Mixed Topics

Glucagon-like peptide 1 (GLP-1) receptor agonists led to a significant reduction in the risk for venous thromboembolism (VTE) among individuals with type 2 diabetes, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, a recent analysis indicated.

Overall, GLP-1 agonist use was associated with a 20% reduction in VTE, compared with DPP-4 inhibitor use, in those with type 2 diabetes, and this benefit held regardless of people’s obesity status, said study investigator Cho-Han Chiang, MD, a medical resident at Mount Auburn Hospital, Cambridge, Massachusetts, who presented the findings at the American Society of Hematology (ASH) 2024 Annual Meeting.

The incidence of VTE has increased by 20% over the past 10 years, and obesity is a risk factor for VTE, Chiang explained. A growing body of evidence demonstrated that GLP-1s provide a variety of cardiovascular benefits in people with type 2 diabetes, but data on VTE benefits remain more limited.

In the retrospective study, the researchers combed electronic health records from the TriNetX global database, which includes more than 250 million patients, and identified adults with type 2 diabetes who were taking a GLP-1 agonist or a DPP-4 inhibitor.

After excluding anyone with prior VTE or atrial fibrillation as well as those treated with both drugs or with oral anticoagulants, patients on GLP-1s were matched with those on DPP-4 inhibitors based on predetermined variables, including age, sex, race, body mass index (BMI), hemoglobin A1c, use of other antidiabetic agents, and underlying comorbidities. VTE was a composite of pulmonary embolism and deep vein thrombosis.

The researchers also performed a subgroup analysis that stratified patients by obesity status, defined as a BMI ≥ 30.

Within 1 year of GLP-1 or DPP-4 prescription, VTE occurred at a rate of 6.5 cases/1000 person-years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (hazard ratio [HR], 0.80; P < .001).

The 20% risk reduction in VTE held across various subgroups of BMI, including among those with obesity, Chiang reported.

Among patients with the highest BMI (≥ 40), VTE occurred at a rate of 7.2 cases/1000 person years in the GLP-1 group vs 9.6 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.74). Among patients with the next highest BMI (30-34.9), VTE occurred at a rate of 4.8 cases/1000 person years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.60). Among those with the lowest BMI (18.5-24.9), VTE occurred significantly less frequently among those in the GLP-1 group — 4.7 cases/1000 person years vs 7.4 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.61).

The lower risk for VTE associated with GLP-1s also held across the individual components of the composite VTE. Pulmonary embolism occurred at a rate of 3.1 cases/1000 person years in the GLP-1 group vs 3.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.78), and deep vein thrombosis occurred in 4.2 cases/1000 person years in the GLP-1 group vs 5.0 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.82).

Interestingly, the GLP-1 and DPP-4 curves started diverging within the first 30 days of the index prescription date, said Chiang.

Session moderator Ghadeer Dawwas, PhD, said in an interview that patients with type 2 diabetes are increasingly using GLP-1 agonists because of the cardiovascular benefits associated with the agents, which include lower risks for stroke and heart failure, but the antithrombotic benefits are still debated.

“The current study indicates that GLP-1 agonists may help lower the risk of VTE in patients with type 2 diabetes, irrespective of their baseline body weight,” said Dawwas, a pharmacoepidemiologist and assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “However, given the current landscape of evidence and the existence of conflicting data on VTE risk, clinicians should proceed with caution and await further studies to validate these findings before making clinical decisions.”

This study was funded by the National Blood Clot Alliance and Conquer Cancer Foundation. Chiang and Dawwas had no disclosures.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 (GLP-1) receptor agonists led to a significant reduction in the risk for venous thromboembolism (VTE) among individuals with type 2 diabetes, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, a recent analysis indicated.

Overall, GLP-1 agonist use was associated with a 20% reduction in VTE, compared with DPP-4 inhibitor use, in those with type 2 diabetes, and this benefit held regardless of people’s obesity status, said study investigator Cho-Han Chiang, MD, a medical resident at Mount Auburn Hospital, Cambridge, Massachusetts, who presented the findings at the American Society of Hematology (ASH) 2024 Annual Meeting.

The incidence of VTE has increased by 20% over the past 10 years, and obesity is a risk factor for VTE, Chiang explained. A growing body of evidence demonstrated that GLP-1s provide a variety of cardiovascular benefits in people with type 2 diabetes, but data on VTE benefits remain more limited.

In the retrospective study, the researchers combed electronic health records from the TriNetX global database, which includes more than 250 million patients, and identified adults with type 2 diabetes who were taking a GLP-1 agonist or a DPP-4 inhibitor.

After excluding anyone with prior VTE or atrial fibrillation as well as those treated with both drugs or with oral anticoagulants, patients on GLP-1s were matched with those on DPP-4 inhibitors based on predetermined variables, including age, sex, race, body mass index (BMI), hemoglobin A1c, use of other antidiabetic agents, and underlying comorbidities. VTE was a composite of pulmonary embolism and deep vein thrombosis.

The researchers also performed a subgroup analysis that stratified patients by obesity status, defined as a BMI ≥ 30.

Within 1 year of GLP-1 or DPP-4 prescription, VTE occurred at a rate of 6.5 cases/1000 person-years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (hazard ratio [HR], 0.80; P < .001).

The 20% risk reduction in VTE held across various subgroups of BMI, including among those with obesity, Chiang reported.

Among patients with the highest BMI (≥ 40), VTE occurred at a rate of 7.2 cases/1000 person years in the GLP-1 group vs 9.6 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.74). Among patients with the next highest BMI (30-34.9), VTE occurred at a rate of 4.8 cases/1000 person years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.60). Among those with the lowest BMI (18.5-24.9), VTE occurred significantly less frequently among those in the GLP-1 group — 4.7 cases/1000 person years vs 7.4 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.61).

The lower risk for VTE associated with GLP-1s also held across the individual components of the composite VTE. Pulmonary embolism occurred at a rate of 3.1 cases/1000 person years in the GLP-1 group vs 3.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.78), and deep vein thrombosis occurred in 4.2 cases/1000 person years in the GLP-1 group vs 5.0 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.82).

Interestingly, the GLP-1 and DPP-4 curves started diverging within the first 30 days of the index prescription date, said Chiang.

Session moderator Ghadeer Dawwas, PhD, said in an interview that patients with type 2 diabetes are increasingly using GLP-1 agonists because of the cardiovascular benefits associated with the agents, which include lower risks for stroke and heart failure, but the antithrombotic benefits are still debated.

“The current study indicates that GLP-1 agonists may help lower the risk of VTE in patients with type 2 diabetes, irrespective of their baseline body weight,” said Dawwas, a pharmacoepidemiologist and assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “However, given the current landscape of evidence and the existence of conflicting data on VTE risk, clinicians should proceed with caution and await further studies to validate these findings before making clinical decisions.”

This study was funded by the National Blood Clot Alliance and Conquer Cancer Foundation. Chiang and Dawwas had no disclosures.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 (GLP-1) receptor agonists led to a significant reduction in the risk for venous thromboembolism (VTE) among individuals with type 2 diabetes, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, a recent analysis indicated.

Overall, GLP-1 agonist use was associated with a 20% reduction in VTE, compared with DPP-4 inhibitor use, in those with type 2 diabetes, and this benefit held regardless of people’s obesity status, said study investigator Cho-Han Chiang, MD, a medical resident at Mount Auburn Hospital, Cambridge, Massachusetts, who presented the findings at the American Society of Hematology (ASH) 2024 Annual Meeting.

The incidence of VTE has increased by 20% over the past 10 years, and obesity is a risk factor for VTE, Chiang explained. A growing body of evidence demonstrated that GLP-1s provide a variety of cardiovascular benefits in people with type 2 diabetes, but data on VTE benefits remain more limited.

In the retrospective study, the researchers combed electronic health records from the TriNetX global database, which includes more than 250 million patients, and identified adults with type 2 diabetes who were taking a GLP-1 agonist or a DPP-4 inhibitor.

After excluding anyone with prior VTE or atrial fibrillation as well as those treated with both drugs or with oral anticoagulants, patients on GLP-1s were matched with those on DPP-4 inhibitors based on predetermined variables, including age, sex, race, body mass index (BMI), hemoglobin A1c, use of other antidiabetic agents, and underlying comorbidities. VTE was a composite of pulmonary embolism and deep vein thrombosis.

The researchers also performed a subgroup analysis that stratified patients by obesity status, defined as a BMI ≥ 30.

Within 1 year of GLP-1 or DPP-4 prescription, VTE occurred at a rate of 6.5 cases/1000 person-years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (hazard ratio [HR], 0.80; P < .001).

The 20% risk reduction in VTE held across various subgroups of BMI, including among those with obesity, Chiang reported.

Among patients with the highest BMI (≥ 40), VTE occurred at a rate of 7.2 cases/1000 person years in the GLP-1 group vs 9.6 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.74). Among patients with the next highest BMI (30-34.9), VTE occurred at a rate of 4.8 cases/1000 person years in the GLP-1 group vs 7.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.60). Among those with the lowest BMI (18.5-24.9), VTE occurred significantly less frequently among those in the GLP-1 group — 4.7 cases/1000 person years vs 7.4 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.61).

The lower risk for VTE associated with GLP-1s also held across the individual components of the composite VTE. Pulmonary embolism occurred at a rate of 3.1 cases/1000 person years in the GLP-1 group vs 3.9 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.78), and deep vein thrombosis occurred in 4.2 cases/1000 person years in the GLP-1 group vs 5.0 cases/1000 person years in the DPP-4 inhibitor group (HR, 0.82).

Interestingly, the GLP-1 and DPP-4 curves started diverging within the first 30 days of the index prescription date, said Chiang.

Session moderator Ghadeer Dawwas, PhD, said in an interview that patients with type 2 diabetes are increasingly using GLP-1 agonists because of the cardiovascular benefits associated with the agents, which include lower risks for stroke and heart failure, but the antithrombotic benefits are still debated.

“The current study indicates that GLP-1 agonists may help lower the risk of VTE in patients with type 2 diabetes, irrespective of their baseline body weight,” said Dawwas, a pharmacoepidemiologist and assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “However, given the current landscape of evidence and the existence of conflicting data on VTE risk, clinicians should proceed with caution and await further studies to validate these findings before making clinical decisions.”

This study was funded by the National Blood Clot Alliance and Conquer Cancer Foundation. Chiang and Dawwas had no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — Significant complications were common in female patients with sickle cell disease (SCD) who underwent fertility preservation (FP) procedures, and 13% required multiple retrieval cycles, a five-center retrospective study found.

Of 46 patients with SCD, complications occurred in 25 of 55 controlled ovarian hyperstimulation cycles, including 29 vaso-occlusive episodes (VOEs), researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

Of 21 post-retrieval VOEs, 19 required emergency department care or hospitalization.

“Baseline sickle cell disease severity is most likely associated with a patient’s risk of complications from an egg retrieval cycle,” study co-author Sarah Cromack, MD, a reproductive endocrinology and infertility fellow at Northwestern University, Chicago, said in an interview.

“Both hematologists and reproductive endocrinologists can use this information to plan ahead and anticipate possible issues, check blood counts prior to and after egg retrieval to see if transfusion is needed, and plan close follow-up during stimulation and immediately after egg retrieval to evaluate and treat pain.”

 

SCD Accelerates Decline in Ovarian Reserve

Pediatric hematologist Lydia H. Pecker, MD, MS, of Johns Hopkins University School of Medicine, Baltimore, the study’s corresponding author, said in an interview that SCD is “a disease of accelerated aging” that leads to accelerated decline in ovarian reserve. “The common indication for fertility preservation in SCD is before bone marrow transplant or gene therapy,” she said, although FP can also be offered to other patients with SCD.

According to Cromack, researchers launched the study to expand information about SCD and FP in light of sparse data about outcomes.

All the 46 patients had hemoglobin SS (HbSS, 93%) and HbSβ0-thalassemia (7%) and a median age of 23.7 (18-28) years. Almost all (44 patients) underwent FP prior to curative treatments, and all had at least one SCD-related complication, mainly cerebrovascular disease (16), acute chest syndrome (23), and more than two VOEs per year (31).

Median anti-Mullerian hormone (AMH) level (2.1 ng/mL), a measurement of ovarian reserve, was lower than the expected level of 2.8-3.4 ng/mL among women in the age range of the patients, the researchers reported. “This is consistent with previous studies showing lower AMH for age in women with sickle cell disease,” Pecker said.

 

Complications in 45% of Retrieval Cycles

“In terms of success of oocyte cryopreservation, the median number of mature eggs frozen was 11,” said co-author and reproductive endocrinologist Jessica Walter, MD, of Northwestern University, in an interview. “Given the average age of 24 years in the cohort, this would give each patient about a 70% estimated probability of at least one live birth from their cohort of frozen eggs. Thus, patients hoping for more than one child may want to consider more than one cycle of egg freezing.”

The rate of complications was “fairly high” at 45% of all cycles, Walter said. “These were mostly complications from underlying sickle cell disease, including unplanned transfusions and admissions for vaso-occlusive crises. Surprisingly, there were very few cases of ovarian hyperstimulation syndrome in this young patient group, which may be due to a combination of underlying vascular disease, lower peak estradiol levels, and slightly less eggs retrieved then would be expected compared to an age-matched healthy controls.”

Any FP complication was associated with more than three VOEs in the year before controlled ovarian hyperstimulation (mean of three VOEs per patient without complications vs six per patient with complications; P = .036).

 

Higher Than Normal Need for Multiple Cycles

Reproductive endocrinologist H. Irene Su, MD, professor and co-director of the Center for OB/GYN Research Innovations at Moores Cancer Center, University of California San Diego, praised the study as “an important report” in an interview.

Su, who wasn’t involved in the research, said the percentage of patients requiring more than one cycle due to cancellation or low oocyte yield — 13% — is “higher than expected, given the young age of this cohort.”

This could reflect the hypothesis that “sickle cell crises and hypoxia adversely affect the finite number of oocytes in the ovary,” she said.

As for the study findings regarding complications, she said the rate “is very high compared to the general infertility or fertility preservation population. It would be good to learn predictors of these outcomes so that fertility and hematology clinicians can work together to stratify risk and supportive services around FP cycles. It would also be good to know if the post-retrieval VOE were unexpected given the patient’s disease activity prior to FP.”

 

Message: FP in SCD Is Feasible, Acceptable

A.D. Mishkin, MD, MPH, associate professor of psychiatry and liaison to the Blood and Marrow Transplantation Program at NewYork–Presbyterian/Columbia University Irving Medical Center, New York City, said in an interview that the study “establishes the feasibility and acceptability of oocyte harvest and preservation in a population of patients with active ongoing symptoms from SCD. It also indicates their interest in pursuing fertility preservation in the setting of frequent crises and the potential for management of ensuing complications.”

Mishkin, who didn’t take part in the research, highlighted the finding that half the patients got access to FP via public insurance or research funding. “Even in this population where most women had multiple complications in the year prior to FP, and even among patients who needed multiple retrievals, these patients wanted to go through that risk to preserve their fertility,” Mishkin said. “This is an important finding given the very limited access many individuals have to FP due to its high cost and limited insurance coverage, which is also largely state-dependent.”

There’s another factor to consider regarding SCD and FP: The potential danger of pregnancy.

Corresponding author Pecker noted that “pregnancy is high risk for people with sickle cell disease. There are very high rates of severe maternal mortality and morbidity even in high-income countries. However, some of this is modifiable with routine use of chronic transfusions during pregnancy and with high-quality and integrated expert SCD and expert maternal fetal medicine care during pregnancy.”

The National Institutes of Health supported the research. Pecker reported receiving research funding from Alexion, Novartis, and Aummune and consulting for Novo Nordisk. Other authors reported no disclosures. Su and Mishkin reported no disclosures.

 

A version of this article appeared on Medscape.com.

SAN DIEGO — Significant complications were common in female patients with sickle cell disease (SCD) who underwent fertility preservation (FP) procedures, and 13% required multiple retrieval cycles, a five-center retrospective study found.

Of 46 patients with SCD, complications occurred in 25 of 55 controlled ovarian hyperstimulation cycles, including 29 vaso-occlusive episodes (VOEs), researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

Of 21 post-retrieval VOEs, 19 required emergency department care or hospitalization.

“Baseline sickle cell disease severity is most likely associated with a patient’s risk of complications from an egg retrieval cycle,” study co-author Sarah Cromack, MD, a reproductive endocrinology and infertility fellow at Northwestern University, Chicago, said in an interview.

“Both hematologists and reproductive endocrinologists can use this information to plan ahead and anticipate possible issues, check blood counts prior to and after egg retrieval to see if transfusion is needed, and plan close follow-up during stimulation and immediately after egg retrieval to evaluate and treat pain.”

 

SCD Accelerates Decline in Ovarian Reserve

Pediatric hematologist Lydia H. Pecker, MD, MS, of Johns Hopkins University School of Medicine, Baltimore, the study’s corresponding author, said in an interview that SCD is “a disease of accelerated aging” that leads to accelerated decline in ovarian reserve. “The common indication for fertility preservation in SCD is before bone marrow transplant or gene therapy,” she said, although FP can also be offered to other patients with SCD.

According to Cromack, researchers launched the study to expand information about SCD and FP in light of sparse data about outcomes.

All the 46 patients had hemoglobin SS (HbSS, 93%) and HbSβ0-thalassemia (7%) and a median age of 23.7 (18-28) years. Almost all (44 patients) underwent FP prior to curative treatments, and all had at least one SCD-related complication, mainly cerebrovascular disease (16), acute chest syndrome (23), and more than two VOEs per year (31).

Median anti-Mullerian hormone (AMH) level (2.1 ng/mL), a measurement of ovarian reserve, was lower than the expected level of 2.8-3.4 ng/mL among women in the age range of the patients, the researchers reported. “This is consistent with previous studies showing lower AMH for age in women with sickle cell disease,” Pecker said.

 

Complications in 45% of Retrieval Cycles

“In terms of success of oocyte cryopreservation, the median number of mature eggs frozen was 11,” said co-author and reproductive endocrinologist Jessica Walter, MD, of Northwestern University, in an interview. “Given the average age of 24 years in the cohort, this would give each patient about a 70% estimated probability of at least one live birth from their cohort of frozen eggs. Thus, patients hoping for more than one child may want to consider more than one cycle of egg freezing.”

The rate of complications was “fairly high” at 45% of all cycles, Walter said. “These were mostly complications from underlying sickle cell disease, including unplanned transfusions and admissions for vaso-occlusive crises. Surprisingly, there were very few cases of ovarian hyperstimulation syndrome in this young patient group, which may be due to a combination of underlying vascular disease, lower peak estradiol levels, and slightly less eggs retrieved then would be expected compared to an age-matched healthy controls.”

Any FP complication was associated with more than three VOEs in the year before controlled ovarian hyperstimulation (mean of three VOEs per patient without complications vs six per patient with complications; P = .036).

 

Higher Than Normal Need for Multiple Cycles

Reproductive endocrinologist H. Irene Su, MD, professor and co-director of the Center for OB/GYN Research Innovations at Moores Cancer Center, University of California San Diego, praised the study as “an important report” in an interview.

Su, who wasn’t involved in the research, said the percentage of patients requiring more than one cycle due to cancellation or low oocyte yield — 13% — is “higher than expected, given the young age of this cohort.”

This could reflect the hypothesis that “sickle cell crises and hypoxia adversely affect the finite number of oocytes in the ovary,” she said.

As for the study findings regarding complications, she said the rate “is very high compared to the general infertility or fertility preservation population. It would be good to learn predictors of these outcomes so that fertility and hematology clinicians can work together to stratify risk and supportive services around FP cycles. It would also be good to know if the post-retrieval VOE were unexpected given the patient’s disease activity prior to FP.”

 

Message: FP in SCD Is Feasible, Acceptable

A.D. Mishkin, MD, MPH, associate professor of psychiatry and liaison to the Blood and Marrow Transplantation Program at NewYork–Presbyterian/Columbia University Irving Medical Center, New York City, said in an interview that the study “establishes the feasibility and acceptability of oocyte harvest and preservation in a population of patients with active ongoing symptoms from SCD. It also indicates their interest in pursuing fertility preservation in the setting of frequent crises and the potential for management of ensuing complications.”

Mishkin, who didn’t take part in the research, highlighted the finding that half the patients got access to FP via public insurance or research funding. “Even in this population where most women had multiple complications in the year prior to FP, and even among patients who needed multiple retrievals, these patients wanted to go through that risk to preserve their fertility,” Mishkin said. “This is an important finding given the very limited access many individuals have to FP due to its high cost and limited insurance coverage, which is also largely state-dependent.”

There’s another factor to consider regarding SCD and FP: The potential danger of pregnancy.

Corresponding author Pecker noted that “pregnancy is high risk for people with sickle cell disease. There are very high rates of severe maternal mortality and morbidity even in high-income countries. However, some of this is modifiable with routine use of chronic transfusions during pregnancy and with high-quality and integrated expert SCD and expert maternal fetal medicine care during pregnancy.”

The National Institutes of Health supported the research. Pecker reported receiving research funding from Alexion, Novartis, and Aummune and consulting for Novo Nordisk. Other authors reported no disclosures. Su and Mishkin reported no disclosures.

 

A version of this article appeared on Medscape.com.

SAN DIEGO — Significant complications were common in female patients with sickle cell disease (SCD) who underwent fertility preservation (FP) procedures, and 13% required multiple retrieval cycles, a five-center retrospective study found.

Of 46 patients with SCD, complications occurred in 25 of 55 controlled ovarian hyperstimulation cycles, including 29 vaso-occlusive episodes (VOEs), researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.

Of 21 post-retrieval VOEs, 19 required emergency department care or hospitalization.

“Baseline sickle cell disease severity is most likely associated with a patient’s risk of complications from an egg retrieval cycle,” study co-author Sarah Cromack, MD, a reproductive endocrinology and infertility fellow at Northwestern University, Chicago, said in an interview.

“Both hematologists and reproductive endocrinologists can use this information to plan ahead and anticipate possible issues, check blood counts prior to and after egg retrieval to see if transfusion is needed, and plan close follow-up during stimulation and immediately after egg retrieval to evaluate and treat pain.”

 

SCD Accelerates Decline in Ovarian Reserve

Pediatric hematologist Lydia H. Pecker, MD, MS, of Johns Hopkins University School of Medicine, Baltimore, the study’s corresponding author, said in an interview that SCD is “a disease of accelerated aging” that leads to accelerated decline in ovarian reserve. “The common indication for fertility preservation in SCD is before bone marrow transplant or gene therapy,” she said, although FP can also be offered to other patients with SCD.

According to Cromack, researchers launched the study to expand information about SCD and FP in light of sparse data about outcomes.

All the 46 patients had hemoglobin SS (HbSS, 93%) and HbSβ0-thalassemia (7%) and a median age of 23.7 (18-28) years. Almost all (44 patients) underwent FP prior to curative treatments, and all had at least one SCD-related complication, mainly cerebrovascular disease (16), acute chest syndrome (23), and more than two VOEs per year (31).

Median anti-Mullerian hormone (AMH) level (2.1 ng/mL), a measurement of ovarian reserve, was lower than the expected level of 2.8-3.4 ng/mL among women in the age range of the patients, the researchers reported. “This is consistent with previous studies showing lower AMH for age in women with sickle cell disease,” Pecker said.

 

Complications in 45% of Retrieval Cycles

“In terms of success of oocyte cryopreservation, the median number of mature eggs frozen was 11,” said co-author and reproductive endocrinologist Jessica Walter, MD, of Northwestern University, in an interview. “Given the average age of 24 years in the cohort, this would give each patient about a 70% estimated probability of at least one live birth from their cohort of frozen eggs. Thus, patients hoping for more than one child may want to consider more than one cycle of egg freezing.”

The rate of complications was “fairly high” at 45% of all cycles, Walter said. “These were mostly complications from underlying sickle cell disease, including unplanned transfusions and admissions for vaso-occlusive crises. Surprisingly, there were very few cases of ovarian hyperstimulation syndrome in this young patient group, which may be due to a combination of underlying vascular disease, lower peak estradiol levels, and slightly less eggs retrieved then would be expected compared to an age-matched healthy controls.”

Any FP complication was associated with more than three VOEs in the year before controlled ovarian hyperstimulation (mean of three VOEs per patient without complications vs six per patient with complications; P = .036).

 

Higher Than Normal Need for Multiple Cycles

Reproductive endocrinologist H. Irene Su, MD, professor and co-director of the Center for OB/GYN Research Innovations at Moores Cancer Center, University of California San Diego, praised the study as “an important report” in an interview.

Su, who wasn’t involved in the research, said the percentage of patients requiring more than one cycle due to cancellation or low oocyte yield — 13% — is “higher than expected, given the young age of this cohort.”

This could reflect the hypothesis that “sickle cell crises and hypoxia adversely affect the finite number of oocytes in the ovary,” she said.

As for the study findings regarding complications, she said the rate “is very high compared to the general infertility or fertility preservation population. It would be good to learn predictors of these outcomes so that fertility and hematology clinicians can work together to stratify risk and supportive services around FP cycles. It would also be good to know if the post-retrieval VOE were unexpected given the patient’s disease activity prior to FP.”

 

Message: FP in SCD Is Feasible, Acceptable

A.D. Mishkin, MD, MPH, associate professor of psychiatry and liaison to the Blood and Marrow Transplantation Program at NewYork–Presbyterian/Columbia University Irving Medical Center, New York City, said in an interview that the study “establishes the feasibility and acceptability of oocyte harvest and preservation in a population of patients with active ongoing symptoms from SCD. It also indicates their interest in pursuing fertility preservation in the setting of frequent crises and the potential for management of ensuing complications.”

Mishkin, who didn’t take part in the research, highlighted the finding that half the patients got access to FP via public insurance or research funding. “Even in this population where most women had multiple complications in the year prior to FP, and even among patients who needed multiple retrievals, these patients wanted to go through that risk to preserve their fertility,” Mishkin said. “This is an important finding given the very limited access many individuals have to FP due to its high cost and limited insurance coverage, which is also largely state-dependent.”

There’s another factor to consider regarding SCD and FP: The potential danger of pregnancy.

Corresponding author Pecker noted that “pregnancy is high risk for people with sickle cell disease. There are very high rates of severe maternal mortality and morbidity even in high-income countries. However, some of this is modifiable with routine use of chronic transfusions during pregnancy and with high-quality and integrated expert SCD and expert maternal fetal medicine care during pregnancy.”

The National Institutes of Health supported the research. Pecker reported receiving research funding from Alexion, Novartis, and Aummune and consulting for Novo Nordisk. Other authors reported no disclosures. Su and Mishkin reported no disclosures.

 

A version of this article appeared on Medscape.com.

We have a tradition at Federal Practitioner where the December editorial usually features some version of the “best and worst” of the last 12 months in government health care. As we close out a difficult year, instead I offer a cautionary yet promising story that epitomizes both risk and benefit.

In some quarters, 2024 has been the year of AI (artificial intelligence).² While in science fiction, superhuman machines, like the Terminator, are often associated with apocalyptic threats, we often forget the positive models of human-technology interaction, such as the protective robot in Lost in Space. While AI is not yet as advanced as what has already been depicted on the screen, it is inextricably interwoven into the daily fabric of our lives. Almost any website you go to for business or pleasure has a chatbot waiting to help (or frustrate) you. Most of us have Alexa, Siri, or another digital assistant organizing our homes and schedules. When I Google “everyday uses of artificial intelligence,” it is AI that responds with an overview.

Medicine is not immune. Renowned physician and scientist Eric Topol, MD, suggests that AI represents a “fourth industrial revolution in medicine” that can dramatically improve health care.³ The US Department of Veterans Affairs (VA) has been at the forefront of this new space.⁴ The story recounted below encapsulates the enormous benefits AI can bring to health care and the vigilance we must exercise to anticipate and mitigate risk for this to be an overall positive transition.

The story begins with a key element of AI change—the machine learning predictive algorithm. In this case, the algorithm was designed to predict—and thereby prevent—the top public health priority in federal practice: suicide. The Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program was launched in 2017 to assist in identifying the top 0.1% of veterans at the highest risk for suicide.⁵

At least at this stage of AI in medicine, the safest and most ethical efforts come from collaborations between health care professionals and AI developers that maximize the very different strengths of each partner. REACH VET is an exemplar of this kind of teamwork. Once the algorithm analyzes > 60 variables to identify veterans at high risk for suicide, data are communicated to a REACH VET program coordinator, who then notifies the practitioner responsible for the veteran’s care so they can put into action evidence-based suicide prevention strategies.⁵

VA researchers in 2021 published a study of 173,313 veterans comparing outcomes before and after entry into the program using a triple differences design. Veterans participating in the program reported an increase in outpatient visits and documentation of safety plans, and a decrease in emergency department visits, inpatient mental health admissions, and recorded suicide attempts.⁶

A US Government Accounting Office analysis found that “REACH VET had identified veterans who had not been identified through other methods.”⁷ This was not just an example of AI hype: as a relatively rare and statistically complicated phenomenon, suicide is notoriously difficult to predict and model. Machine learning algorithms like REACH VET have unprecedented potential to assist and augment suicide prevention.⁸

In 2023, veteran service organizations and journalists raised concerns that the AI algorithm was biased and ignored critical risk factors that put some veterans at increased risk. Based on their analysis, they claimed that the algorithm did not account for risk factors uniquely associated with women veterans, namely military sexual trauma and intimate partner violence.⁹ Women are the most rapidly growing VA population, yet too often they encounter health care disparities, harassment, and stigmatization when seeking care. The Congressional Veterans Affairs committees investigated and introduced legislation to update the algorithm.¹⁰

VA experts dispute these claims, and a computer science PhD may be required to understand the debate. But as the history of medicine has shown us, every treatment and procedure has benefits and risks. No matter how bright and shiny the technology initially appears, a soft scientific underbelly emerges sooner or later. Just as with REACH VET, algorithm bias is often discovered during deployment when the logic of the laboratory encounters the unpredictable variety of humankind.¹¹ Frequently, those problems are—as with REACH VET— not solely or even primarily technical ones. The data mirror society and reflect its biases.

For learning organizations like the VA and the US Department of Defense (DoD), the criticisms of REACH VET signal the need to engage in continuous performance improvement. AI requires the human trainers and supervisors who teach the machines to continuously revise and update their lesson plans. The most recent VA data show that in 2021, 6392 veterans died by suicide.¹² In Congressional testimony, VA leaders reported that as of May 2024, REACH VET was operating in 28 VA facilities and had identified 6700 high-risk veterans.13 REACH VET can save veteran’s lives, which is the sine qua non for our federal health care systems.

The algorithm should be improved to identify ALL veterans so they receive lifesaving interventions. Every veteran’s life is sacred; the algorithm that may prevent suicide must be continuously improved. That is why our representatives did not propose to ban REACH VET or enforce an AI winter on the VA and DoD. Instead, they called for an update to the algorithm, underscoring the value of machine learning for suicide prediction and prevention.

The epigraph from one of the top AI ethicists and scientists in the world makes the point that AI is not the moral agent here: it is fallible humans who must keep learning along with machines. That is why, at the end of 2024, VA experts are revising the algorithm so REACH VET can help prevent even more veteran suicides in 2025 and beyond.¹⁴

We have a tradition at Federal Practitioner where the December editorial usually features some version of the “best and worst” of the last 12 months in government health care. As we close out a difficult year, instead I offer a cautionary yet promising story that epitomizes both risk and benefit.

In some quarters, 2024 has been the year of AI (artificial intelligence).² While in science fiction, superhuman machines, like the Terminator, are often associated with apocalyptic threats, we often forget the positive models of human-technology interaction, such as the protective robot in Lost in Space. While AI is not yet as advanced as what has already been depicted on the screen, it is inextricably interwoven into the daily fabric of our lives. Almost any website you go to for business or pleasure has a chatbot waiting to help (or frustrate) you. Most of us have Alexa, Siri, or another digital assistant organizing our homes and schedules. When I Google “everyday uses of artificial intelligence,” it is AI that responds with an overview.

Medicine is not immune. Renowned physician and scientist Eric Topol, MD, suggests that AI represents a “fourth industrial revolution in medicine” that can dramatically improve health care.³ The US Department of Veterans Affairs (VA) has been at the forefront of this new space.⁴ The story recounted below encapsulates the enormous benefits AI can bring to health care and the vigilance we must exercise to anticipate and mitigate risk for this to be an overall positive transition.

The story begins with a key element of AI change—the machine learning predictive algorithm. In this case, the algorithm was designed to predict—and thereby prevent—the top public health priority in federal practice: suicide. The Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program was launched in 2017 to assist in identifying the top 0.1% of veterans at the highest risk for suicide.⁵

At least at this stage of AI in medicine, the safest and most ethical efforts come from collaborations between health care professionals and AI developers that maximize the very different strengths of each partner. REACH VET is an exemplar of this kind of teamwork. Once the algorithm analyzes > 60 variables to identify veterans at high risk for suicide, data are communicated to a REACH VET program coordinator, who then notifies the practitioner responsible for the veteran’s care so they can put into action evidence-based suicide prevention strategies.⁵

VA researchers in 2021 published a study of 173,313 veterans comparing outcomes before and after entry into the program using a triple differences design. Veterans participating in the program reported an increase in outpatient visits and documentation of safety plans, and a decrease in emergency department visits, inpatient mental health admissions, and recorded suicide attempts.⁶

A US Government Accounting Office analysis found that “REACH VET had identified veterans who had not been identified through other methods.”⁷ This was not just an example of AI hype: as a relatively rare and statistically complicated phenomenon, suicide is notoriously difficult to predict and model. Machine learning algorithms like REACH VET have unprecedented potential to assist and augment suicide prevention.⁸

In 2023, veteran service organizations and journalists raised concerns that the AI algorithm was biased and ignored critical risk factors that put some veterans at increased risk. Based on their analysis, they claimed that the algorithm did not account for risk factors uniquely associated with women veterans, namely military sexual trauma and intimate partner violence.⁹ Women are the most rapidly growing VA population, yet too often they encounter health care disparities, harassment, and stigmatization when seeking care. The Congressional Veterans Affairs committees investigated and introduced legislation to update the algorithm.¹⁰

VA experts dispute these claims, and a computer science PhD may be required to understand the debate. But as the history of medicine has shown us, every treatment and procedure has benefits and risks. No matter how bright and shiny the technology initially appears, a soft scientific underbelly emerges sooner or later. Just as with REACH VET, algorithm bias is often discovered during deployment when the logic of the laboratory encounters the unpredictable variety of humankind.¹¹ Frequently, those problems are—as with REACH VET— not solely or even primarily technical ones. The data mirror society and reflect its biases.

For learning organizations like the VA and the US Department of Defense (DoD), the criticisms of REACH VET signal the need to engage in continuous performance improvement. AI requires the human trainers and supervisors who teach the machines to continuously revise and update their lesson plans. The most recent VA data show that in 2021, 6392 veterans died by suicide.¹² In Congressional testimony, VA leaders reported that as of May 2024, REACH VET was operating in 28 VA facilities and had identified 6700 high-risk veterans.13 REACH VET can save veteran’s lives, which is the sine qua non for our federal health care systems.

The algorithm should be improved to identify ALL veterans so they receive lifesaving interventions. Every veteran’s life is sacred; the algorithm that may prevent suicide must be continuously improved. That is why our representatives did not propose to ban REACH VET or enforce an AI winter on the VA and DoD. Instead, they called for an update to the algorithm, underscoring the value of machine learning for suicide prediction and prevention.

The epigraph from one of the top AI ethicists and scientists in the world makes the point that AI is not the moral agent here: it is fallible humans who must keep learning along with machines. That is why, at the end of 2024, VA experts are revising the algorithm so REACH VET can help prevent even more veteran suicides in 2025 and beyond.¹⁴

We have a tradition at Federal Practitioner where the December editorial usually features some version of the “best and worst” of the last 12 months in government health care. As we close out a difficult year, instead I offer a cautionary yet promising story that epitomizes both risk and benefit.

In some quarters, 2024 has been the year of AI (artificial intelligence).² While in science fiction, superhuman machines, like the Terminator, are often associated with apocalyptic threats, we often forget the positive models of human-technology interaction, such as the protective robot in Lost in Space. While AI is not yet as advanced as what has already been depicted on the screen, it is inextricably interwoven into the daily fabric of our lives. Almost any website you go to for business or pleasure has a chatbot waiting to help (or frustrate) you. Most of us have Alexa, Siri, or another digital assistant organizing our homes and schedules. When I Google “everyday uses of artificial intelligence,” it is AI that responds with an overview.

Medicine is not immune. Renowned physician and scientist Eric Topol, MD, suggests that AI represents a “fourth industrial revolution in medicine” that can dramatically improve health care.³ The US Department of Veterans Affairs (VA) has been at the forefront of this new space.⁴ The story recounted below encapsulates the enormous benefits AI can bring to health care and the vigilance we must exercise to anticipate and mitigate risk for this to be an overall positive transition.

The story begins with a key element of AI change—the machine learning predictive algorithm. In this case, the algorithm was designed to predict—and thereby prevent—the top public health priority in federal practice: suicide. The Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program was launched in 2017 to assist in identifying the top 0.1% of veterans at the highest risk for suicide.⁵

At least at this stage of AI in medicine, the safest and most ethical efforts come from collaborations between health care professionals and AI developers that maximize the very different strengths of each partner. REACH VET is an exemplar of this kind of teamwork. Once the algorithm analyzes > 60 variables to identify veterans at high risk for suicide, data are communicated to a REACH VET program coordinator, who then notifies the practitioner responsible for the veteran’s care so they can put into action evidence-based suicide prevention strategies.⁵

VA researchers in 2021 published a study of 173,313 veterans comparing outcomes before and after entry into the program using a triple differences design. Veterans participating in the program reported an increase in outpatient visits and documentation of safety plans, and a decrease in emergency department visits, inpatient mental health admissions, and recorded suicide attempts.⁶

A US Government Accounting Office analysis found that “REACH VET had identified veterans who had not been identified through other methods.”⁷ This was not just an example of AI hype: as a relatively rare and statistically complicated phenomenon, suicide is notoriously difficult to predict and model. Machine learning algorithms like REACH VET have unprecedented potential to assist and augment suicide prevention.⁸

In 2023, veteran service organizations and journalists raised concerns that the AI algorithm was biased and ignored critical risk factors that put some veterans at increased risk. Based on their analysis, they claimed that the algorithm did not account for risk factors uniquely associated with women veterans, namely military sexual trauma and intimate partner violence.⁹ Women are the most rapidly growing VA population, yet too often they encounter health care disparities, harassment, and stigmatization when seeking care. The Congressional Veterans Affairs committees investigated and introduced legislation to update the algorithm.¹⁰

VA experts dispute these claims, and a computer science PhD may be required to understand the debate. But as the history of medicine has shown us, every treatment and procedure has benefits and risks. No matter how bright and shiny the technology initially appears, a soft scientific underbelly emerges sooner or later. Just as with REACH VET, algorithm bias is often discovered during deployment when the logic of the laboratory encounters the unpredictable variety of humankind.¹¹ Frequently, those problems are—as with REACH VET— not solely or even primarily technical ones. The data mirror society and reflect its biases.

For learning organizations like the VA and the US Department of Defense (DoD), the criticisms of REACH VET signal the need to engage in continuous performance improvement. AI requires the human trainers and supervisors who teach the machines to continuously revise and update their lesson plans. The most recent VA data show that in 2021, 6392 veterans died by suicide.¹² In Congressional testimony, VA leaders reported that as of May 2024, REACH VET was operating in 28 VA facilities and had identified 6700 high-risk veterans.13 REACH VET can save veteran’s lives, which is the sine qua non for our federal health care systems.

The algorithm should be improved to identify ALL veterans so they receive lifesaving interventions. Every veteran’s life is sacred; the algorithm that may prevent suicide must be continuously improved. That is why our representatives did not propose to ban REACH VET or enforce an AI winter on the VA and DoD. Instead, they called for an update to the algorithm, underscoring the value of machine learning for suicide prediction and prevention.

The epigraph from one of the top AI ethicists and scientists in the world makes the point that AI is not the moral agent here: it is fallible humans who must keep learning along with machines. That is why, at the end of 2024, VA experts are revising the algorithm so REACH VET can help prevent even more veteran suicides in 2025 and beyond.¹⁴

Recipients of allogeneic hematopoietic cell transplantation (allo-HCT) for blood disorders who maintain diets high in fiber show significant improvements in overall survival and a reduced risk of developing the potentially life-threatening complication of acute graft-versus-host disease (aGVHD), new research shows.

Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits. 

“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.

Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.

Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.

However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.

For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.

Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration. 

Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).

After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health. 

Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).

Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD. 

Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).

However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).

A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.

The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.

“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview. 

“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.

“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”

Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.

The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.

“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.

“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.

Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned. 

“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said. 

 

High-Fiber Diet Slows MM Disease Progression?

The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).

NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.

Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m² or higher.

The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI. 

Notably, two patients in the study had stabilization of disease progression.

“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement. 

“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.

The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.

Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not. 

“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.

The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.

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

Recipients of allogeneic hematopoietic cell transplantation (allo-HCT) for blood disorders who maintain diets high in fiber show significant improvements in overall survival and a reduced risk of developing the potentially life-threatening complication of acute graft-versus-host disease (aGVHD), new research shows.

Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits. 

“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.

Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.

Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.

However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.

For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.

Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration. 

Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).

After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health. 

Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).

Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD. 

Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).

However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).

A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.

The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.

“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview. 

“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.

“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”

Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.

The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.

“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.

“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.

Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned. 

“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said. 

 

High-Fiber Diet Slows MM Disease Progression?

The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).

NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.

Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m² or higher.

The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI. 

Notably, two patients in the study had stabilization of disease progression.

“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement. 

“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.

The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.

Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not. 

“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.

The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.

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

Recipients of allogeneic hematopoietic cell transplantation (allo-HCT) for blood disorders who maintain diets high in fiber show significant improvements in overall survival and a reduced risk of developing the potentially life-threatening complication of acute graft-versus-host disease (aGVHD), new research shows.

Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits. 

“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.

Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.

Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.

However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.

For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.

Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration. 

Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).

After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health. 

Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).

Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD. 

Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).

However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).

A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.

The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.

“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview. 

“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.

“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”

Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.

The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.

“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.

“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.

Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned. 

“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said. 

 

High-Fiber Diet Slows MM Disease Progression?

The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).

NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.

Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m² or higher.

The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI. 

Notably, two patients in the study had stabilization of disease progression.

“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement. 

“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.

The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.

Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not. 

“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.

The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.

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

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

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

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

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

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

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

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

Cyclosporine is a calcineurin inhibitor and immunosuppressive medication with several indications, including prevention of parenchymal organ and bone marrow transplant rejection as well as treatment of numerous dermatologic conditions (eg, psoriasis, atopic dermatitis). Although it is an effective medication, there are many known adverse effects including nephrotoxicity, hypertension, and gingival hyperplasia.¹ Addressing symptomatic cyclosporine-induced gingival hyperplasia can be challenging, especially if continued use of cyclosporine is necessary for adequate control of the underlying disease. We present a simplified approach for conservative management of cyclosporine-induced gingival hyperplasia that allows for continued use of cyclosporine.

Practice Gap

Cyclosporine-induced gingival hyperplasia is a fibrous overgrowth of the interdental papilla and labial gingiva that may lead to gum pain, difficulty eating, gingivitis, and/ or tooth decay or loss.² The condition usually occurs 3 to 6 months after starting cyclosporine but may occur as soon as 1 month later.^1,3 The pathophysiology of this adverse effect is incompletely understood, but several mechanisms have been implicated, including upregulation of the salivary proinflammatory cytokines IL-1α, IL-8, and IL-6.¹ Additionally, patients with cyclosporine-induced gingival hyperplasia have increased bacterial colonization with species such as Porphyromonas gingivalis.⁴ Risk factors for cyclosporine- induced gingival hyperplasia include higher serum concentrations (>400 ng/mL) of cyclosporine, history of gingival hyperplasia, concomitant use of calcium channel blockers, and insufficient oral hygiene.^2,3 A study by Seymour and Smith⁵ found that proper oral hygiene leads to less severe cases of cyclosporine-induced gingival hyperplasia but does not prevent gingival overgrowth. Treatment of cyclosporine-induced gingival hyperplasia traditionally involves targeting oral bacteria and reducing inflammation. Decreasing dental plaque through regular tooth-brushing and interdental cleaning may reduce symptoms such as bleeding and discomfort of the gums.

The intensity of cyclosporine-induced gingival hyperplasia can be reduced with chlorhexidine or azithromycin. Individually, each therapy has been shown to clinically improve cyclosporine-induced gingival hyperplasia; however, to our knowledge the combination of these treatments has not been reported.¹ We present a simplified approach to treating cyclosporine-induced gingival hyperplasia using both azithromycin and chlorhexidine. This conservative approach results in effective and sustained improvement of gingival hyperplasia while allowing patients to continue cyclosporine therapy to control underlying disease with minimal adverse effects.

Technique

Before initiating treatment, it is important to confirm that the etiology of gingival hyperplasia is due to cyclosporine use and rule out nutritional deficiencies and autoimmune conditions as potential causes. Be sure to inquire about nutritional intake, systemic symptoms, and family history of autoimmune conditions. Our approach includes the use of azithromycin 500 mg once daily for 7 days followed by chlorhexidine 0.12% oral solution 15 mL twice daily (swish undiluted for 30 seconds, then spit) for at least 3 months for optimal management of gingival hyperplasia. Chlorhexidine should be continued for at least 6 months to maintain symptom resolution. While cyclosporine therapy may be continued throughout the duration of this regimen, consider switching to other immunosuppressive medications that are not associated with gingival hyperplasia (eg, tacrolimus) if symptoms are severe and/or resistant to therapy.^1,6

We applied this technique to treat cyclosporine-induced gingival hyperplasia in a 28-year-old woman with a 3-year history of primary aplastic anemia. The patient initially presented with pain and bleeding of the gums of several months’ duration and reported experiencing gum pain when eating solid foods. Her medications included cyclosporine 225 mg daily for aplastic anemia and dapsone 100 mg daily for pneumocystis pneumonia prophylaxis, both of which were taken for the past 6 months. Oral examination revealed pink to bright red hyperplastic gingivae (Figure). She had no other symptoms associated with aplastic anemia and no signs of vitamin or nutritional deficiencies. She denied pre-existing periodontitis prior to starting cyclosporine and reported that the symptoms started several months after initiating cyclosporine therapy. Thus, the clinical diagnosis of cyclosporine-induced gingival hyperplasia was made, and treatment with azithromycin and chlorhexidine was initiated with marked reduction in symptoms.

Conservative management of gingival hyperplasia with oral hygiene including regular tooth-brushing and flossing and antimicrobial therapies was preferred in this patient to reduce gum pain and minimize the risk for tooth loss while also limiting the use of surgically invasive interventions. Due to limited therapeutic options for aplastic anemia, continued administration of cyclosporine was necessary in our patient to prevent further complications.

Practice Implications

The precise mechanism by which azithromycin treats gingival hyperplasia is unclear but may involve its antimicrobial and anti-inflammatory properties. Small concentrations of azithromycin have been shown to persist in macrophages and fibroblasts of the gingiva even with short-term administration of 3 to 5 days.⁷ Chlorhexidine is another antimicrobial agent often used in oral rinse solutions to decrease plaque formation and prevent gingivitis. Chlorhexidine can reduce cyclosporine-induced gingival overgrowth when used twice daily.⁸ After rinsing with chlorhexidine, saliva exhibits antibacterial activity for up to 5 hours; however, tooth and gum discoloration may occur.⁸

Recurrence of gingival hyperplasia is likely if cyclosporine is not discontinued or maintained with treatment.³ Conventional gingivectomy should be considered for cases in which conservative treatment is ineffective, aesthetic concerns arise, or gingival hyperplasia persists for more than 6 to 12 months after discontinuing cyclosporine.¹

We theorize that the microbial properties of azithromycin and chlorhexidine help reduce periodontal inflammation and bacterial overgrowth in patients with cyclosporine-induced gingival hyperplasia, which allows for restoration of gingival health. Our case highlights the efficacy of our treatment approach using a 7-day course of azithromycin followed by twice-daily use of chlorhexidine oral rinse in the treatment of cyclosporine-induced gingival hyperplasia with continued use of cyclosporine.

Cyclosporine is a calcineurin inhibitor and immunosuppressive medication with several indications, including prevention of parenchymal organ and bone marrow transplant rejection as well as treatment of numerous dermatologic conditions (eg, psoriasis, atopic dermatitis). Although it is an effective medication, there are many known adverse effects including nephrotoxicity, hypertension, and gingival hyperplasia.¹ Addressing symptomatic cyclosporine-induced gingival hyperplasia can be challenging, especially if continued use of cyclosporine is necessary for adequate control of the underlying disease. We present a simplified approach for conservative management of cyclosporine-induced gingival hyperplasia that allows for continued use of cyclosporine.

Practice Gap

Cyclosporine-induced gingival hyperplasia is a fibrous overgrowth of the interdental papilla and labial gingiva that may lead to gum pain, difficulty eating, gingivitis, and/ or tooth decay or loss.² The condition usually occurs 3 to 6 months after starting cyclosporine but may occur as soon as 1 month later.^1,3 The pathophysiology of this adverse effect is incompletely understood, but several mechanisms have been implicated, including upregulation of the salivary proinflammatory cytokines IL-1α, IL-8, and IL-6.¹ Additionally, patients with cyclosporine-induced gingival hyperplasia have increased bacterial colonization with species such as Porphyromonas gingivalis.⁴ Risk factors for cyclosporine- induced gingival hyperplasia include higher serum concentrations (>400 ng/mL) of cyclosporine, history of gingival hyperplasia, concomitant use of calcium channel blockers, and insufficient oral hygiene.^2,3 A study by Seymour and Smith⁵ found that proper oral hygiene leads to less severe cases of cyclosporine-induced gingival hyperplasia but does not prevent gingival overgrowth. Treatment of cyclosporine-induced gingival hyperplasia traditionally involves targeting oral bacteria and reducing inflammation. Decreasing dental plaque through regular tooth-brushing and interdental cleaning may reduce symptoms such as bleeding and discomfort of the gums.

The intensity of cyclosporine-induced gingival hyperplasia can be reduced with chlorhexidine or azithromycin. Individually, each therapy has been shown to clinically improve cyclosporine-induced gingival hyperplasia; however, to our knowledge the combination of these treatments has not been reported.¹ We present a simplified approach to treating cyclosporine-induced gingival hyperplasia using both azithromycin and chlorhexidine. This conservative approach results in effective and sustained improvement of gingival hyperplasia while allowing patients to continue cyclosporine therapy to control underlying disease with minimal adverse effects.

Technique

Before initiating treatment, it is important to confirm that the etiology of gingival hyperplasia is due to cyclosporine use and rule out nutritional deficiencies and autoimmune conditions as potential causes. Be sure to inquire about nutritional intake, systemic symptoms, and family history of autoimmune conditions. Our approach includes the use of azithromycin 500 mg once daily for 7 days followed by chlorhexidine 0.12% oral solution 15 mL twice daily (swish undiluted for 30 seconds, then spit) for at least 3 months for optimal management of gingival hyperplasia. Chlorhexidine should be continued for at least 6 months to maintain symptom resolution. While cyclosporine therapy may be continued throughout the duration of this regimen, consider switching to other immunosuppressive medications that are not associated with gingival hyperplasia (eg, tacrolimus) if symptoms are severe and/or resistant to therapy.^1,6

We applied this technique to treat cyclosporine-induced gingival hyperplasia in a 28-year-old woman with a 3-year history of primary aplastic anemia. The patient initially presented with pain and bleeding of the gums of several months’ duration and reported experiencing gum pain when eating solid foods. Her medications included cyclosporine 225 mg daily for aplastic anemia and dapsone 100 mg daily for pneumocystis pneumonia prophylaxis, both of which were taken for the past 6 months. Oral examination revealed pink to bright red hyperplastic gingivae (Figure). She had no other symptoms associated with aplastic anemia and no signs of vitamin or nutritional deficiencies. She denied pre-existing periodontitis prior to starting cyclosporine and reported that the symptoms started several months after initiating cyclosporine therapy. Thus, the clinical diagnosis of cyclosporine-induced gingival hyperplasia was made, and treatment with azithromycin and chlorhexidine was initiated with marked reduction in symptoms.

Conservative management of gingival hyperplasia with oral hygiene including regular tooth-brushing and flossing and antimicrobial therapies was preferred in this patient to reduce gum pain and minimize the risk for tooth loss while also limiting the use of surgically invasive interventions. Due to limited therapeutic options for aplastic anemia, continued administration of cyclosporine was necessary in our patient to prevent further complications.

Practice Implications

The precise mechanism by which azithromycin treats gingival hyperplasia is unclear but may involve its antimicrobial and anti-inflammatory properties. Small concentrations of azithromycin have been shown to persist in macrophages and fibroblasts of the gingiva even with short-term administration of 3 to 5 days.⁷ Chlorhexidine is another antimicrobial agent often used in oral rinse solutions to decrease plaque formation and prevent gingivitis. Chlorhexidine can reduce cyclosporine-induced gingival overgrowth when used twice daily.⁸ After rinsing with chlorhexidine, saliva exhibits antibacterial activity for up to 5 hours; however, tooth and gum discoloration may occur.⁸

Recurrence of gingival hyperplasia is likely if cyclosporine is not discontinued or maintained with treatment.³ Conventional gingivectomy should be considered for cases in which conservative treatment is ineffective, aesthetic concerns arise, or gingival hyperplasia persists for more than 6 to 12 months after discontinuing cyclosporine.¹

We theorize that the microbial properties of azithromycin and chlorhexidine help reduce periodontal inflammation and bacterial overgrowth in patients with cyclosporine-induced gingival hyperplasia, which allows for restoration of gingival health. Our case highlights the efficacy of our treatment approach using a 7-day course of azithromycin followed by twice-daily use of chlorhexidine oral rinse in the treatment of cyclosporine-induced gingival hyperplasia with continued use of cyclosporine.

Cyclosporine is a calcineurin inhibitor and immunosuppressive medication with several indications, including prevention of parenchymal organ and bone marrow transplant rejection as well as treatment of numerous dermatologic conditions (eg, psoriasis, atopic dermatitis). Although it is an effective medication, there are many known adverse effects including nephrotoxicity, hypertension, and gingival hyperplasia.¹ Addressing symptomatic cyclosporine-induced gingival hyperplasia can be challenging, especially if continued use of cyclosporine is necessary for adequate control of the underlying disease. We present a simplified approach for conservative management of cyclosporine-induced gingival hyperplasia that allows for continued use of cyclosporine.

Practice Gap

Cyclosporine-induced gingival hyperplasia is a fibrous overgrowth of the interdental papilla and labial gingiva that may lead to gum pain, difficulty eating, gingivitis, and/ or tooth decay or loss.² The condition usually occurs 3 to 6 months after starting cyclosporine but may occur as soon as 1 month later.^1,3 The pathophysiology of this adverse effect is incompletely understood, but several mechanisms have been implicated, including upregulation of the salivary proinflammatory cytokines IL-1α, IL-8, and IL-6.¹ Additionally, patients with cyclosporine-induced gingival hyperplasia have increased bacterial colonization with species such as Porphyromonas gingivalis.⁴ Risk factors for cyclosporine- induced gingival hyperplasia include higher serum concentrations (>400 ng/mL) of cyclosporine, history of gingival hyperplasia, concomitant use of calcium channel blockers, and insufficient oral hygiene.^2,3 A study by Seymour and Smith⁵ found that proper oral hygiene leads to less severe cases of cyclosporine-induced gingival hyperplasia but does not prevent gingival overgrowth. Treatment of cyclosporine-induced gingival hyperplasia traditionally involves targeting oral bacteria and reducing inflammation. Decreasing dental plaque through regular tooth-brushing and interdental cleaning may reduce symptoms such as bleeding and discomfort of the gums.

The intensity of cyclosporine-induced gingival hyperplasia can be reduced with chlorhexidine or azithromycin. Individually, each therapy has been shown to clinically improve cyclosporine-induced gingival hyperplasia; however, to our knowledge the combination of these treatments has not been reported.¹ We present a simplified approach to treating cyclosporine-induced gingival hyperplasia using both azithromycin and chlorhexidine. This conservative approach results in effective and sustained improvement of gingival hyperplasia while allowing patients to continue cyclosporine therapy to control underlying disease with minimal adverse effects.

Technique

Before initiating treatment, it is important to confirm that the etiology of gingival hyperplasia is due to cyclosporine use and rule out nutritional deficiencies and autoimmune conditions as potential causes. Be sure to inquire about nutritional intake, systemic symptoms, and family history of autoimmune conditions. Our approach includes the use of azithromycin 500 mg once daily for 7 days followed by chlorhexidine 0.12% oral solution 15 mL twice daily (swish undiluted for 30 seconds, then spit) for at least 3 months for optimal management of gingival hyperplasia. Chlorhexidine should be continued for at least 6 months to maintain symptom resolution. While cyclosporine therapy may be continued throughout the duration of this regimen, consider switching to other immunosuppressive medications that are not associated with gingival hyperplasia (eg, tacrolimus) if symptoms are severe and/or resistant to therapy.^1,6

We applied this technique to treat cyclosporine-induced gingival hyperplasia in a 28-year-old woman with a 3-year history of primary aplastic anemia. The patient initially presented with pain and bleeding of the gums of several months’ duration and reported experiencing gum pain when eating solid foods. Her medications included cyclosporine 225 mg daily for aplastic anemia and dapsone 100 mg daily for pneumocystis pneumonia prophylaxis, both of which were taken for the past 6 months. Oral examination revealed pink to bright red hyperplastic gingivae (Figure). She had no other symptoms associated with aplastic anemia and no signs of vitamin or nutritional deficiencies. She denied pre-existing periodontitis prior to starting cyclosporine and reported that the symptoms started several months after initiating cyclosporine therapy. Thus, the clinical diagnosis of cyclosporine-induced gingival hyperplasia was made, and treatment with azithromycin and chlorhexidine was initiated with marked reduction in symptoms.

Conservative management of gingival hyperplasia with oral hygiene including regular tooth-brushing and flossing and antimicrobial therapies was preferred in this patient to reduce gum pain and minimize the risk for tooth loss while also limiting the use of surgically invasive interventions. Due to limited therapeutic options for aplastic anemia, continued administration of cyclosporine was necessary in our patient to prevent further complications.

Practice Implications

The precise mechanism by which azithromycin treats gingival hyperplasia is unclear but may involve its antimicrobial and anti-inflammatory properties. Small concentrations of azithromycin have been shown to persist in macrophages and fibroblasts of the gingiva even with short-term administration of 3 to 5 days.⁷ Chlorhexidine is another antimicrobial agent often used in oral rinse solutions to decrease plaque formation and prevent gingivitis. Chlorhexidine can reduce cyclosporine-induced gingival overgrowth when used twice daily.⁸ After rinsing with chlorhexidine, saliva exhibits antibacterial activity for up to 5 hours; however, tooth and gum discoloration may occur.⁸

Recurrence of gingival hyperplasia is likely if cyclosporine is not discontinued or maintained with treatment.³ Conventional gingivectomy should be considered for cases in which conservative treatment is ineffective, aesthetic concerns arise, or gingival hyperplasia persists for more than 6 to 12 months after discontinuing cyclosporine.¹

We theorize that the microbial properties of azithromycin and chlorhexidine help reduce periodontal inflammation and bacterial overgrowth in patients with cyclosporine-induced gingival hyperplasia, which allows for restoration of gingival health. Our case highlights the efficacy of our treatment approach using a 7-day course of azithromycin followed by twice-daily use of chlorhexidine oral rinse in the treatment of cyclosporine-induced gingival hyperplasia with continued use of cyclosporine.

Rose Gerber was 39, mother to a third grader and a kindergartener, when the diagnosis came: Advanced HER2-positive breast cancer.

“On one of my first or second appointments, I took in a little picture of Alexander and Isabella,” Gerber said. Gerber showed her oncologist the picture and told her: “I’ll do anything. I just want to be there for them.”

That was 21 years ago. Today, her current cancer status is “no evidence of disease.”

Over the past 2 decades, Gerber has gotten to be there for her children. Her youngest is now a television producer and her oldest, a CPA.

In that time, Gerber has had one constant: Her oncologist, Kandhasamy Jagathambal, MD, or Dr. Jaga, as she’s often called. 

“I’ve seen multiple physicians over my 21 years, but my oncologist has always been the focal point, guiding me in the right direction,” Gerber said in an interview.

Over the years, Jaga guided Gerber through a range of treatment decisions, including a Herceptin clinical trial that the mom of two views as lifesaving. Jaga often took on the role of both doctor and therapist, even providing comfort in the smaller moments when Gerber would fret about her weight gain.

The oncologist-patient “bond is very, very, very special,” said Gerber, who now works as director of patient advocacy and education at the Community Oncology Alliance.

Gerber isn’t alone in calling out the depth of the oncologist-patient bond.

Over years, sometimes decades, patients and oncologists can experience a whole world together: The treatment successes, relapses, uncertainties, and tough calls. As a result, a deep therapeutic alliance often develops. And with each new hurdle or decision, that collaborative, human connection between doctor and patient continues to form new layers.

“It’s like a shared bonding experience over trauma, like strangers trapped on a subway and then we get out, and we’re now on the other side, celebrating together,” said Saad Khan, MD, an associate professor of medicine (oncology) at Stanford University in California.

 

Connecting Through Stress

Although studies exploring the oncologist-patient bond are limited, some research suggests that a strong therapeutic alliance between patients and oncologists not only provides a foundation for quality care but can also help improve patients’ quality of life, protect against suicidal ideation, and increase treatment adherence.

Because of how stressful and frightening a cancer diagnosis can be, creating “a trusting, uninterrupted, almost sacred environment for them” is paramount for Khan. “I have no doubt that the most important part of their treatment is that they find an oncologist in whom they have total confidence,” Khan wrote in a blog.

The stress that patients with cancer experience is well documented, but oncologists take on a lot themselves and can also experience intense stress (.

“I consider my patient’s battles to be my battles,” Khan wrote.

The stress can start with the daily schedule. Oncologists often have a high volume of patients and tend to spend more time with each individual than most.

According to a 2023 survey, oncologists see about 68 patients a week, on average, but some oncologists, like Khan, have many more. Khan typically sees 20-30 patients a day and continues to care for many over years.

The survey also found that oncologists tend to spend a lot of time with their patients. Compared with other physicians, oncologists are two times more likely to spend at least 25 minutes with each patient.

With this kind of patient volume and time, Khan said, “you’re going to be exhausted.”

What can compound the exhaustion are the occasions oncologists need to deliver bad news — this treatment isn’t working, your cancer has come roaring back and, perhaps the hardest, we have no therapeutic options left. The end-of-life conversations, in particular, can be heartbreaking, especially when a patient is young and not ready to stop trying.

“It can be hard for doctors to discuss the end of life,” Don Dizon, MD, director of the Pelvic Malignancies Program at Lifespan Cancer Institute and director of Medical Oncology at Rhode Island Hospital, Providence, wrote in a column in 2023. Instead, it can be tempting and is often easier to focus on the next treatment, “instilling hope that there’s more that can be done,” even if doing more will only do harm.

In the face of these challenging decisions, growing a personal connection with patients over time can help keep oncologists going.

“We’re not just chemotherapy salesmen,” Khan said in an interview. “We get to know their social support network, who’s going to be driving them [to and from appointments], where they go on vacation, their cat’s name, who their neighbors are.”

 

A ‘Special Relationship’

Ralph V. Boccia, MD, is often asked what he does.

The next question that often comes — “Why do I do what I do?” — is Boccia’s favorite.

“Someone needs to take these patients through their journey,” Boccia, the founder of The Center for Cancer and Blood Disorders, Bethesda, Maryland, typically responds. He also often notes that “it is a special relationship you develop with the patient and their families.”

Boccia thinks about one long-term patient who captures this bond.

Joan Pinson, 70, was diagnosed with multiple myeloma about 25 years ago, when patients’ average survival was about 4 years.

Over a quarter century, Pinson has pivoted to different treatments, amid multiple relapses and remissions. Throughout most of this cancer journey, Boccia has been her primary oncologist, performing a stem cell transplant in 2000 and steering her to six clinical trials.

Her last relapse was 2 years ago, and since then she has been doing well on oral chemotherapy.

“Every time I relapsed, by the next appointment, he’d say, ‘here is what we are going to do,’ ” Pinson recalled. “I never worried, I never panicked. I knew he would take care of me.”

Over the years, Pinson and Boccia have shared many personal moments, sometimes by accident. One special moment happened early on in Pinson’s cancer journey. During an appointment, Boccia had “one ear to the phone” as his wife was about to deliver their first baby, Pinson recalled.

Later, Pinson met that child as a young man working in Boccia’s lab. She has also met Boccia’s wife, a nurse, when she filled in one day in the chemotherapy room.

Boccia now also treats Pinson’s husband who has prostate cancer, and he ruled out cancer when Pinson’s son, now in his 40s, had some worrisome symptoms.

More than 2 decades ago, Pinson told Boccia her goal was to see her youngest child graduate from high school. Now, six grandsons later, she has lived far beyond that goal.

“He has kept me alive,” said Pinson.

 

The Dying Patient

Harsha Vyas, MD, FACP, remembers the first encounter his office had with a 29-year-old woman referred with a diagnosis of stage IV breast cancer.

After just 15 minutes in the waiting room, the woman announced she was leaving. Although office staff assured the woman that she was next, the patient walked out.

Several months later, Vyas was called for an inpatient consult. It was the same woman.

Her lungs were full of fluid, and she was struggling to breathe, said Vyas, president and CEO of the Cancer Center of Middle Georgia, Dublin, and assistant professor at Augusta University in Georgia.

The woman, a single mother, told Vyas about her three young kids at home and asked him, “Doc, do something, please help me,” he recalled.

“Absolutely,” Vyas told her. But he had to be brutally honest about her prognosis and firm that she needed to follow his instructions. “You have a breast cancer I cannot cure,” he said. “All I can do is control the disease.”

From that first day, until the day she died, she came to every appointment and followed the treatment plan Vyas laid out.

For about 2 years, she responded well to treatment. And as the time passed and the trust grew, she began to open up to him. She showed him pictures. She talked about her children and being a mother.

“I’ve got to get my kids in a better place. I’m going to be there for them,” he recalled her saying.

Vyas admired her resourcefulness. She held down a part-time job, working retail and at a local restaurant. She figured out childcare so she could get to her chemotherapy appointments every 3 weeks and manage the copays.

Several years later, when she knew she was approaching the end of her life, she asked Vyas a question that hit hard.

“Doc, I don’t want to die and my kids find me dead. What can we do about it?”

Vyas, who has three daughters, imagined how traumatic this would be for a child. She and Vyas made the shared decision to cease treatment and begin home hospice. When the end was approaching, a hospice worker took over, waiting for bodily functions to cease.

When news of a death comes, “I say a little prayer, it’s almost like a send-off for that soul. That helps me absorb the news ... and let it go.”

But when the bond grows strong over time, as with his patient with breast cancer, Vyas said, “a piece of her is still with me.”

Khan had no relevant disclosures. Boccia and Vyas had no disclosures.

A version of this article appeared on Medscape.com.

Rose Gerber was 39, mother to a third grader and a kindergartener, when the diagnosis came: Advanced HER2-positive breast cancer.

“On one of my first or second appointments, I took in a little picture of Alexander and Isabella,” Gerber said. Gerber showed her oncologist the picture and told her: “I’ll do anything. I just want to be there for them.”

That was 21 years ago. Today, her current cancer status is “no evidence of disease.”

Over the past 2 decades, Gerber has gotten to be there for her children. Her youngest is now a television producer and her oldest, a CPA.

In that time, Gerber has had one constant: Her oncologist, Kandhasamy Jagathambal, MD, or Dr. Jaga, as she’s often called. 

“I’ve seen multiple physicians over my 21 years, but my oncologist has always been the focal point, guiding me in the right direction,” Gerber said in an interview.

Over the years, Jaga guided Gerber through a range of treatment decisions, including a Herceptin clinical trial that the mom of two views as lifesaving. Jaga often took on the role of both doctor and therapist, even providing comfort in the smaller moments when Gerber would fret about her weight gain.

The oncologist-patient “bond is very, very, very special,” said Gerber, who now works as director of patient advocacy and education at the Community Oncology Alliance.

Gerber isn’t alone in calling out the depth of the oncologist-patient bond.

Over years, sometimes decades, patients and oncologists can experience a whole world together: The treatment successes, relapses, uncertainties, and tough calls. As a result, a deep therapeutic alliance often develops. And with each new hurdle or decision, that collaborative, human connection between doctor and patient continues to form new layers.

“It’s like a shared bonding experience over trauma, like strangers trapped on a subway and then we get out, and we’re now on the other side, celebrating together,” said Saad Khan, MD, an associate professor of medicine (oncology) at Stanford University in California.

 

Connecting Through Stress

Although studies exploring the oncologist-patient bond are limited, some research suggests that a strong therapeutic alliance between patients and oncologists not only provides a foundation for quality care but can also help improve patients’ quality of life, protect against suicidal ideation, and increase treatment adherence.

Because of how stressful and frightening a cancer diagnosis can be, creating “a trusting, uninterrupted, almost sacred environment for them” is paramount for Khan. “I have no doubt that the most important part of their treatment is that they find an oncologist in whom they have total confidence,” Khan wrote in a blog.

The stress that patients with cancer experience is well documented, but oncologists take on a lot themselves and can also experience intense stress (.

“I consider my patient’s battles to be my battles,” Khan wrote.

The stress can start with the daily schedule. Oncologists often have a high volume of patients and tend to spend more time with each individual than most.

According to a 2023 survey, oncologists see about 68 patients a week, on average, but some oncologists, like Khan, have many more. Khan typically sees 20-30 patients a day and continues to care for many over years.

The survey also found that oncologists tend to spend a lot of time with their patients. Compared with other physicians, oncologists are two times more likely to spend at least 25 minutes with each patient.

With this kind of patient volume and time, Khan said, “you’re going to be exhausted.”

What can compound the exhaustion are the occasions oncologists need to deliver bad news — this treatment isn’t working, your cancer has come roaring back and, perhaps the hardest, we have no therapeutic options left. The end-of-life conversations, in particular, can be heartbreaking, especially when a patient is young and not ready to stop trying.

“It can be hard for doctors to discuss the end of life,” Don Dizon, MD, director of the Pelvic Malignancies Program at Lifespan Cancer Institute and director of Medical Oncology at Rhode Island Hospital, Providence, wrote in a column in 2023. Instead, it can be tempting and is often easier to focus on the next treatment, “instilling hope that there’s more that can be done,” even if doing more will only do harm.

In the face of these challenging decisions, growing a personal connection with patients over time can help keep oncologists going.

“We’re not just chemotherapy salesmen,” Khan said in an interview. “We get to know their social support network, who’s going to be driving them [to and from appointments], where they go on vacation, their cat’s name, who their neighbors are.”

 

A ‘Special Relationship’

Ralph V. Boccia, MD, is often asked what he does.

The next question that often comes — “Why do I do what I do?” — is Boccia’s favorite.

“Someone needs to take these patients through their journey,” Boccia, the founder of The Center for Cancer and Blood Disorders, Bethesda, Maryland, typically responds. He also often notes that “it is a special relationship you develop with the patient and their families.”

Boccia thinks about one long-term patient who captures this bond.

Joan Pinson, 70, was diagnosed with multiple myeloma about 25 years ago, when patients’ average survival was about 4 years.

Over a quarter century, Pinson has pivoted to different treatments, amid multiple relapses and remissions. Throughout most of this cancer journey, Boccia has been her primary oncologist, performing a stem cell transplant in 2000 and steering her to six clinical trials.

Her last relapse was 2 years ago, and since then she has been doing well on oral chemotherapy.

“Every time I relapsed, by the next appointment, he’d say, ‘here is what we are going to do,’ ” Pinson recalled. “I never worried, I never panicked. I knew he would take care of me.”

Over the years, Pinson and Boccia have shared many personal moments, sometimes by accident. One special moment happened early on in Pinson’s cancer journey. During an appointment, Boccia had “one ear to the phone” as his wife was about to deliver their first baby, Pinson recalled.

Later, Pinson met that child as a young man working in Boccia’s lab. She has also met Boccia’s wife, a nurse, when she filled in one day in the chemotherapy room.

Boccia now also treats Pinson’s husband who has prostate cancer, and he ruled out cancer when Pinson’s son, now in his 40s, had some worrisome symptoms.

More than 2 decades ago, Pinson told Boccia her goal was to see her youngest child graduate from high school. Now, six grandsons later, she has lived far beyond that goal.

“He has kept me alive,” said Pinson.

 

The Dying Patient

Harsha Vyas, MD, FACP, remembers the first encounter his office had with a 29-year-old woman referred with a diagnosis of stage IV breast cancer.

After just 15 minutes in the waiting room, the woman announced she was leaving. Although office staff assured the woman that she was next, the patient walked out.

Several months later, Vyas was called for an inpatient consult. It was the same woman.

Her lungs were full of fluid, and she was struggling to breathe, said Vyas, president and CEO of the Cancer Center of Middle Georgia, Dublin, and assistant professor at Augusta University in Georgia.

The woman, a single mother, told Vyas about her three young kids at home and asked him, “Doc, do something, please help me,” he recalled.

“Absolutely,” Vyas told her. But he had to be brutally honest about her prognosis and firm that she needed to follow his instructions. “You have a breast cancer I cannot cure,” he said. “All I can do is control the disease.”

From that first day, until the day she died, she came to every appointment and followed the treatment plan Vyas laid out.

For about 2 years, she responded well to treatment. And as the time passed and the trust grew, she began to open up to him. She showed him pictures. She talked about her children and being a mother.

“I’ve got to get my kids in a better place. I’m going to be there for them,” he recalled her saying.

Vyas admired her resourcefulness. She held down a part-time job, working retail and at a local restaurant. She figured out childcare so she could get to her chemotherapy appointments every 3 weeks and manage the copays.

Several years later, when she knew she was approaching the end of her life, she asked Vyas a question that hit hard.

“Doc, I don’t want to die and my kids find me dead. What can we do about it?”

Vyas, who has three daughters, imagined how traumatic this would be for a child. She and Vyas made the shared decision to cease treatment and begin home hospice. When the end was approaching, a hospice worker took over, waiting for bodily functions to cease.

When news of a death comes, “I say a little prayer, it’s almost like a send-off for that soul. That helps me absorb the news ... and let it go.”

But when the bond grows strong over time, as with his patient with breast cancer, Vyas said, “a piece of her is still with me.”

Khan had no relevant disclosures. Boccia and Vyas had no disclosures.

A version of this article appeared on Medscape.com.

Rose Gerber was 39, mother to a third grader and a kindergartener, when the diagnosis came: Advanced HER2-positive breast cancer.

“On one of my first or second appointments, I took in a little picture of Alexander and Isabella,” Gerber said. Gerber showed her oncologist the picture and told her: “I’ll do anything. I just want to be there for them.”

That was 21 years ago. Today, her current cancer status is “no evidence of disease.”

Over the past 2 decades, Gerber has gotten to be there for her children. Her youngest is now a television producer and her oldest, a CPA.

In that time, Gerber has had one constant: Her oncologist, Kandhasamy Jagathambal, MD, or Dr. Jaga, as she’s often called. 

“I’ve seen multiple physicians over my 21 years, but my oncologist has always been the focal point, guiding me in the right direction,” Gerber said in an interview.

Over the years, Jaga guided Gerber through a range of treatment decisions, including a Herceptin clinical trial that the mom of two views as lifesaving. Jaga often took on the role of both doctor and therapist, even providing comfort in the smaller moments when Gerber would fret about her weight gain.

The oncologist-patient “bond is very, very, very special,” said Gerber, who now works as director of patient advocacy and education at the Community Oncology Alliance.

Gerber isn’t alone in calling out the depth of the oncologist-patient bond.

Over years, sometimes decades, patients and oncologists can experience a whole world together: The treatment successes, relapses, uncertainties, and tough calls. As a result, a deep therapeutic alliance often develops. And with each new hurdle or decision, that collaborative, human connection between doctor and patient continues to form new layers.

“It’s like a shared bonding experience over trauma, like strangers trapped on a subway and then we get out, and we’re now on the other side, celebrating together,” said Saad Khan, MD, an associate professor of medicine (oncology) at Stanford University in California.

 

Connecting Through Stress

Although studies exploring the oncologist-patient bond are limited, some research suggests that a strong therapeutic alliance between patients and oncologists not only provides a foundation for quality care but can also help improve patients’ quality of life, protect against suicidal ideation, and increase treatment adherence.

Because of how stressful and frightening a cancer diagnosis can be, creating “a trusting, uninterrupted, almost sacred environment for them” is paramount for Khan. “I have no doubt that the most important part of their treatment is that they find an oncologist in whom they have total confidence,” Khan wrote in a blog.

The stress that patients with cancer experience is well documented, but oncologists take on a lot themselves and can also experience intense stress (.

“I consider my patient’s battles to be my battles,” Khan wrote.

The stress can start with the daily schedule. Oncologists often have a high volume of patients and tend to spend more time with each individual than most.

According to a 2023 survey, oncologists see about 68 patients a week, on average, but some oncologists, like Khan, have many more. Khan typically sees 20-30 patients a day and continues to care for many over years.

The survey also found that oncologists tend to spend a lot of time with their patients. Compared with other physicians, oncologists are two times more likely to spend at least 25 minutes with each patient.

With this kind of patient volume and time, Khan said, “you’re going to be exhausted.”

What can compound the exhaustion are the occasions oncologists need to deliver bad news — this treatment isn’t working, your cancer has come roaring back and, perhaps the hardest, we have no therapeutic options left. The end-of-life conversations, in particular, can be heartbreaking, especially when a patient is young and not ready to stop trying.

“It can be hard for doctors to discuss the end of life,” Don Dizon, MD, director of the Pelvic Malignancies Program at Lifespan Cancer Institute and director of Medical Oncology at Rhode Island Hospital, Providence, wrote in a column in 2023. Instead, it can be tempting and is often easier to focus on the next treatment, “instilling hope that there’s more that can be done,” even if doing more will only do harm.

In the face of these challenging decisions, growing a personal connection with patients over time can help keep oncologists going.

“We’re not just chemotherapy salesmen,” Khan said in an interview. “We get to know their social support network, who’s going to be driving them [to and from appointments], where they go on vacation, their cat’s name, who their neighbors are.”

 

A ‘Special Relationship’

Ralph V. Boccia, MD, is often asked what he does.

The next question that often comes — “Why do I do what I do?” — is Boccia’s favorite.

“Someone needs to take these patients through their journey,” Boccia, the founder of The Center for Cancer and Blood Disorders, Bethesda, Maryland, typically responds. He also often notes that “it is a special relationship you develop with the patient and their families.”

Boccia thinks about one long-term patient who captures this bond.

Joan Pinson, 70, was diagnosed with multiple myeloma about 25 years ago, when patients’ average survival was about 4 years.

Over a quarter century, Pinson has pivoted to different treatments, amid multiple relapses and remissions. Throughout most of this cancer journey, Boccia has been her primary oncologist, performing a stem cell transplant in 2000 and steering her to six clinical trials.

Her last relapse was 2 years ago, and since then she has been doing well on oral chemotherapy.

“Every time I relapsed, by the next appointment, he’d say, ‘here is what we are going to do,’ ” Pinson recalled. “I never worried, I never panicked. I knew he would take care of me.”

Over the years, Pinson and Boccia have shared many personal moments, sometimes by accident. One special moment happened early on in Pinson’s cancer journey. During an appointment, Boccia had “one ear to the phone” as his wife was about to deliver their first baby, Pinson recalled.

Later, Pinson met that child as a young man working in Boccia’s lab. She has also met Boccia’s wife, a nurse, when she filled in one day in the chemotherapy room.

Boccia now also treats Pinson’s husband who has prostate cancer, and he ruled out cancer when Pinson’s son, now in his 40s, had some worrisome symptoms.

More than 2 decades ago, Pinson told Boccia her goal was to see her youngest child graduate from high school. Now, six grandsons later, she has lived far beyond that goal.

“He has kept me alive,” said Pinson.

 

The Dying Patient

Harsha Vyas, MD, FACP, remembers the first encounter his office had with a 29-year-old woman referred with a diagnosis of stage IV breast cancer.

After just 15 minutes in the waiting room, the woman announced she was leaving. Although office staff assured the woman that she was next, the patient walked out.

Several months later, Vyas was called for an inpatient consult. It was the same woman.

Her lungs were full of fluid, and she was struggling to breathe, said Vyas, president and CEO of the Cancer Center of Middle Georgia, Dublin, and assistant professor at Augusta University in Georgia.

The woman, a single mother, told Vyas about her three young kids at home and asked him, “Doc, do something, please help me,” he recalled.

“Absolutely,” Vyas told her. But he had to be brutally honest about her prognosis and firm that she needed to follow his instructions. “You have a breast cancer I cannot cure,” he said. “All I can do is control the disease.”

From that first day, until the day she died, she came to every appointment and followed the treatment plan Vyas laid out.

For about 2 years, she responded well to treatment. And as the time passed and the trust grew, she began to open up to him. She showed him pictures. She talked about her children and being a mother.

“I’ve got to get my kids in a better place. I’m going to be there for them,” he recalled her saying.

Vyas admired her resourcefulness. She held down a part-time job, working retail and at a local restaurant. She figured out childcare so she could get to her chemotherapy appointments every 3 weeks and manage the copays.

Several years later, when she knew she was approaching the end of her life, she asked Vyas a question that hit hard.

“Doc, I don’t want to die and my kids find me dead. What can we do about it?”

Vyas, who has three daughters, imagined how traumatic this would be for a child. She and Vyas made the shared decision to cease treatment and begin home hospice. When the end was approaching, a hospice worker took over, waiting for bodily functions to cease.

When news of a death comes, “I say a little prayer, it’s almost like a send-off for that soul. That helps me absorb the news ... and let it go.”

But when the bond grows strong over time, as with his patient with breast cancer, Vyas said, “a piece of her is still with me.”

Khan had no relevant disclosures. Boccia and Vyas had no disclosures.

A version of this article appeared on Medscape.com.