-Fetal Medicine.

The findings have prompted the institution to begin administering prophylactic methylergonovine in addition to oxytocin at the time of cesarean deliveries, according to the researchers.

“The addition of prophylactic methylergonovine improved uterine tone, decreased the requirement of additional uterotonic agents, decreased the risk of postpartum hemorrhage, and decreased the need for blood transfusions,” lead author Nicole Masse, MD, assistant professor of maternal-fetal medicine at the University of Iowa, said in an interview.

Abnormal uterine tone is the leading cause of postpartum hemorrhage, Dr. Masse said. “Satisfactory uterine tone following delivery is essential. This study found a decreased need for blood transfusions in patients who received prophylactic methylergonovine. Given the risks of blood transfusions, which can include disease transmission and allergic reactions, transfusions should be avoided whenever possible.”

Conducted between June 2019 and February 2021, the single-center, randomized controlled trial of 160 women undergoing an intrapartum cesarean birth is the largest of its kind to date, Dr. Masse said. Women received either intravenous oxytocin at a dose of 300 mU per minute plus 1 mL of intramuscular normal saline (n = 80) or intravenous oxytocin at a dose of 300 mU per minute plus 0.2 mg (1 mL) of intramuscular methylergonovine (n = 80).

Women who received prophylactic methylergonovine required significantly less additional uterotonic agents than those who received oxytocin alone (20% vs. 55%; relative risk, 0.36; 95% confidence interval 0.22-0.59), according to the researchers. Those receiving methylergonovine were more likely to experience improved uterine tone (80% vs. 41.2%; RR, 1.94; 95% CI, 1.46-2.56), a lower incidence of postpartum hemorrhage (35% vs. 58.8%; RR, 0.6; 95% CI, 0.42-0.85), decreased need for a blood transfusion (5% vs. 22.5%; RR, 0.22; 95% CI, 0.08-0.63), and lower mean quantitative blood loss (996 mL vs. 1,315 mL; P = .004), they reported.      

“As the majority of postpartum hemorrhages are preventable, this study is clinically relevant and can serve to decrease the morbidity associated with postpartum hemorrhage,” Dr. Masse said.

Jennifer Choi, DO, clinical assistant professor of maternal-fetal medicine at Stony Brook University Hospital, New York, said the Iowa team’s results are contrary to prior studies showing no benefit with simultaneous use of oxytocin and ergot alkaloids.    

“It would be interesting to see long-term benefits across a diverse population,” she said. “But as methylergonovine is a known contraindication to hypertensive and cardiovascular disorders, including pre-eclampsia, patients would have to be carefully screened.”

Kecia Gaither, MD, MPH, associate professor of clinical obstetrics and gynecology at Weill Cornell Medicine, New York, called the study “a novel idea, but more research and higher numbers are needed for a substantive conclusion.”

Additional studies should look at variables such as the number of prior cesarean deliveries, body mass index, presence of uterine myomas, presence of abnormal placentation (placenta accreta, increta, percreta), and presence of multiple gestation, said Dr. Gaither, who also is director of perinatal services at NYC Health + Hospitals/Lincoln.

“Methergine [methylergonovine] use is contraindicated in women with hypertension/pre-eclampsia spectrum, mitral valve prolapse, history of coronary artery disease, and liver pathology,” she noted.

The researchers reported no relevant financial conflicts of interest.

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

Methylergonovine is often used to control severe bleeding immediately after cesarean deliveries. But a new study suggests that the ergot alkaloid agent could benefit these women if administered before delivery, researchers from the University of Iowa Hospitals, Iowa City, reported in the January edition of the American Journal of Obstetrics and Gynecology. The data were presented Feb. 4 at the 2022 virtual Pregnancy Meeting of the Society of Maternal-Fetal Medicine.

The findings have prompted the institution to begin administering prophylactic methylergonovine in addition to oxytocin at the time of cesarean deliveries, according to the researchers.

“The addition of prophylactic methylergonovine improved uterine tone, decreased the requirement of additional uterotonic agents, decreased the risk of postpartum hemorrhage, and decreased the need for blood transfusions,” lead author Nicole Masse, MD, assistant professor of maternal-fetal medicine at the University of Iowa, said in an interview.

Abnormal uterine tone is the leading cause of postpartum hemorrhage, Dr. Masse said. “Satisfactory uterine tone following delivery is essential. This study found a decreased need for blood transfusions in patients who received prophylactic methylergonovine. Given the risks of blood transfusions, which can include disease transmission and allergic reactions, transfusions should be avoided whenever possible.”

Conducted between June 2019 and February 2021, the single-center, randomized controlled trial of 160 women undergoing an intrapartum cesarean birth is the largest of its kind to date, Dr. Masse said. Women received either intravenous oxytocin at a dose of 300 mU per minute plus 1 mL of intramuscular normal saline (n = 80) or intravenous oxytocin at a dose of 300 mU per minute plus 0.2 mg (1 mL) of intramuscular methylergonovine (n = 80).

Women who received prophylactic methylergonovine required significantly less additional uterotonic agents than those who received oxytocin alone (20% vs. 55%; relative risk, 0.36; 95% confidence interval 0.22-0.59), according to the researchers. Those receiving methylergonovine were more likely to experience improved uterine tone (80% vs. 41.2%; RR, 1.94; 95% CI, 1.46-2.56), a lower incidence of postpartum hemorrhage (35% vs. 58.8%; RR, 0.6; 95% CI, 0.42-0.85), decreased need for a blood transfusion (5% vs. 22.5%; RR, 0.22; 95% CI, 0.08-0.63), and lower mean quantitative blood loss (996 mL vs. 1,315 mL; P = .004), they reported.      

“As the majority of postpartum hemorrhages are preventable, this study is clinically relevant and can serve to decrease the morbidity associated with postpartum hemorrhage,” Dr. Masse said.

Jennifer Choi, DO, clinical assistant professor of maternal-fetal medicine at Stony Brook University Hospital, New York, said the Iowa team’s results are contrary to prior studies showing no benefit with simultaneous use of oxytocin and ergot alkaloids.    

“It would be interesting to see long-term benefits across a diverse population,” she said. “But as methylergonovine is a known contraindication to hypertensive and cardiovascular disorders, including pre-eclampsia, patients would have to be carefully screened.”

Kecia Gaither, MD, MPH, associate professor of clinical obstetrics and gynecology at Weill Cornell Medicine, New York, called the study “a novel idea, but more research and higher numbers are needed for a substantive conclusion.”

Additional studies should look at variables such as the number of prior cesarean deliveries, body mass index, presence of uterine myomas, presence of abnormal placentation (placenta accreta, increta, percreta), and presence of multiple gestation, said Dr. Gaither, who also is director of perinatal services at NYC Health + Hospitals/Lincoln.

“Methergine [methylergonovine] use is contraindicated in women with hypertension/pre-eclampsia spectrum, mitral valve prolapse, history of coronary artery disease, and liver pathology,” she noted.

The researchers reported no relevant financial conflicts of interest.

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

Low-dose aspirin may increase risk of postpartum bleeding if patients don’t discontinue its use at least 7 days before delivery, but it’s otherwise unclear whether its use increases bleeding risk, according to research presented Feb. 5 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“These findings were a little surprising to me because we have generally been taught that aspirin is safe to continue up until delivery with minimal risk,” Jenny Mei, MD, a maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview after attending the presentation. “Theoretically it makes sense that it may increase bleeding risk, but multiple studies in the past analyzing its use with gynecological surgery show minimal risk, which was conferred to the obstetrical population as well.”

She noted, however, that patients prescribed low-dose aspirin already have risk factors that may increase their risk of postpartum bleeding, and the study’s finding of possible increased risk was not statistically significant after accounting for those confounders. “I wouldn’t change my practice management over it, but it does raise awareness that all interventions likely come with some risk,” Dr. Mei said.

Hypertensive disorders of pregnancy are responsible for 6.6% of U.S. pregnancy-related deaths. The SMFM currently recommends low-dose aspirin starting at 12 weeks’ gestation in patients at high risk for preeclampsia, which includes people with multifetal gestation, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease, or a history of preeclampsia. However, previous research has shown mixed results on the safety of low-dose aspirin in terms of bleeding risk, Kelsey White, MD, a second-year maternal-fetal medicine fellow of the Yale University, New Haven, Conn., told attendees.

This retrospective study compared a bleeding composite endpoint among those who did and did not take low-dose aspirin between January 2018 and April 2021. The composite included an estimated blood loss of greater than 1,000 mL, postpartum hemorrhage based on ICD-9/10 code diagnosis, and red blood cell transfusion. The researchers also compared bleeding risk within the aspirin group based on discontinuation at greater or less than 7 days before delivery.

Among 16,980 patients, 11.3% were prescribed low-dose aspirin. The patients prescribed low-dose aspirin significantly differed from those not prescribed it in all demographic and clinical characteristics except placenta accreta spectrum. The average age of the aspirin group was 39 years, compared with 24 years in the nonaspirin group (P < .01). More of the aspirin group patients were Hispanic and Black, and 52.3% of patients taking aspirin had a body mass index greater than 30 kg/m², compared with 22.9% of the nonaspirin group. Rates of diabetes, lupus, fibroids, nonaspirin anticoagulation use, cesarean delivery, and preterm delivery were all greater in the aspirin group.

In addition, 43.9% of the patients in the aspirin group had a hypertensive disorder, including 20.2% with preeclampsia, compared with 17.1% with hypertensive disorders, including 6.2% with preeclampsia, in the group not taking aspirin (P < .0001). “This shows that a high-risk population was prescribed aspirin, which correlates to the recommended prescription guidelines,” Dr. White said.

The postpartum bleeding composite outcome occurred in 14.7% of patients in the low-dose aspirin group, compared with 9.2% of patients in the nonaspirin group, for an unadjusted 1.7 times greater risk of bleeding (95% confidence interval, 1.49-1.96). After adjustment for confounders, the risk declined and was no longer statistically significant (aOR = 1.15; 95% CI, 0.98-1.34).

Meanwhile, 15% of those who discontinued aspirin within 7 days of delivery had postpartum bleeding, compared with 9% of those who discontinued aspirin at 7 or more days before delivery (P = .03).

Therefore, while the study found only a possible, nonsignificant association between low-dose aspirin and postpartum bleeding, risk of bleeding was significantly greater among those who discontinued aspirin only in the last week before delivery.

”Our study is timely and supports a recent Swedish study [that] found an increased risk of intrapartum bleeding, postpartum hemorrhage, and postpartum hematoma,” Dr. White said. She also noted that the United States Preventive Services Task Force changed their recommendation in 2021 for low-dose aspirin prophylaxis for cardiovascular disease.

“They now recommend against the use of low-dose aspirin for prevention in adults without a history of cardiovascular disease,” Dr. White said. “The change in recommendations came after recent randomized control trials showed that low-dose aspirin had very little benefit and may increase the risk of bleeding.”

However, Dr. White added that they “do not believe this study should be used to make any clinical decisions.” While the study had a large sample size, it was limited by its retrospective reliance on EMR data, including the EMR medication list, and the researchers couldn’t assess patient compliance or patient use of over-the-counter aspirin not recorded in the EMR.

Deirdre Lyell, MD, a professor of maternal-fetal medicine at Stanford (Calif.) University, agreed that the findings should not impact clinical practice given its limitations.

“The investigators could not entirely identify who stopped low-dose aspirin and when. When they estimated timing of stoppage of low-dose aspirin, their data suggested a small benefit among those who discontinued it at least 7 days before delivery, though this should be interpreted with caution, given the potential inaccuracy in these data,” Dr. Lyell, who was not involved in the study, said in an interview. “Their study did not examine factors that should be used to confirm if there are real differences in blood loss, such as changes in blood counts before and after delivery, or more use of medications that we use to stop heavy bleeding.”

In fact, Dr. Lyell noted, other research at the SMFM meeting found ”that low-dose aspirin is not used frequently enough in patients who might benefit, such as those at high risk for preeclampsia,” she said. ”Low-dose aspirin among those at increased risk has been shown to reduce rates of preeclampsia, reducing the likelihood of risky situations for moms and babies.”

The authors had no disclosures. Dr. Lyell has consulted for Bloomlife, a uterine contraction and fetal monitor. Dr. White and Dr. Mei had no disclosures.
 

Low-dose aspirin may increase risk of postpartum bleeding if patients don’t discontinue its use at least 7 days before delivery, but it’s otherwise unclear whether its use increases bleeding risk, according to research presented Feb. 5 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“These findings were a little surprising to me because we have generally been taught that aspirin is safe to continue up until delivery with minimal risk,” Jenny Mei, MD, a maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview after attending the presentation. “Theoretically it makes sense that it may increase bleeding risk, but multiple studies in the past analyzing its use with gynecological surgery show minimal risk, which was conferred to the obstetrical population as well.”

She noted, however, that patients prescribed low-dose aspirin already have risk factors that may increase their risk of postpartum bleeding, and the study’s finding of possible increased risk was not statistically significant after accounting for those confounders. “I wouldn’t change my practice management over it, but it does raise awareness that all interventions likely come with some risk,” Dr. Mei said.

Hypertensive disorders of pregnancy are responsible for 6.6% of U.S. pregnancy-related deaths. The SMFM currently recommends low-dose aspirin starting at 12 weeks’ gestation in patients at high risk for preeclampsia, which includes people with multifetal gestation, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease, or a history of preeclampsia. However, previous research has shown mixed results on the safety of low-dose aspirin in terms of bleeding risk, Kelsey White, MD, a second-year maternal-fetal medicine fellow of the Yale University, New Haven, Conn., told attendees.

This retrospective study compared a bleeding composite endpoint among those who did and did not take low-dose aspirin between January 2018 and April 2021. The composite included an estimated blood loss of greater than 1,000 mL, postpartum hemorrhage based on ICD-9/10 code diagnosis, and red blood cell transfusion. The researchers also compared bleeding risk within the aspirin group based on discontinuation at greater or less than 7 days before delivery.

Among 16,980 patients, 11.3% were prescribed low-dose aspirin. The patients prescribed low-dose aspirin significantly differed from those not prescribed it in all demographic and clinical characteristics except placenta accreta spectrum. The average age of the aspirin group was 39 years, compared with 24 years in the nonaspirin group (P < .01). More of the aspirin group patients were Hispanic and Black, and 52.3% of patients taking aspirin had a body mass index greater than 30 kg/m², compared with 22.9% of the nonaspirin group. Rates of diabetes, lupus, fibroids, nonaspirin anticoagulation use, cesarean delivery, and preterm delivery were all greater in the aspirin group.

In addition, 43.9% of the patients in the aspirin group had a hypertensive disorder, including 20.2% with preeclampsia, compared with 17.1% with hypertensive disorders, including 6.2% with preeclampsia, in the group not taking aspirin (P < .0001). “This shows that a high-risk population was prescribed aspirin, which correlates to the recommended prescription guidelines,” Dr. White said.

The postpartum bleeding composite outcome occurred in 14.7% of patients in the low-dose aspirin group, compared with 9.2% of patients in the nonaspirin group, for an unadjusted 1.7 times greater risk of bleeding (95% confidence interval, 1.49-1.96). After adjustment for confounders, the risk declined and was no longer statistically significant (aOR = 1.15; 95% CI, 0.98-1.34).

Meanwhile, 15% of those who discontinued aspirin within 7 days of delivery had postpartum bleeding, compared with 9% of those who discontinued aspirin at 7 or more days before delivery (P = .03).

Therefore, while the study found only a possible, nonsignificant association between low-dose aspirin and postpartum bleeding, risk of bleeding was significantly greater among those who discontinued aspirin only in the last week before delivery.

”Our study is timely and supports a recent Swedish study [that] found an increased risk of intrapartum bleeding, postpartum hemorrhage, and postpartum hematoma,” Dr. White said. She also noted that the United States Preventive Services Task Force changed their recommendation in 2021 for low-dose aspirin prophylaxis for cardiovascular disease.

“They now recommend against the use of low-dose aspirin for prevention in adults without a history of cardiovascular disease,” Dr. White said. “The change in recommendations came after recent randomized control trials showed that low-dose aspirin had very little benefit and may increase the risk of bleeding.”

However, Dr. White added that they “do not believe this study should be used to make any clinical decisions.” While the study had a large sample size, it was limited by its retrospective reliance on EMR data, including the EMR medication list, and the researchers couldn’t assess patient compliance or patient use of over-the-counter aspirin not recorded in the EMR.

Deirdre Lyell, MD, a professor of maternal-fetal medicine at Stanford (Calif.) University, agreed that the findings should not impact clinical practice given its limitations.

“The investigators could not entirely identify who stopped low-dose aspirin and when. When they estimated timing of stoppage of low-dose aspirin, their data suggested a small benefit among those who discontinued it at least 7 days before delivery, though this should be interpreted with caution, given the potential inaccuracy in these data,” Dr. Lyell, who was not involved in the study, said in an interview. “Their study did not examine factors that should be used to confirm if there are real differences in blood loss, such as changes in blood counts before and after delivery, or more use of medications that we use to stop heavy bleeding.”

In fact, Dr. Lyell noted, other research at the SMFM meeting found ”that low-dose aspirin is not used frequently enough in patients who might benefit, such as those at high risk for preeclampsia,” she said. ”Low-dose aspirin among those at increased risk has been shown to reduce rates of preeclampsia, reducing the likelihood of risky situations for moms and babies.”

The authors had no disclosures. Dr. Lyell has consulted for Bloomlife, a uterine contraction and fetal monitor. Dr. White and Dr. Mei had no disclosures.
 

Low-dose aspirin may increase risk of postpartum bleeding if patients don’t discontinue its use at least 7 days before delivery, but it’s otherwise unclear whether its use increases bleeding risk, according to research presented Feb. 5 at the meeting sponsored by the Society for Maternal-Fetal Medicine.

“These findings were a little surprising to me because we have generally been taught that aspirin is safe to continue up until delivery with minimal risk,” Jenny Mei, MD, a maternal-fetal medicine fellow at the University of California, Los Angeles, said in an interview after attending the presentation. “Theoretically it makes sense that it may increase bleeding risk, but multiple studies in the past analyzing its use with gynecological surgery show minimal risk, which was conferred to the obstetrical population as well.”

She noted, however, that patients prescribed low-dose aspirin already have risk factors that may increase their risk of postpartum bleeding, and the study’s finding of possible increased risk was not statistically significant after accounting for those confounders. “I wouldn’t change my practice management over it, but it does raise awareness that all interventions likely come with some risk,” Dr. Mei said.

Hypertensive disorders of pregnancy are responsible for 6.6% of U.S. pregnancy-related deaths. The SMFM currently recommends low-dose aspirin starting at 12 weeks’ gestation in patients at high risk for preeclampsia, which includes people with multifetal gestation, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease, or a history of preeclampsia. However, previous research has shown mixed results on the safety of low-dose aspirin in terms of bleeding risk, Kelsey White, MD, a second-year maternal-fetal medicine fellow of the Yale University, New Haven, Conn., told attendees.

This retrospective study compared a bleeding composite endpoint among those who did and did not take low-dose aspirin between January 2018 and April 2021. The composite included an estimated blood loss of greater than 1,000 mL, postpartum hemorrhage based on ICD-9/10 code diagnosis, and red blood cell transfusion. The researchers also compared bleeding risk within the aspirin group based on discontinuation at greater or less than 7 days before delivery.

Among 16,980 patients, 11.3% were prescribed low-dose aspirin. The patients prescribed low-dose aspirin significantly differed from those not prescribed it in all demographic and clinical characteristics except placenta accreta spectrum. The average age of the aspirin group was 39 years, compared with 24 years in the nonaspirin group (P < .01). More of the aspirin group patients were Hispanic and Black, and 52.3% of patients taking aspirin had a body mass index greater than 30 kg/m², compared with 22.9% of the nonaspirin group. Rates of diabetes, lupus, fibroids, nonaspirin anticoagulation use, cesarean delivery, and preterm delivery were all greater in the aspirin group.

In addition, 43.9% of the patients in the aspirin group had a hypertensive disorder, including 20.2% with preeclampsia, compared with 17.1% with hypertensive disorders, including 6.2% with preeclampsia, in the group not taking aspirin (P < .0001). “This shows that a high-risk population was prescribed aspirin, which correlates to the recommended prescription guidelines,” Dr. White said.

The postpartum bleeding composite outcome occurred in 14.7% of patients in the low-dose aspirin group, compared with 9.2% of patients in the nonaspirin group, for an unadjusted 1.7 times greater risk of bleeding (95% confidence interval, 1.49-1.96). After adjustment for confounders, the risk declined and was no longer statistically significant (aOR = 1.15; 95% CI, 0.98-1.34).

Meanwhile, 15% of those who discontinued aspirin within 7 days of delivery had postpartum bleeding, compared with 9% of those who discontinued aspirin at 7 or more days before delivery (P = .03).

Therefore, while the study found only a possible, nonsignificant association between low-dose aspirin and postpartum bleeding, risk of bleeding was significantly greater among those who discontinued aspirin only in the last week before delivery.

”Our study is timely and supports a recent Swedish study [that] found an increased risk of intrapartum bleeding, postpartum hemorrhage, and postpartum hematoma,” Dr. White said. She also noted that the United States Preventive Services Task Force changed their recommendation in 2021 for low-dose aspirin prophylaxis for cardiovascular disease.

“They now recommend against the use of low-dose aspirin for prevention in adults without a history of cardiovascular disease,” Dr. White said. “The change in recommendations came after recent randomized control trials showed that low-dose aspirin had very little benefit and may increase the risk of bleeding.”

However, Dr. White added that they “do not believe this study should be used to make any clinical decisions.” While the study had a large sample size, it was limited by its retrospective reliance on EMR data, including the EMR medication list, and the researchers couldn’t assess patient compliance or patient use of over-the-counter aspirin not recorded in the EMR.

Deirdre Lyell, MD, a professor of maternal-fetal medicine at Stanford (Calif.) University, agreed that the findings should not impact clinical practice given its limitations.

“The investigators could not entirely identify who stopped low-dose aspirin and when. When they estimated timing of stoppage of low-dose aspirin, their data suggested a small benefit among those who discontinued it at least 7 days before delivery, though this should be interpreted with caution, given the potential inaccuracy in these data,” Dr. Lyell, who was not involved in the study, said in an interview. “Their study did not examine factors that should be used to confirm if there are real differences in blood loss, such as changes in blood counts before and after delivery, or more use of medications that we use to stop heavy bleeding.”

In fact, Dr. Lyell noted, other research at the SMFM meeting found ”that low-dose aspirin is not used frequently enough in patients who might benefit, such as those at high risk for preeclampsia,” she said. ”Low-dose aspirin among those at increased risk has been shown to reduce rates of preeclampsia, reducing the likelihood of risky situations for moms and babies.”

The authors had no disclosures. Dr. Lyell has consulted for Bloomlife, a uterine contraction and fetal monitor. Dr. White and Dr. Mei had no disclosures.
 

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

A digital algorithm using 24 patient characteristics identifies far more women who are likely to develop a postpartum hemorrhage than currently used tools to predict the risk for bleeding after delivery, according to a study published in the Journal of the American Medical Informatics Association.

About 1 in 10 of the roughly 700 pregnancy-related deaths in the United States are caused by postpartum hemorrhage, according to the U.S. Centers for Disease Control and Prevention. These deaths disproportionately occur among Black women, for whom studies show the risk of dying from a postpartum hemorrhage is fivefold greater than that of White women.

“Postpartum hemorrhage is a preventable medical emergency but remains the leading cause of maternal mortality globally,” the study’s senior author Li Li, MD, senior vice president of clinical informatics at Sema4, a company that uses artificial intelligence and machine learning to develop data-based clinical tools, told this news organization. “Early intervention is critical for reducing postpartum hemorrhage morbidity and mortality.”
 

Porous predictors

Existing tools for risk prediction are not particularly effective, Dr. Li said. For example, the American College of Obstetricians and Gynecologists’ (ACOG) Safe Motherhood Initiative offers checklists of clinical characteristics to classify women as low, medium, or high risk. However, 40% of the women classified as low risk based on this type of tool experience a hemorrhage.

ACOG also recommends quantifying blood loss during delivery or immediately after to identify women who are hemorrhaging, because imprecise estimates from clinicians may delay urgently needed care. Yet many hospitals have not implemented methods for measuring bleeding, said Dr. Li, who also is an assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, New York.

To develop a more precise way of identifying women at risk, Dr. Li and colleagues turned to artificial intelligence technology to create a “digital phenotype” based on approximately 72,000 births in the Mount Sinai Health System.

The digital tool retrospectively identified about 6,600 cases of postpartum hemorrhage, about 3.8 times the roughly 1,700 cases that would have been predicted based on methods that estimate blood loss. A blinded physician review of a subset of 45 patient charts – including 26 patients who experienced a hemorrhage, 11 who didn’t, and 6 with unclear outcomes – found that the digital approach was 89% percent accurate at identifying cases, whereas blood loss–based methods were accurate 67% of the time.

Several of the 24 characteristics included in the model appear in other risk predictors, including whether a woman has had a previous cesarean delivery or prior postdelivery bleeding and whether she has anemia or related blood disorders. Among the rest were risk factors that have been identified in the literature, including maternal blood pressure, time from admission to delivery, and average pulse during hospitalization. Five more features were new: red blood cell count and distribution width, mean corpuscular hemoglobin, absolute neutrophil count, and white blood cell count.

“These [new] values are easily obtainable from standard blood draws in the hospital but are not currently used in clinical practice to estimate postpartum hemorrhage risk,” Dr. Li said.

In a related retrospective study, Dr. Li and her colleagues used the new tool to classify women into high, low, or medium risk categories. They found that 28% of the women the algorithm classified as high risk experienced a postpartum hemorrhage compared with 15% to 19% of the women classified as high risk by standard predictive tools. They also identified potential “inflection points” where changes in vital signs may suggest a substantial increase in risk. For example, women whose median blood pressure during labor and delivery was above 132 mm Hg had an 11% average increase in their risk for bleeding. 

By more precisely identifying women at risk, the new method “could be used to pre-emptively allocate resources that can ultimately reduce postpartum hemorrhage morbidity and mortality,” Dr. Li said. Sema4 is launching a prospective clinical trial to further assess the algorithm, she added.  
 

Finding the continuum of risk

Holly Ende, MD, an obstetric anesthesiologist at Vanderbilt University Medical Center, Nashville, Tenn., said approaches that leverage electronic health records to identify women at risk for hemorrhage have many advantages over currently used tools.

“Machine learning models or statistical models are able to take into account many more risk factors and weigh each of those risk factors based on how much they contribute to risk,” Dr. Ende, who was not involved in the new studies, told this news organization. “We can stratify women more on a continuum.”

But digital approaches have potential downsides.

“Machine learning algorithms can be developed in such a way that perpetuates racial bias, and it’s important to be aware of potential biases in coded algorithms,” Dr. Li said. To help reduce such bias, they used a database that included a racially and ethnically diverse patient population, but she acknowledged that additional research is needed.

Dr. Ende, the coauthor of a commentary in Obstetrics & Gynecology on risk assessment for postpartum hemorrhage, said algorithm developers must be sensitive to pre-existing disparities in health care that may affect the data they use to build the software.

She pointed to uterine atony – a known risk factor for hemorrhage – as an example. In her own research, she and her colleagues identified women with atony by searching their medical records for medications used to treat the condition. But when they ran their model, Black women were less likely to develop uterine atony, which the team knew wasn’t true in the real world. They traced the problem to an existing disparity in obstetric care: Black women with uterine atony were less likely than women of other races to receive medications for the condition.

“People need to be cognizant as they are developing these types of prediction models and be extremely careful to avoid perpetuating any disparities in care,” Dr. Ende cautioned. On the other hand, if carefully developed, these tools might also help reduce disparities in health care by standardizing risk stratification and clinical practices, she said.

In addition to independent validation of data-based risk prediction tools, Dr. Ende said ensuring that clinicians are properly trained to use these tools is crucial.

“Implementation may be the biggest limitation,” she said.

Dr. Ende and Dr. Li have disclosed no relevant financial relationships.

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

A digital algorithm using 24 patient characteristics identifies far more women who are likely to develop a postpartum hemorrhage than currently used tools to predict the risk for bleeding after delivery, according to a study published in the Journal of the American Medical Informatics Association.

About 1 in 10 of the roughly 700 pregnancy-related deaths in the United States are caused by postpartum hemorrhage, according to the U.S. Centers for Disease Control and Prevention. These deaths disproportionately occur among Black women, for whom studies show the risk of dying from a postpartum hemorrhage is fivefold greater than that of White women.

“Postpartum hemorrhage is a preventable medical emergency but remains the leading cause of maternal mortality globally,” the study’s senior author Li Li, MD, senior vice president of clinical informatics at Sema4, a company that uses artificial intelligence and machine learning to develop data-based clinical tools, told this news organization. “Early intervention is critical for reducing postpartum hemorrhage morbidity and mortality.”
 

Porous predictors

Existing tools for risk prediction are not particularly effective, Dr. Li said. For example, the American College of Obstetricians and Gynecologists’ (ACOG) Safe Motherhood Initiative offers checklists of clinical characteristics to classify women as low, medium, or high risk. However, 40% of the women classified as low risk based on this type of tool experience a hemorrhage.

ACOG also recommends quantifying blood loss during delivery or immediately after to identify women who are hemorrhaging, because imprecise estimates from clinicians may delay urgently needed care. Yet many hospitals have not implemented methods for measuring bleeding, said Dr. Li, who also is an assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, New York.

To develop a more precise way of identifying women at risk, Dr. Li and colleagues turned to artificial intelligence technology to create a “digital phenotype” based on approximately 72,000 births in the Mount Sinai Health System.

The digital tool retrospectively identified about 6,600 cases of postpartum hemorrhage, about 3.8 times the roughly 1,700 cases that would have been predicted based on methods that estimate blood loss. A blinded physician review of a subset of 45 patient charts – including 26 patients who experienced a hemorrhage, 11 who didn’t, and 6 with unclear outcomes – found that the digital approach was 89% percent accurate at identifying cases, whereas blood loss–based methods were accurate 67% of the time.

Several of the 24 characteristics included in the model appear in other risk predictors, including whether a woman has had a previous cesarean delivery or prior postdelivery bleeding and whether she has anemia or related blood disorders. Among the rest were risk factors that have been identified in the literature, including maternal blood pressure, time from admission to delivery, and average pulse during hospitalization. Five more features were new: red blood cell count and distribution width, mean corpuscular hemoglobin, absolute neutrophil count, and white blood cell count.

“These [new] values are easily obtainable from standard blood draws in the hospital but are not currently used in clinical practice to estimate postpartum hemorrhage risk,” Dr. Li said.

In a related retrospective study, Dr. Li and her colleagues used the new tool to classify women into high, low, or medium risk categories. They found that 28% of the women the algorithm classified as high risk experienced a postpartum hemorrhage compared with 15% to 19% of the women classified as high risk by standard predictive tools. They also identified potential “inflection points” where changes in vital signs may suggest a substantial increase in risk. For example, women whose median blood pressure during labor and delivery was above 132 mm Hg had an 11% average increase in their risk for bleeding. 

By more precisely identifying women at risk, the new method “could be used to pre-emptively allocate resources that can ultimately reduce postpartum hemorrhage morbidity and mortality,” Dr. Li said. Sema4 is launching a prospective clinical trial to further assess the algorithm, she added.  
 

Finding the continuum of risk

Holly Ende, MD, an obstetric anesthesiologist at Vanderbilt University Medical Center, Nashville, Tenn., said approaches that leverage electronic health records to identify women at risk for hemorrhage have many advantages over currently used tools.

“Machine learning models or statistical models are able to take into account many more risk factors and weigh each of those risk factors based on how much they contribute to risk,” Dr. Ende, who was not involved in the new studies, told this news organization. “We can stratify women more on a continuum.”

But digital approaches have potential downsides.

“Machine learning algorithms can be developed in such a way that perpetuates racial bias, and it’s important to be aware of potential biases in coded algorithms,” Dr. Li said. To help reduce such bias, they used a database that included a racially and ethnically diverse patient population, but she acknowledged that additional research is needed.

Dr. Ende, the coauthor of a commentary in Obstetrics & Gynecology on risk assessment for postpartum hemorrhage, said algorithm developers must be sensitive to pre-existing disparities in health care that may affect the data they use to build the software.

She pointed to uterine atony – a known risk factor for hemorrhage – as an example. In her own research, she and her colleagues identified women with atony by searching their medical records for medications used to treat the condition. But when they ran their model, Black women were less likely to develop uterine atony, which the team knew wasn’t true in the real world. They traced the problem to an existing disparity in obstetric care: Black women with uterine atony were less likely than women of other races to receive medications for the condition.

“People need to be cognizant as they are developing these types of prediction models and be extremely careful to avoid perpetuating any disparities in care,” Dr. Ende cautioned. On the other hand, if carefully developed, these tools might also help reduce disparities in health care by standardizing risk stratification and clinical practices, she said.

In addition to independent validation of data-based risk prediction tools, Dr. Ende said ensuring that clinicians are properly trained to use these tools is crucial.

“Implementation may be the biggest limitation,” she said.

Dr. Ende and Dr. Li have disclosed no relevant financial relationships.

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

A digital algorithm using 24 patient characteristics identifies far more women who are likely to develop a postpartum hemorrhage than currently used tools to predict the risk for bleeding after delivery, according to a study published in the Journal of the American Medical Informatics Association.

About 1 in 10 of the roughly 700 pregnancy-related deaths in the United States are caused by postpartum hemorrhage, according to the U.S. Centers for Disease Control and Prevention. These deaths disproportionately occur among Black women, for whom studies show the risk of dying from a postpartum hemorrhage is fivefold greater than that of White women.

“Postpartum hemorrhage is a preventable medical emergency but remains the leading cause of maternal mortality globally,” the study’s senior author Li Li, MD, senior vice president of clinical informatics at Sema4, a company that uses artificial intelligence and machine learning to develop data-based clinical tools, told this news organization. “Early intervention is critical for reducing postpartum hemorrhage morbidity and mortality.”
 

Porous predictors

Existing tools for risk prediction are not particularly effective, Dr. Li said. For example, the American College of Obstetricians and Gynecologists’ (ACOG) Safe Motherhood Initiative offers checklists of clinical characteristics to classify women as low, medium, or high risk. However, 40% of the women classified as low risk based on this type of tool experience a hemorrhage.

ACOG also recommends quantifying blood loss during delivery or immediately after to identify women who are hemorrhaging, because imprecise estimates from clinicians may delay urgently needed care. Yet many hospitals have not implemented methods for measuring bleeding, said Dr. Li, who also is an assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, New York.

To develop a more precise way of identifying women at risk, Dr. Li and colleagues turned to artificial intelligence technology to create a “digital phenotype” based on approximately 72,000 births in the Mount Sinai Health System.

The digital tool retrospectively identified about 6,600 cases of postpartum hemorrhage, about 3.8 times the roughly 1,700 cases that would have been predicted based on methods that estimate blood loss. A blinded physician review of a subset of 45 patient charts – including 26 patients who experienced a hemorrhage, 11 who didn’t, and 6 with unclear outcomes – found that the digital approach was 89% percent accurate at identifying cases, whereas blood loss–based methods were accurate 67% of the time.

Several of the 24 characteristics included in the model appear in other risk predictors, including whether a woman has had a previous cesarean delivery or prior postdelivery bleeding and whether she has anemia or related blood disorders. Among the rest were risk factors that have been identified in the literature, including maternal blood pressure, time from admission to delivery, and average pulse during hospitalization. Five more features were new: red blood cell count and distribution width, mean corpuscular hemoglobin, absolute neutrophil count, and white blood cell count.

“These [new] values are easily obtainable from standard blood draws in the hospital but are not currently used in clinical practice to estimate postpartum hemorrhage risk,” Dr. Li said.

In a related retrospective study, Dr. Li and her colleagues used the new tool to classify women into high, low, or medium risk categories. They found that 28% of the women the algorithm classified as high risk experienced a postpartum hemorrhage compared with 15% to 19% of the women classified as high risk by standard predictive tools. They also identified potential “inflection points” where changes in vital signs may suggest a substantial increase in risk. For example, women whose median blood pressure during labor and delivery was above 132 mm Hg had an 11% average increase in their risk for bleeding. 

By more precisely identifying women at risk, the new method “could be used to pre-emptively allocate resources that can ultimately reduce postpartum hemorrhage morbidity and mortality,” Dr. Li said. Sema4 is launching a prospective clinical trial to further assess the algorithm, she added.  
 

Finding the continuum of risk

Holly Ende, MD, an obstetric anesthesiologist at Vanderbilt University Medical Center, Nashville, Tenn., said approaches that leverage electronic health records to identify women at risk for hemorrhage have many advantages over currently used tools.

“Machine learning models or statistical models are able to take into account many more risk factors and weigh each of those risk factors based on how much they contribute to risk,” Dr. Ende, who was not involved in the new studies, told this news organization. “We can stratify women more on a continuum.”

But digital approaches have potential downsides.

“Machine learning algorithms can be developed in such a way that perpetuates racial bias, and it’s important to be aware of potential biases in coded algorithms,” Dr. Li said. To help reduce such bias, they used a database that included a racially and ethnically diverse patient population, but she acknowledged that additional research is needed.

Dr. Ende, the coauthor of a commentary in Obstetrics & Gynecology on risk assessment for postpartum hemorrhage, said algorithm developers must be sensitive to pre-existing disparities in health care that may affect the data they use to build the software.

She pointed to uterine atony – a known risk factor for hemorrhage – as an example. In her own research, she and her colleagues identified women with atony by searching their medical records for medications used to treat the condition. But when they ran their model, Black women were less likely to develop uterine atony, which the team knew wasn’t true in the real world. They traced the problem to an existing disparity in obstetric care: Black women with uterine atony were less likely than women of other races to receive medications for the condition.

“People need to be cognizant as they are developing these types of prediction models and be extremely careful to avoid perpetuating any disparities in care,” Dr. Ende cautioned. On the other hand, if carefully developed, these tools might also help reduce disparities in health care by standardizing risk stratification and clinical practices, she said.

In addition to independent validation of data-based risk prediction tools, Dr. Ende said ensuring that clinicians are properly trained to use these tools is crucial.

“Implementation may be the biggest limitation,” she said.

Dr. Ende and Dr. Li have disclosed no relevant financial relationships.

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

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.