The cutoff for programmed death–ligand 1 (PD-L1) combined positive score (CPS) of at least 10 for using pembrolizumab (Keytruda) to treat metastatic triple-negative breast cancer (mTNBC) is able to identify patients who are expected to derive most benefit, shows an analysis of KEYNOTE-355 recently presented at the San Antonio Breast Cancer Symposium.

Patients enrolled in KEYNOTE-355 – which is a phase 3, placebo-controlled trial of 847 patients – were stratified by CPS scores of at least 1 and at least 10, with the latter group in which adding pembrolizumab to chemotherapy was shown to significantly improve both overall survival and progression-free survival.

As it was unclear whether taking a more fine-grained approach would reveal specific CPS scores at which pembrolizumab would be beneficial, Javier Cortes, MD, PhD, International Breast Cancer Center, Barcelona, and colleagues divided the patients into four CPS levels: less than 1, 1-9, 10-19, and at least 20.

Patients with a CPS 10-19 and at least 20 given pembrolizumab alongside chemotherapy had an overall survival benefit of 29% and 28%, respectively, while the PFS improvement was 30% and 38%. In the CPS of less than 1 and 1-9 groups, there were no discernible benefits from adding the checkpoint inhibitor.

“Given the similar outcomes in the CPS 10-19 and the CPS ≥20 subgroups, a CPS of 10 or more is a reasonable cutoff to define the population of patients with metastatic TNBC that might have benefit from the addition of pembrolizumab to chemotherapy,” Dr. Cortes said. “In my opinion, these results provide further support for pembrolizumab in combination with chemotherapy as a good option, maybe a standard of care for some patients ... with local recurrent unresectable or metastatic TNBC whose tumors express PD-1 CPS ≥10.”

Invited discussant Hope S. Rugo, MD, said the study demonstrates that PD-L1 CPS of at least 10 is “clearly the optimal cutoff for differentiating benefit from pembrolizumab” and confirms the combination with chemotherapy as a “standard of care in this population”.

However, there are a number of outstanding questions in the metastatic setting, she said, including the test used to determine PD-L1 expression.

“Clearly the test that you order should be matched to the planned checkpoint inhibitor, and we look forward to additional data” on the relative overlap of the assays used in both the current study and in KEYNOTE-522.

However, IMpassion130 showed there is “incomplete overlap in terms of the two antibodies and tests that have been used to define PD-L1 positivity in breast cancer,” said Dr. Rugo, professor of medicine in hematology and oncology at the University of California, San Francisco.

“For excellent responders, can chemotherapy and eventually immunotherapy be discontinued, and when is it optimal? How long should we be continuing the combination and how long should we continue the checkpoint inhibitor alone?” she asked.

“Certainly in my own clinical practice,” Dr. Rugo explained, “in those excellent responders, it’s difficult to know when to stop the checkpoint inhibitor, but sometimes toxicity tells us the answer to that question. At some point, we need to stop therapy and understand what happens to those patients.”

She said that only 38% of patients in the current study benefited from pembrolizumab. “How can we amplify the immune response in those patients who do not have PD-L1–positive disease to further extend this benefit, and can we extend the efficacy to other subtypes? There are ongoing studies evaluating this question,” Dr. Rugo said.

Dr. Cortes said that KEYNOTE-355 showed the addition of pembrolizumab to chemotherapy led to clinically meaningful improvements in both PFS and overall survival versus chemotherapy alone in the first-line treatment of mTNBC.

However, that benefit was seen only in patients with a PD-L1 CPS of at least 10, while there was no statistically significant improvement in either PFS or overall survival in those with a CPS of at least 1.

He explained that 847 patients with previously untreated locally recurrent or metastatic TNBC, or those who had been treated at least 6 months prior to disease recurrence, were randomized 2:1 to pembrolizumab or placebo plus chemotherapy.

For the current analysis, they substratified patients by PD-L1 CPS into less than 1, which accounted for 24.9% of patients; 1-9, seen in 36.2%-38.4%; 10-19, accounting for 13.9%-14.1%; and at least 20, seen in 22.8%-24.7% of patients.

Dr. Cortes said the overall survival rate among patients with CPS of at least 10 was 70.5% for patients treated with pembrolizumab plus chemotherapy versus 81.6% for those assigned to placebo, at a significant hazard ratio of 0.73 (P = .0093).

Among patients with CPS of at least 1, the overall survival rate was 79.1% with pembrolizumab plus chemotherapy and 83.9% in those given placebo, at a nonsignificant hazard ratio of 0.86. This translated into an HR of 0.89 in the intention-to-treat analysis.

Turning to the novel subgroups, Dr. Cortes showed that the HR for overall survival for pembrolizumab versus placebo was nonsignificant in patients with CPS of at least 1, at 0.97, and in those with CPS 1-9, at 1.09.

However, the HRs were markedly improved in patients with CPD 10-19, at 0.71, and in those with CPS of at least 20, at 0.72, showing that the “relative benefit of adding pembrolizumab to chemotherapy was pretty much the same ... suggesting that CPS ≥10 could be a reasonable cutoff.”

In both of these groups, there was a sustained separation in the overall survival curves starting at around 10 months.

Turning to the PFS results, Dr Cortes said the event-free rate was 65.5% with the addition of pembrolizumab to chemotherapy in patients with PD-L1 CPS of at least 10, while those given placebo had a rate of 78.6%, at an HR of 0.66.

In patients with PD-L1 CPS of at least 1, the HR was 0.75, or 0.82 in the intention-to-treat analysis.

“As with overall survival,” he said, there was a “trend toward improved efficacy with PD-L1 enrichment with the addition of pembrolizumab to chemotherapy, although the PFS benefit in the pembro arm was slightly greater in the CPS ≥20 subgroup, compared to the CPS 10-19 subgroup.”

However, they highlighted that the difference was “small and the confidence intervals clearly overlapped.”

Why does PD-L1 expression play a role in response to pembrolizumab in mTNBC, but not in the early disease setting as seen in KEYNOTE-522?

“This is a question we have raised many, many times and have had many debates on,” Dr. Cortes said. “They are two completely different populations with the early breast cancer setting completely different to that in metastatic disease. Maybe the microenvironment plays a different role there, maybe we have to explore more in detail other biomarkers. I also think that different drugs were used in the neoadjuvant setting. We still have many unanswered questions.”

Dr. Rugo suggested that previous studies have given some clues to these questions with reductions in PD-L1 expression and tumor-infiltrating leukocytes observed between primary and metastatic disease.

The immune differences between primary and metastatic disease lead to immune escape, she said, adding: “This is clearly complicated by mutational complexity under the pressure of treatment.”

The study was funded by Merck Sharp and Dohme. Dr. Cortes and Dr. Rugo reported relationships with numerous pharmaceutical companies.

The cutoff for programmed death–ligand 1 (PD-L1) combined positive score (CPS) of at least 10 for using pembrolizumab (Keytruda) to treat metastatic triple-negative breast cancer (mTNBC) is able to identify patients who are expected to derive most benefit, shows an analysis of KEYNOTE-355 recently presented at the San Antonio Breast Cancer Symposium.

Patients enrolled in KEYNOTE-355 – which is a phase 3, placebo-controlled trial of 847 patients – were stratified by CPS scores of at least 1 and at least 10, with the latter group in which adding pembrolizumab to chemotherapy was shown to significantly improve both overall survival and progression-free survival.

As it was unclear whether taking a more fine-grained approach would reveal specific CPS scores at which pembrolizumab would be beneficial, Javier Cortes, MD, PhD, International Breast Cancer Center, Barcelona, and colleagues divided the patients into four CPS levels: less than 1, 1-9, 10-19, and at least 20.

Patients with a CPS 10-19 and at least 20 given pembrolizumab alongside chemotherapy had an overall survival benefit of 29% and 28%, respectively, while the PFS improvement was 30% and 38%. In the CPS of less than 1 and 1-9 groups, there were no discernible benefits from adding the checkpoint inhibitor.

“Given the similar outcomes in the CPS 10-19 and the CPS ≥20 subgroups, a CPS of 10 or more is a reasonable cutoff to define the population of patients with metastatic TNBC that might have benefit from the addition of pembrolizumab to chemotherapy,” Dr. Cortes said. “In my opinion, these results provide further support for pembrolizumab in combination with chemotherapy as a good option, maybe a standard of care for some patients ... with local recurrent unresectable or metastatic TNBC whose tumors express PD-1 CPS ≥10.”

Invited discussant Hope S. Rugo, MD, said the study demonstrates that PD-L1 CPS of at least 10 is “clearly the optimal cutoff for differentiating benefit from pembrolizumab” and confirms the combination with chemotherapy as a “standard of care in this population”.

However, there are a number of outstanding questions in the metastatic setting, she said, including the test used to determine PD-L1 expression.

“Clearly the test that you order should be matched to the planned checkpoint inhibitor, and we look forward to additional data” on the relative overlap of the assays used in both the current study and in KEYNOTE-522.

However, IMpassion130 showed there is “incomplete overlap in terms of the two antibodies and tests that have been used to define PD-L1 positivity in breast cancer,” said Dr. Rugo, professor of medicine in hematology and oncology at the University of California, San Francisco.

“For excellent responders, can chemotherapy and eventually immunotherapy be discontinued, and when is it optimal? How long should we be continuing the combination and how long should we continue the checkpoint inhibitor alone?” she asked.

“Certainly in my own clinical practice,” Dr. Rugo explained, “in those excellent responders, it’s difficult to know when to stop the checkpoint inhibitor, but sometimes toxicity tells us the answer to that question. At some point, we need to stop therapy and understand what happens to those patients.”

She said that only 38% of patients in the current study benefited from pembrolizumab. “How can we amplify the immune response in those patients who do not have PD-L1–positive disease to further extend this benefit, and can we extend the efficacy to other subtypes? There are ongoing studies evaluating this question,” Dr. Rugo said.

Dr. Cortes said that KEYNOTE-355 showed the addition of pembrolizumab to chemotherapy led to clinically meaningful improvements in both PFS and overall survival versus chemotherapy alone in the first-line treatment of mTNBC.

However, that benefit was seen only in patients with a PD-L1 CPS of at least 10, while there was no statistically significant improvement in either PFS or overall survival in those with a CPS of at least 1.

He explained that 847 patients with previously untreated locally recurrent or metastatic TNBC, or those who had been treated at least 6 months prior to disease recurrence, were randomized 2:1 to pembrolizumab or placebo plus chemotherapy.

For the current analysis, they substratified patients by PD-L1 CPS into less than 1, which accounted for 24.9% of patients; 1-9, seen in 36.2%-38.4%; 10-19, accounting for 13.9%-14.1%; and at least 20, seen in 22.8%-24.7% of patients.

Dr. Cortes said the overall survival rate among patients with CPS of at least 10 was 70.5% for patients treated with pembrolizumab plus chemotherapy versus 81.6% for those assigned to placebo, at a significant hazard ratio of 0.73 (P = .0093).

Among patients with CPS of at least 1, the overall survival rate was 79.1% with pembrolizumab plus chemotherapy and 83.9% in those given placebo, at a nonsignificant hazard ratio of 0.86. This translated into an HR of 0.89 in the intention-to-treat analysis.

Turning to the novel subgroups, Dr. Cortes showed that the HR for overall survival for pembrolizumab versus placebo was nonsignificant in patients with CPS of at least 1, at 0.97, and in those with CPS 1-9, at 1.09.

However, the HRs were markedly improved in patients with CPD 10-19, at 0.71, and in those with CPS of at least 20, at 0.72, showing that the “relative benefit of adding pembrolizumab to chemotherapy was pretty much the same ... suggesting that CPS ≥10 could be a reasonable cutoff.”

In both of these groups, there was a sustained separation in the overall survival curves starting at around 10 months.

Turning to the PFS results, Dr Cortes said the event-free rate was 65.5% with the addition of pembrolizumab to chemotherapy in patients with PD-L1 CPS of at least 10, while those given placebo had a rate of 78.6%, at an HR of 0.66.

In patients with PD-L1 CPS of at least 1, the HR was 0.75, or 0.82 in the intention-to-treat analysis.

“As with overall survival,” he said, there was a “trend toward improved efficacy with PD-L1 enrichment with the addition of pembrolizumab to chemotherapy, although the PFS benefit in the pembro arm was slightly greater in the CPS ≥20 subgroup, compared to the CPS 10-19 subgroup.”

However, they highlighted that the difference was “small and the confidence intervals clearly overlapped.”

Why does PD-L1 expression play a role in response to pembrolizumab in mTNBC, but not in the early disease setting as seen in KEYNOTE-522?

“This is a question we have raised many, many times and have had many debates on,” Dr. Cortes said. “They are two completely different populations with the early breast cancer setting completely different to that in metastatic disease. Maybe the microenvironment plays a different role there, maybe we have to explore more in detail other biomarkers. I also think that different drugs were used in the neoadjuvant setting. We still have many unanswered questions.”

Dr. Rugo suggested that previous studies have given some clues to these questions with reductions in PD-L1 expression and tumor-infiltrating leukocytes observed between primary and metastatic disease.

The immune differences between primary and metastatic disease lead to immune escape, she said, adding: “This is clearly complicated by mutational complexity under the pressure of treatment.”

The study was funded by Merck Sharp and Dohme. Dr. Cortes and Dr. Rugo reported relationships with numerous pharmaceutical companies.

The cutoff for programmed death–ligand 1 (PD-L1) combined positive score (CPS) of at least 10 for using pembrolizumab (Keytruda) to treat metastatic triple-negative breast cancer (mTNBC) is able to identify patients who are expected to derive most benefit, shows an analysis of KEYNOTE-355 recently presented at the San Antonio Breast Cancer Symposium.

Patients enrolled in KEYNOTE-355 – which is a phase 3, placebo-controlled trial of 847 patients – were stratified by CPS scores of at least 1 and at least 10, with the latter group in which adding pembrolizumab to chemotherapy was shown to significantly improve both overall survival and progression-free survival.

As it was unclear whether taking a more fine-grained approach would reveal specific CPS scores at which pembrolizumab would be beneficial, Javier Cortes, MD, PhD, International Breast Cancer Center, Barcelona, and colleagues divided the patients into four CPS levels: less than 1, 1-9, 10-19, and at least 20.

Patients with a CPS 10-19 and at least 20 given pembrolizumab alongside chemotherapy had an overall survival benefit of 29% and 28%, respectively, while the PFS improvement was 30% and 38%. In the CPS of less than 1 and 1-9 groups, there were no discernible benefits from adding the checkpoint inhibitor.

“Given the similar outcomes in the CPS 10-19 and the CPS ≥20 subgroups, a CPS of 10 or more is a reasonable cutoff to define the population of patients with metastatic TNBC that might have benefit from the addition of pembrolizumab to chemotherapy,” Dr. Cortes said. “In my opinion, these results provide further support for pembrolizumab in combination with chemotherapy as a good option, maybe a standard of care for some patients ... with local recurrent unresectable or metastatic TNBC whose tumors express PD-1 CPS ≥10.”

Invited discussant Hope S. Rugo, MD, said the study demonstrates that PD-L1 CPS of at least 10 is “clearly the optimal cutoff for differentiating benefit from pembrolizumab” and confirms the combination with chemotherapy as a “standard of care in this population”.

However, there are a number of outstanding questions in the metastatic setting, she said, including the test used to determine PD-L1 expression.

“Clearly the test that you order should be matched to the planned checkpoint inhibitor, and we look forward to additional data” on the relative overlap of the assays used in both the current study and in KEYNOTE-522.

However, IMpassion130 showed there is “incomplete overlap in terms of the two antibodies and tests that have been used to define PD-L1 positivity in breast cancer,” said Dr. Rugo, professor of medicine in hematology and oncology at the University of California, San Francisco.

“For excellent responders, can chemotherapy and eventually immunotherapy be discontinued, and when is it optimal? How long should we be continuing the combination and how long should we continue the checkpoint inhibitor alone?” she asked.

“Certainly in my own clinical practice,” Dr. Rugo explained, “in those excellent responders, it’s difficult to know when to stop the checkpoint inhibitor, but sometimes toxicity tells us the answer to that question. At some point, we need to stop therapy and understand what happens to those patients.”

She said that only 38% of patients in the current study benefited from pembrolizumab. “How can we amplify the immune response in those patients who do not have PD-L1–positive disease to further extend this benefit, and can we extend the efficacy to other subtypes? There are ongoing studies evaluating this question,” Dr. Rugo said.

Dr. Cortes said that KEYNOTE-355 showed the addition of pembrolizumab to chemotherapy led to clinically meaningful improvements in both PFS and overall survival versus chemotherapy alone in the first-line treatment of mTNBC.

However, that benefit was seen only in patients with a PD-L1 CPS of at least 10, while there was no statistically significant improvement in either PFS or overall survival in those with a CPS of at least 1.

He explained that 847 patients with previously untreated locally recurrent or metastatic TNBC, or those who had been treated at least 6 months prior to disease recurrence, were randomized 2:1 to pembrolizumab or placebo plus chemotherapy.

For the current analysis, they substratified patients by PD-L1 CPS into less than 1, which accounted for 24.9% of patients; 1-9, seen in 36.2%-38.4%; 10-19, accounting for 13.9%-14.1%; and at least 20, seen in 22.8%-24.7% of patients.

Dr. Cortes said the overall survival rate among patients with CPS of at least 10 was 70.5% for patients treated with pembrolizumab plus chemotherapy versus 81.6% for those assigned to placebo, at a significant hazard ratio of 0.73 (P = .0093).

Among patients with CPS of at least 1, the overall survival rate was 79.1% with pembrolizumab plus chemotherapy and 83.9% in those given placebo, at a nonsignificant hazard ratio of 0.86. This translated into an HR of 0.89 in the intention-to-treat analysis.

Turning to the novel subgroups, Dr. Cortes showed that the HR for overall survival for pembrolizumab versus placebo was nonsignificant in patients with CPS of at least 1, at 0.97, and in those with CPS 1-9, at 1.09.

However, the HRs were markedly improved in patients with CPD 10-19, at 0.71, and in those with CPS of at least 20, at 0.72, showing that the “relative benefit of adding pembrolizumab to chemotherapy was pretty much the same ... suggesting that CPS ≥10 could be a reasonable cutoff.”

In both of these groups, there was a sustained separation in the overall survival curves starting at around 10 months.

Turning to the PFS results, Dr Cortes said the event-free rate was 65.5% with the addition of pembrolizumab to chemotherapy in patients with PD-L1 CPS of at least 10, while those given placebo had a rate of 78.6%, at an HR of 0.66.

In patients with PD-L1 CPS of at least 1, the HR was 0.75, or 0.82 in the intention-to-treat analysis.

“As with overall survival,” he said, there was a “trend toward improved efficacy with PD-L1 enrichment with the addition of pembrolizumab to chemotherapy, although the PFS benefit in the pembro arm was slightly greater in the CPS ≥20 subgroup, compared to the CPS 10-19 subgroup.”

However, they highlighted that the difference was “small and the confidence intervals clearly overlapped.”

Why does PD-L1 expression play a role in response to pembrolizumab in mTNBC, but not in the early disease setting as seen in KEYNOTE-522?

“This is a question we have raised many, many times and have had many debates on,” Dr. Cortes said. “They are two completely different populations with the early breast cancer setting completely different to that in metastatic disease. Maybe the microenvironment plays a different role there, maybe we have to explore more in detail other biomarkers. I also think that different drugs were used in the neoadjuvant setting. We still have many unanswered questions.”

Dr. Rugo suggested that previous studies have given some clues to these questions with reductions in PD-L1 expression and tumor-infiltrating leukocytes observed between primary and metastatic disease.

The immune differences between primary and metastatic disease lead to immune escape, she said, adding: “This is clearly complicated by mutational complexity under the pressure of treatment.”

The study was funded by Merck Sharp and Dohme. Dr. Cortes and Dr. Rugo reported relationships with numerous pharmaceutical companies.

Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.

Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.

In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).

Cluster 1 was referred to as IBS^P microbiome type because of its pathogenic properties, and cluster 2 as IBS^H microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.

“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBS^P microbiomes compared with IBS^H microbiomes,” the researchers said.

More specifically, the IBS^P microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBS^H microbiomes were similar to healthy controls.

After 4 weeks on the low FODMAP diet, the IBS^P microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBS^H and healthy controls did not demonstrate a significant shift.

Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBS^P group than the IBS^H group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBS^P microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.

The distinct responses of the IBS^P and IBS^H microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.

The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.

However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
 

Setting the stage for focused studies

The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.

The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.

Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.

The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”

The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.

“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted. 

However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.

“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.

The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.

Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome. 

Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.

Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.

In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).

Cluster 1 was referred to as IBS^P microbiome type because of its pathogenic properties, and cluster 2 as IBS^H microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.

“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBS^P microbiomes compared with IBS^H microbiomes,” the researchers said.

More specifically, the IBS^P microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBS^H microbiomes were similar to healthy controls.

After 4 weeks on the low FODMAP diet, the IBS^P microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBS^H and healthy controls did not demonstrate a significant shift.

Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBS^P group than the IBS^H group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBS^P microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.

The distinct responses of the IBS^P and IBS^H microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.

The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.

However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
 

Setting the stage for focused studies

The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.

The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.

Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.

The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”

The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.

“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted. 

However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.

“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.

The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.

Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome. 

Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.

Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.

In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).

Cluster 1 was referred to as IBS^P microbiome type because of its pathogenic properties, and cluster 2 as IBS^H microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.

“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBS^P microbiomes compared with IBS^H microbiomes,” the researchers said.

More specifically, the IBS^P microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBS^H microbiomes were similar to healthy controls.

After 4 weeks on the low FODMAP diet, the IBS^P microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBS^H and healthy controls did not demonstrate a significant shift.

Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBS^P group than the IBS^H group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBS^P microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.

The distinct responses of the IBS^P and IBS^H microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.

The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.

However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
 

Setting the stage for focused studies

The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.

The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.

Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.

The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”

The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.

“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted. 

However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.

“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.

The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.

Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome. 

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

[email protected]

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

[email protected]

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

[email protected]

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

Tisagenlecleucel failed to outperform standard of care treatment when given as a second-line treatment for certain patients with relapsed/refractory aggressive non-Hodgkin lymphomas, according to results of a randomized, phase 3 trial.

The chimeric antigen receptor (CAR) T-cell therapy did not improve event-free survival (EFS) in this phase 3 BELINDA study, potentially because of study design decisions or imbalances in relevant patient characteristics, according to the study investigators.

Despite the negative result, insights from this study will inform the development of future clinical trials of CAR T-cell therapy, said BELINDA investigator Michael R. Bishop, MD, of the David and Etta Jonas Center for Cellular Therapy, University of Chicago.

Findings of BELINDA, presented at the annual meeting of the American Society of Hematology, stand in contrast to two other high-profile CAR T-cell therapy studies also presented at the meeting. Those other studies demonstrated significant improvements in EFS in the second-line treatment of large B-cell lymphomas.

“All of us are excited to see that the other two trials were positive, and we were hoping that ours would be as well, but there are significant differences in the trial design,” Dr. Bishop said in a press conference held at the ASH meeting.

Tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell therapy, is already approved by the Food and Drug Administration for the treatment of patients with relapsed or refractory large B-cell lymphomas after at least two other lines of systemic therapy.

The aim of the pivotal phase 3, randomized, multicenter BELINDA study was to evaluate tisa-cel earlier in the course of treatment for patients with more aggressive disease, according to Dr. Bishop.

About two-thirds of non-Hodgkin lymphoma patients will be cured with first-line treatment. However, very poor outcomes are seen among patients with disease that does not respond to the initial treatment or that reoccurs shortly afterward, Dr. Bishop said.

The standard of care approach for those patients is second-line therapy, he noted, usually with combination chemoimmunotherapy, followed by autologous stem cell transplant if the disease responds to chemotherapy.

“Unfortunately, only a minority of those patients will be found to have chemotherapy-sensitive disease and be able to go on to autologous stem cell transplantation,” Dr. Bishop said. “And even in that subgroup of patients, the outcomes are relatively poor.”

Accordingly, the phase 3 BELINDA study enrolled patients with aggressive non-Hodgkin lymphomas that either did not respond to first-line treatment or that reoccurred within 12 months.

The primary endpoint of the study was EFS, defined as the time from randomization to either stable or progressive disease at or after a week 12 assessment or to any-cause death at any time.

While that primary endpoint was not met for tisa-cel versus standard of care therapy, two other randomized, phase 3 studies presented at the ASH meeting did demonstrate that CAR T-cell therapy extended EFS when given as a second-line lymphoma treatment.

In the randomized, phase 3 ZUMA-7 trial, axicabtagene ciloleucel (axi-cel) significantly improved EFS versus standard of care in the treatment of patients with large B-cell lymphoma refractory to or relapsed within 12 months of adequate first-line therapy, according to investigators.

Similarly, the investigators said that treatment with lisocabtagene maraleucel (liso-cel) led to a significant improvement in EFS in TRANSFORM, a randomized, phase 3 clinical trial that enrolled patients with large B-cell lymphoma that was refractory to first-line therapy or else relapsed within 12 months of that treatment.

“It’s very possible that either or both the patient characteristics and the study design is what led to the difference in the top-line study results,” lymphoma specialist Andrew M. Evens, DO, said in an interview.

There were substantial differences between the studies in terms of what was allowed as optional bridging therapy and salvage therapy, according to Dr. Evens, associate director for clinical services and director of the lymphoma program at Rutgers Cancer Institute in New Brunswick, N.J.

“In ZUMA-7, they only allowed steroids as bridging therapy,” said Dr. Evens, who was not an investigator on any of the three second-line CAR T-cell studies.

In the BELINDA study, optional platinum-based chemotherapy bridging treatment allowed in one arm of the study could have potentially delayed tisa-cel infusion until after the week 6 assessment, study investigators reported in their ASH meeting abstract.

Differences in lymphodepleting therapy prior to CAR T-cell therapy could have also played a role. According to Dr. Bishop, the total doses of cyclophosphamide and fludarabine in BELINDA were 900 mg/m2 and 75 mg/m2, respectively, while in the other two trials, doses were 1,500 mg/m² and 90 mg/m², respectively.

Lymphodepleting chemotherapy is “extremely important” in the success of CAR T-cell therapeutic approaches, he noted at the press conference.

Dr. Bishop reported receiving consultancy fees from Arcellx, Autolus Therapeutics, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis. He also reported research funding from Bristol-Myers Squibb and Kite/Gilead.

When it comes to the acute management of migraines, newer is not necessarily better, according to an analysis of studies comparing triptans – the standard of care – to two newer classifications of medications. The findings, published in JAMA Network Open, “may imply that triptans will remain the current mainstay of specific acute migraine treatment,” suggested senior author Shuu-Jiun Wang, MD, from the National Yang Ming Chiao Tung University, and the Taipei Veterans General Hospital, both in Taipei, Taiwan, and his coauthors. However, lasmiditan (a 5-hydroxytryptamine_1F receptor agonist) and rimegepant and ubrogepant (both calcitonin gene-related peptide [CGRP] antagonists) might still have unique advantages, since triptans are contraindicated for patients with cardiovascular risks, they said.

The systemic review and meta-analysis showed that, for the outcome of pain freedom and pain relief at 2 hours after the dose, the three newer agents worked better than placebo, but were inferior to most triptans. However, ubrogepant and rimegepant, which received U.S. Food and Drug Administration approval for the treatment of acute migraine in adults in December 2019 and February 2020, respectively, might be associated with fewer risks of adverse events (AEs), compared with triptans. “These new effective therapeutic options enrich the therapeutic categories of specific acute migraine treatments and may provide an opportunity to decrease the risks of barbiturate or opioid overuse or addiction,” they wrote.

The meta-analysis included 64 randomized, controlled trials involving 46,442 participants (74%-87% female across studies; age range, 36-43 years). All studies examined clinically relevant outcomes in patients with International Headache Society criteria for migraine, and compared currently available migraine-specific acute treatments with each other or placebo. The drugs were examined at doses with widespread clinical use and included: ergotamine, dihydroergotamine, sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, lasmiditan, rimegepant, and ubrogepant.

The findings showed that all drug treatments were associated with a higher odds ratio for pain freedom, compared with placebo, except for sumatriptan, 10-mg nasal spray. The most effective drug was eletriptan 40 mg (OR, 5.59), and the least effective was lasmiditan 50 mg (OR, 1.65). Most triptans were associated with higher ORs for both pain freedom and pain relief at 2 hours, compared with lasmiditan, rimegepant, or ubrogepant, while comparisons between lasmiditan, rimegepant, and ubrogepant for these outcomes showed no statistically significant difference, they reported.

Lasmiditan was associated with the highest risk of any AEs, “however, the AEs were tolerable and were not considered serious. … Therefore, we suggest that the benefits should be weighed against the risk of its AEs when considering the clinical application of lasmiditan,” they wrote. Certain triptans (rizatriptan, sumatriptan, and zolmitriptan) were also associated with a higher risk of any AEs, compared with the CGRP antagonists. “Nevertheless, most of the AEs were mild to moderate, and the percentages of serious AEs were low (0.0%-2.1%).”

Finally, the authors noted that their observations of successful treatment with 5-hydroxytriptamine_1F receptor agonists and CGRP antagonists “reveals that vasoconstriction is not essential for antimigraine therapy.” which could have implications for future pharmaceutical development.
 

Older and newer medications each have advantages

“Triptans will be around for a long time, but the newer medications are here to stay,” said Alan M. Rapoport, MD, in reaction to the study. “Before this publication, we knew that the 2-hour efficacy results of the newer medications were not quite as good as the faster-acting triptans; and after this network meta-analysis we are more sure of that,” said Dr. Rapoport, of the department of neurology at University of California, Los Angeles. “But the fact that the three newer medications do not constrict blood vessels and can easily be given even to patients with contraindications to triptans, or patients that simply are at greater risk due to obesity, smoking history, family history, diabetes, lack of exercise, or higher lipid levels, puts them into a desirable category.”

Calling it a “very carefully done” systematic review, Dr. Rapoport had a few caveats about the strength of the research. The trials that were included were not identically designed and were performed in different areas, by different investigators, on different patients, he noted. They were also not head-to-head trials “which ensures that the resultant data are more pure.” The studies also looked only at rapid results at 2 hours after dosing. “In my experience, patients are often satisfied with the response times from these newer agents; and doctors and patients both are happy that they are not vasoconstrictive,” he said. “The researchers also omitted studies looking at zolmitriptan nasal spray, which I have found to be rapid in onset and efficacious with few adverse events.”

Finally, Dr. Rapoport noted that one condition not examined in the review was medication overuse headache (MOH), which is “a major problem with patients that have high-frequency episodic migraine and chronic migraine. To our knowledge thus far, the two gepants (ubrogepant and rimegepant) do not appear to cause MOH when taken frequently, and these agents may end up being a treatment for this condition.”

Dr Wang reported receiving personal fees from Eli Lilly, Daiichi-Sankyo, Norvatis Taiwan, Biogen, Pfizer, and Bayer; and grants from AbbVie, Norvatis, Eli Lilly, Taiwan Ministry of Technology and Science, Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. No other disclosures were reported. Dr. Rapoport serves as an advisor for AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano; he is on the Speakers Bureau of AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries. He is Editor-in-Chief of Neurology Reviews.

The study was funded by the Ministry of Science and Technology, Taiwan, Ministry of Education, Taiwan, and the Brain Research Center, National Yang Ming Chiao Tung University.

When it comes to the acute management of migraines, newer is not necessarily better, according to an analysis of studies comparing triptans – the standard of care – to two newer classifications of medications. The findings, published in JAMA Network Open, “may imply that triptans will remain the current mainstay of specific acute migraine treatment,” suggested senior author Shuu-Jiun Wang, MD, from the National Yang Ming Chiao Tung University, and the Taipei Veterans General Hospital, both in Taipei, Taiwan, and his coauthors. However, lasmiditan (a 5-hydroxytryptamine_1F receptor agonist) and rimegepant and ubrogepant (both calcitonin gene-related peptide [CGRP] antagonists) might still have unique advantages, since triptans are contraindicated for patients with cardiovascular risks, they said.

The systemic review and meta-analysis showed that, for the outcome of pain freedom and pain relief at 2 hours after the dose, the three newer agents worked better than placebo, but were inferior to most triptans. However, ubrogepant and rimegepant, which received U.S. Food and Drug Administration approval for the treatment of acute migraine in adults in December 2019 and February 2020, respectively, might be associated with fewer risks of adverse events (AEs), compared with triptans. “These new effective therapeutic options enrich the therapeutic categories of specific acute migraine treatments and may provide an opportunity to decrease the risks of barbiturate or opioid overuse or addiction,” they wrote.

The meta-analysis included 64 randomized, controlled trials involving 46,442 participants (74%-87% female across studies; age range, 36-43 years). All studies examined clinically relevant outcomes in patients with International Headache Society criteria for migraine, and compared currently available migraine-specific acute treatments with each other or placebo. The drugs were examined at doses with widespread clinical use and included: ergotamine, dihydroergotamine, sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, lasmiditan, rimegepant, and ubrogepant.

The findings showed that all drug treatments were associated with a higher odds ratio for pain freedom, compared with placebo, except for sumatriptan, 10-mg nasal spray. The most effective drug was eletriptan 40 mg (OR, 5.59), and the least effective was lasmiditan 50 mg (OR, 1.65). Most triptans were associated with higher ORs for both pain freedom and pain relief at 2 hours, compared with lasmiditan, rimegepant, or ubrogepant, while comparisons between lasmiditan, rimegepant, and ubrogepant for these outcomes showed no statistically significant difference, they reported.

Lasmiditan was associated with the highest risk of any AEs, “however, the AEs were tolerable and were not considered serious. … Therefore, we suggest that the benefits should be weighed against the risk of its AEs when considering the clinical application of lasmiditan,” they wrote. Certain triptans (rizatriptan, sumatriptan, and zolmitriptan) were also associated with a higher risk of any AEs, compared with the CGRP antagonists. “Nevertheless, most of the AEs were mild to moderate, and the percentages of serious AEs were low (0.0%-2.1%).”

Finally, the authors noted that their observations of successful treatment with 5-hydroxytriptamine_1F receptor agonists and CGRP antagonists “reveals that vasoconstriction is not essential for antimigraine therapy.” which could have implications for future pharmaceutical development.
 

Older and newer medications each have advantages

“Triptans will be around for a long time, but the newer medications are here to stay,” said Alan M. Rapoport, MD, in reaction to the study. “Before this publication, we knew that the 2-hour efficacy results of the newer medications were not quite as good as the faster-acting triptans; and after this network meta-analysis we are more sure of that,” said Dr. Rapoport, of the department of neurology at University of California, Los Angeles. “But the fact that the three newer medications do not constrict blood vessels and can easily be given even to patients with contraindications to triptans, or patients that simply are at greater risk due to obesity, smoking history, family history, diabetes, lack of exercise, or higher lipid levels, puts them into a desirable category.”

Calling it a “very carefully done” systematic review, Dr. Rapoport had a few caveats about the strength of the research. The trials that were included were not identically designed and were performed in different areas, by different investigators, on different patients, he noted. They were also not head-to-head trials “which ensures that the resultant data are more pure.” The studies also looked only at rapid results at 2 hours after dosing. “In my experience, patients are often satisfied with the response times from these newer agents; and doctors and patients both are happy that they are not vasoconstrictive,” he said. “The researchers also omitted studies looking at zolmitriptan nasal spray, which I have found to be rapid in onset and efficacious with few adverse events.”

Finally, Dr. Rapoport noted that one condition not examined in the review was medication overuse headache (MOH), which is “a major problem with patients that have high-frequency episodic migraine and chronic migraine. To our knowledge thus far, the two gepants (ubrogepant and rimegepant) do not appear to cause MOH when taken frequently, and these agents may end up being a treatment for this condition.”

Dr Wang reported receiving personal fees from Eli Lilly, Daiichi-Sankyo, Norvatis Taiwan, Biogen, Pfizer, and Bayer; and grants from AbbVie, Norvatis, Eli Lilly, Taiwan Ministry of Technology and Science, Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. No other disclosures were reported. Dr. Rapoport serves as an advisor for AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano; he is on the Speakers Bureau of AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries. He is Editor-in-Chief of Neurology Reviews.

The study was funded by the Ministry of Science and Technology, Taiwan, Ministry of Education, Taiwan, and the Brain Research Center, National Yang Ming Chiao Tung University.

When it comes to the acute management of migraines, newer is not necessarily better, according to an analysis of studies comparing triptans – the standard of care – to two newer classifications of medications. The findings, published in JAMA Network Open, “may imply that triptans will remain the current mainstay of specific acute migraine treatment,” suggested senior author Shuu-Jiun Wang, MD, from the National Yang Ming Chiao Tung University, and the Taipei Veterans General Hospital, both in Taipei, Taiwan, and his coauthors. However, lasmiditan (a 5-hydroxytryptamine_1F receptor agonist) and rimegepant and ubrogepant (both calcitonin gene-related peptide [CGRP] antagonists) might still have unique advantages, since triptans are contraindicated for patients with cardiovascular risks, they said.

The systemic review and meta-analysis showed that, for the outcome of pain freedom and pain relief at 2 hours after the dose, the three newer agents worked better than placebo, but were inferior to most triptans. However, ubrogepant and rimegepant, which received U.S. Food and Drug Administration approval for the treatment of acute migraine in adults in December 2019 and February 2020, respectively, might be associated with fewer risks of adverse events (AEs), compared with triptans. “These new effective therapeutic options enrich the therapeutic categories of specific acute migraine treatments and may provide an opportunity to decrease the risks of barbiturate or opioid overuse or addiction,” they wrote.

The meta-analysis included 64 randomized, controlled trials involving 46,442 participants (74%-87% female across studies; age range, 36-43 years). All studies examined clinically relevant outcomes in patients with International Headache Society criteria for migraine, and compared currently available migraine-specific acute treatments with each other or placebo. The drugs were examined at doses with widespread clinical use and included: ergotamine, dihydroergotamine, sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, lasmiditan, rimegepant, and ubrogepant.

The findings showed that all drug treatments were associated with a higher odds ratio for pain freedom, compared with placebo, except for sumatriptan, 10-mg nasal spray. The most effective drug was eletriptan 40 mg (OR, 5.59), and the least effective was lasmiditan 50 mg (OR, 1.65). Most triptans were associated with higher ORs for both pain freedom and pain relief at 2 hours, compared with lasmiditan, rimegepant, or ubrogepant, while comparisons between lasmiditan, rimegepant, and ubrogepant for these outcomes showed no statistically significant difference, they reported.

Lasmiditan was associated with the highest risk of any AEs, “however, the AEs were tolerable and were not considered serious. … Therefore, we suggest that the benefits should be weighed against the risk of its AEs when considering the clinical application of lasmiditan,” they wrote. Certain triptans (rizatriptan, sumatriptan, and zolmitriptan) were also associated with a higher risk of any AEs, compared with the CGRP antagonists. “Nevertheless, most of the AEs were mild to moderate, and the percentages of serious AEs were low (0.0%-2.1%).”

Finally, the authors noted that their observations of successful treatment with 5-hydroxytriptamine_1F receptor agonists and CGRP antagonists “reveals that vasoconstriction is not essential for antimigraine therapy.” which could have implications for future pharmaceutical development.
 

Older and newer medications each have advantages

“Triptans will be around for a long time, but the newer medications are here to stay,” said Alan M. Rapoport, MD, in reaction to the study. “Before this publication, we knew that the 2-hour efficacy results of the newer medications were not quite as good as the faster-acting triptans; and after this network meta-analysis we are more sure of that,” said Dr. Rapoport, of the department of neurology at University of California, Los Angeles. “But the fact that the three newer medications do not constrict blood vessels and can easily be given even to patients with contraindications to triptans, or patients that simply are at greater risk due to obesity, smoking history, family history, diabetes, lack of exercise, or higher lipid levels, puts them into a desirable category.”

Calling it a “very carefully done” systematic review, Dr. Rapoport had a few caveats about the strength of the research. The trials that were included were not identically designed and were performed in different areas, by different investigators, on different patients, he noted. They were also not head-to-head trials “which ensures that the resultant data are more pure.” The studies also looked only at rapid results at 2 hours after dosing. “In my experience, patients are often satisfied with the response times from these newer agents; and doctors and patients both are happy that they are not vasoconstrictive,” he said. “The researchers also omitted studies looking at zolmitriptan nasal spray, which I have found to be rapid in onset and efficacious with few adverse events.”

Finally, Dr. Rapoport noted that one condition not examined in the review was medication overuse headache (MOH), which is “a major problem with patients that have high-frequency episodic migraine and chronic migraine. To our knowledge thus far, the two gepants (ubrogepant and rimegepant) do not appear to cause MOH when taken frequently, and these agents may end up being a treatment for this condition.”

Dr Wang reported receiving personal fees from Eli Lilly, Daiichi-Sankyo, Norvatis Taiwan, Biogen, Pfizer, and Bayer; and grants from AbbVie, Norvatis, Eli Lilly, Taiwan Ministry of Technology and Science, Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work. No other disclosures were reported. Dr. Rapoport serves as an advisor for AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano; he is on the Speakers Bureau of AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries. He is Editor-in-Chief of Neurology Reviews.

The study was funded by the Ministry of Science and Technology, Taiwan, Ministry of Education, Taiwan, and the Brain Research Center, National Yang Ming Chiao Tung University.

People with multiple preexisting chronic conditions experience a longer wait to receive a diagnosis of cancer and are more likely to be referred to an emergency department for their cancer, according to new research.

These findings are based on a retrospective study of data from 11,716 cancer patients from the United Kingdom’s National Cancer Diagnosis Audit – an initiative that aimed to better understand the journey of cancer patients from primary care to diagnosis. Three-quarters of the study participants had at least one morbidity in their primary care record, according to the authors of the new research, which was published in Family Practice (2021 Nov 30. doi: 10.1093/fampra/cmab139).

In their analysis of all of the patient data, Minjoung M. Koo and colleagues found that the median time between first presenting to a primary care physician with cancer symptoms and being referred to a specialist was 5 days. For all patients studied, the median time to receiving a cancer diagnosis was 42 days, the investigators wrote.

Patients with multiple morbidities were 26% more likely to have their cancer diagnosed at least 60 days after the initial primary care consultation than were those without morbidities (95% confidence interval, 1.10-1.45). This was true after adjustment for confounders, including morbidity, sex, age, and cancer. Similarly, those with a Charlson score of 3 or above – signifying more severe comorbidities – had a 19% greater odds of being diagnosed more than 60 days after presenting to primary care (95% CI, 1.01-1.40)
 

Older adults ‘less likely to be screen-detected’

Dr. Fran Boyle, professor of medical oncology at the University of Sydney, Australia, said it wasn’t clear from the study whether people with multiple comorbidities may have symptoms that cloud the diagnostic process, or whether short primary care consultations may not allow for enough time to manage multiple issues.

“Older adults typically have more comorbidities, and they are less likely to be screen-detected; for example, breast cancer screening and bowel cancer screening typically stop after 75,” said Dr. Boyle, director of Patricia Ritchie Centre for Cancer Care and Research at Sydney’s Mater Hospital.

Dr. Boyle pointed to a recent systematic review in Australian rural oncology that suggested that patients with more comorbidities tend to be offered less intense treatment, and have higher operative mortality and morbidity, which can contribute to less effective therapy.
 

Referral delays seen in multiple patient groups

Ms. Koo, from the University College London and the National Disease Registration Service in the United Kingdom, and coauthors noted a nonsignificant trend toward increased intervals between primary care consultation and referral or diagnosis even in patients with one or more comorbidities.

A higher burden of comorbidities also meant patients were more likely to have more than one primary care consultation before being referred to a specialist. Those with three or more comorbidities were 21% more likely to have at least three consultations before referral, compared with patients with no comorbidities (95% CI, 1.05-1.40, P = .010).

Overall, 60% of the participants in the study experienced at least one investigation into whether they had cancer by a primary care clinician before being referred to a specialist.
 

Morbidities linked with emergency referral

The study also saw an association between morbidities and the likelihood of receiving an emergency referral. Those with three or more morbidities were 60% more likely to have an emergency referral than were those with no comorbidities. Those with a Charlson score of three or above were 61% more likely to be referred to an emergency department.

“The greater likelihood of clinical complexity or acute deterior­ation among individuals with multiple or severe chronic conditions means that an emergency referral may be clinically appropriate,” the authors wrote.

Commenting on the findings, Dr. Diane M. Harper, professor of family medicine at the University of Michigan, Ann Arbor, said primary care patients often have multiple chronic illnesses, and the relationship between the physician and patients determines how quickly symptoms of cancer are explored.

“What this work cannot explore is the quality of discussions between the physician and the patient, nor can it explore how the decision to go to the ED was made,” said Dr. Harper, president of the North American Primary Care Research Group. “Exploring these data would provide important information to the physician-patient dyad.”
 

Diagnostic difficulty might have been at play, according to authors

The investigators didn’t find any evidence of an interaction between cancer site, number of morbidities, and referral or diagnostic time, except in cases of colorectal cancer, where patients with multiple morbidities were more likely to experience a longer wait between primary care consultation and diagnosis.

The authors observed that diagnostic difficulty of the cancer might have been at play here, given that colorectal cancer can have a broad symptom signature.

“This was less often observed among patients diagnosed with a cancer that had a narrow symptom signature (“easy” diagnostic difficulty, e.g. breast cancer) or a broad symptom signature of mostly low PPVs (“hard” diagnostic difficulty, e.g. brain cancer),” they wrote.

The authors concluded that “it is reasonable to sug­gest that both improvement efforts and future research in this field should target patients with multiple or severe morbidity, and explore the reasons for prolonged diagnostic intervals in specialist care.”

The study was supported by Cancer Research UK. The authors and experts interviewed for this piece did not declare having any conflicts of interest.

People with multiple preexisting chronic conditions experience a longer wait to receive a diagnosis of cancer and are more likely to be referred to an emergency department for their cancer, according to new research.

These findings are based on a retrospective study of data from 11,716 cancer patients from the United Kingdom’s National Cancer Diagnosis Audit – an initiative that aimed to better understand the journey of cancer patients from primary care to diagnosis. Three-quarters of the study participants had at least one morbidity in their primary care record, according to the authors of the new research, which was published in Family Practice (2021 Nov 30. doi: 10.1093/fampra/cmab139).

In their analysis of all of the patient data, Minjoung M. Koo and colleagues found that the median time between first presenting to a primary care physician with cancer symptoms and being referred to a specialist was 5 days. For all patients studied, the median time to receiving a cancer diagnosis was 42 days, the investigators wrote.

Patients with multiple morbidities were 26% more likely to have their cancer diagnosed at least 60 days after the initial primary care consultation than were those without morbidities (95% confidence interval, 1.10-1.45). This was true after adjustment for confounders, including morbidity, sex, age, and cancer. Similarly, those with a Charlson score of 3 or above – signifying more severe comorbidities – had a 19% greater odds of being diagnosed more than 60 days after presenting to primary care (95% CI, 1.01-1.40)
 

Older adults ‘less likely to be screen-detected’

Dr. Fran Boyle, professor of medical oncology at the University of Sydney, Australia, said it wasn’t clear from the study whether people with multiple comorbidities may have symptoms that cloud the diagnostic process, or whether short primary care consultations may not allow for enough time to manage multiple issues.

“Older adults typically have more comorbidities, and they are less likely to be screen-detected; for example, breast cancer screening and bowel cancer screening typically stop after 75,” said Dr. Boyle, director of Patricia Ritchie Centre for Cancer Care and Research at Sydney’s Mater Hospital.

Dr. Boyle pointed to a recent systematic review in Australian rural oncology that suggested that patients with more comorbidities tend to be offered less intense treatment, and have higher operative mortality and morbidity, which can contribute to less effective therapy.
 

Referral delays seen in multiple patient groups

Ms. Koo, from the University College London and the National Disease Registration Service in the United Kingdom, and coauthors noted a nonsignificant trend toward increased intervals between primary care consultation and referral or diagnosis even in patients with one or more comorbidities.

A higher burden of comorbidities also meant patients were more likely to have more than one primary care consultation before being referred to a specialist. Those with three or more comorbidities were 21% more likely to have at least three consultations before referral, compared with patients with no comorbidities (95% CI, 1.05-1.40, P = .010).

Overall, 60% of the participants in the study experienced at least one investigation into whether they had cancer by a primary care clinician before being referred to a specialist.
 

Morbidities linked with emergency referral

The study also saw an association between morbidities and the likelihood of receiving an emergency referral. Those with three or more morbidities were 60% more likely to have an emergency referral than were those with no comorbidities. Those with a Charlson score of three or above were 61% more likely to be referred to an emergency department.

“The greater likelihood of clinical complexity or acute deterior­ation among individuals with multiple or severe chronic conditions means that an emergency referral may be clinically appropriate,” the authors wrote.

Commenting on the findings, Dr. Diane M. Harper, professor of family medicine at the University of Michigan, Ann Arbor, said primary care patients often have multiple chronic illnesses, and the relationship between the physician and patients determines how quickly symptoms of cancer are explored.

“What this work cannot explore is the quality of discussions between the physician and the patient, nor can it explore how the decision to go to the ED was made,” said Dr. Harper, president of the North American Primary Care Research Group. “Exploring these data would provide important information to the physician-patient dyad.”
 

Diagnostic difficulty might have been at play, according to authors

The investigators didn’t find any evidence of an interaction between cancer site, number of morbidities, and referral or diagnostic time, except in cases of colorectal cancer, where patients with multiple morbidities were more likely to experience a longer wait between primary care consultation and diagnosis.

The authors observed that diagnostic difficulty of the cancer might have been at play here, given that colorectal cancer can have a broad symptom signature.

“This was less often observed among patients diagnosed with a cancer that had a narrow symptom signature (“easy” diagnostic difficulty, e.g. breast cancer) or a broad symptom signature of mostly low PPVs (“hard” diagnostic difficulty, e.g. brain cancer),” they wrote.

The authors concluded that “it is reasonable to sug­gest that both improvement efforts and future research in this field should target patients with multiple or severe morbidity, and explore the reasons for prolonged diagnostic intervals in specialist care.”

The study was supported by Cancer Research UK. The authors and experts interviewed for this piece did not declare having any conflicts of interest.

People with multiple preexisting chronic conditions experience a longer wait to receive a diagnosis of cancer and are more likely to be referred to an emergency department for their cancer, according to new research.

These findings are based on a retrospective study of data from 11,716 cancer patients from the United Kingdom’s National Cancer Diagnosis Audit – an initiative that aimed to better understand the journey of cancer patients from primary care to diagnosis. Three-quarters of the study participants had at least one morbidity in their primary care record, according to the authors of the new research, which was published in Family Practice (2021 Nov 30. doi: 10.1093/fampra/cmab139).

In their analysis of all of the patient data, Minjoung M. Koo and colleagues found that the median time between first presenting to a primary care physician with cancer symptoms and being referred to a specialist was 5 days. For all patients studied, the median time to receiving a cancer diagnosis was 42 days, the investigators wrote.

Patients with multiple morbidities were 26% more likely to have their cancer diagnosed at least 60 days after the initial primary care consultation than were those without morbidities (95% confidence interval, 1.10-1.45). This was true after adjustment for confounders, including morbidity, sex, age, and cancer. Similarly, those with a Charlson score of 3 or above – signifying more severe comorbidities – had a 19% greater odds of being diagnosed more than 60 days after presenting to primary care (95% CI, 1.01-1.40)
 

Older adults ‘less likely to be screen-detected’

Dr. Fran Boyle, professor of medical oncology at the University of Sydney, Australia, said it wasn’t clear from the study whether people with multiple comorbidities may have symptoms that cloud the diagnostic process, or whether short primary care consultations may not allow for enough time to manage multiple issues.

“Older adults typically have more comorbidities, and they are less likely to be screen-detected; for example, breast cancer screening and bowel cancer screening typically stop after 75,” said Dr. Boyle, director of Patricia Ritchie Centre for Cancer Care and Research at Sydney’s Mater Hospital.

Dr. Boyle pointed to a recent systematic review in Australian rural oncology that suggested that patients with more comorbidities tend to be offered less intense treatment, and have higher operative mortality and morbidity, which can contribute to less effective therapy.
 

Referral delays seen in multiple patient groups

Ms. Koo, from the University College London and the National Disease Registration Service in the United Kingdom, and coauthors noted a nonsignificant trend toward increased intervals between primary care consultation and referral or diagnosis even in patients with one or more comorbidities.

A higher burden of comorbidities also meant patients were more likely to have more than one primary care consultation before being referred to a specialist. Those with three or more comorbidities were 21% more likely to have at least three consultations before referral, compared with patients with no comorbidities (95% CI, 1.05-1.40, P = .010).

Overall, 60% of the participants in the study experienced at least one investigation into whether they had cancer by a primary care clinician before being referred to a specialist.
 

Morbidities linked with emergency referral

The study also saw an association between morbidities and the likelihood of receiving an emergency referral. Those with three or more morbidities were 60% more likely to have an emergency referral than were those with no comorbidities. Those with a Charlson score of three or above were 61% more likely to be referred to an emergency department.

“The greater likelihood of clinical complexity or acute deterior­ation among individuals with multiple or severe chronic conditions means that an emergency referral may be clinically appropriate,” the authors wrote.

Commenting on the findings, Dr. Diane M. Harper, professor of family medicine at the University of Michigan, Ann Arbor, said primary care patients often have multiple chronic illnesses, and the relationship between the physician and patients determines how quickly symptoms of cancer are explored.

“What this work cannot explore is the quality of discussions between the physician and the patient, nor can it explore how the decision to go to the ED was made,” said Dr. Harper, president of the North American Primary Care Research Group. “Exploring these data would provide important information to the physician-patient dyad.”
 

Diagnostic difficulty might have been at play, according to authors

The investigators didn’t find any evidence of an interaction between cancer site, number of morbidities, and referral or diagnostic time, except in cases of colorectal cancer, where patients with multiple morbidities were more likely to experience a longer wait between primary care consultation and diagnosis.

The authors observed that diagnostic difficulty of the cancer might have been at play here, given that colorectal cancer can have a broad symptom signature.

“This was less often observed among patients diagnosed with a cancer that had a narrow symptom signature (“easy” diagnostic difficulty, e.g. breast cancer) or a broad symptom signature of mostly low PPVs (“hard” diagnostic difficulty, e.g. brain cancer),” they wrote.

The authors concluded that “it is reasonable to sug­gest that both improvement efforts and future research in this field should target patients with multiple or severe morbidity, and explore the reasons for prolonged diagnostic intervals in specialist care.”

The study was supported by Cancer Research UK. The authors and experts interviewed for this piece did not declare having any conflicts of interest.

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

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

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

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

ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.

“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.

“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
 

Early promise

A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.

“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.

“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.

“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.

“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
 

Study results

The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.

The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.

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

It has been 19 years since the publication of the landmark AFFIRM trial.¹ At the time of publication, a “rhythm control” strategy was the preferred therapy, with a rate control approach an accepted alternative. AFFIRM showed no mortality benefit of rhythm control over rate control, and its result dramatically shifted the paradigm of atrial fibrillation (AF) management. However, the high crossover rate between treatment arms may have biased the study toward the null hypothesis. Post hoc analyses of AFFIRM and other observational studies indicate that sinus rhythm was associated with a lower risk of death.² Since AFFIRM, technical advances and procedural experience have improved the safety and efficacy of catheter ablation (CA), and recently published randomized trials have shown improved outcomes with rhythm control. This Progress Note summarizes the recent evidence, updating hospitalists on the management of AF, including inpatient cardioversion, patient selection for CA, use of antiarrhythmic drugs (AADs), and lifestyle modifications associated with maintenance of sinus rhythm.

A PubMed search for recent publications using combined the MeSH terms “atrial fibrillation” with “catheter ablation,” “antiarrhythmic drugs,” and “lifestyle modifications.” Our review filtered for randomized trials, guidelines, and selected reviews. 

Urgent cardioversion is recommended for those with hemodynamic instability, AF associated ischemia, or acute heart failure.³ Whether to perform elective cardioversion depends on AF duration, symptoms, and the initial evaluation for structural heart disease or reversible causes of AF. Evaluation for new-onset AF includes eliciting a history of AF-associated comorbidities (hypertension, alcohol use, obstructive sleep apnea) and an echocardiogram and thyroid, renal, and liver function tests.³ Stable patients with AF precipitated by high-catecholamine states (eg, postoperative AF, sepsis, hyperthyroidism, pulmonary embolism, substance use) require management of the underlying condition before considering rhythm control. Inpatient electrical or pharmacologic cardioversion may be considered for patients with stable, new-onset AF sufficiently symptomatic to require hospitalization. Pre-procedure anticoagulation and a transesophageal echocardiogram to rule out left atrial thrombus before cardioversion is preferred for a first episode of AF suspected of lasting longer than 48 hours but requires anesthesia and considerable resources. In resource-constrained settings, patients asymptomatic once rate controlled may be safely discharged with a referral for outpatient cardioversion.

For patients with structural heart disease (left atrial dilation), previously failed cardioversion, or recurrent AF, initiating AADs (eg, ibutilide, amiodarone) before electrical cardioversion can improve the success rate of cardioversion.³ Ibutilide infusion requires cardiology consultation and postinfusion hemodynamic and QTc monitoring. Defer immediate cardioversion among stable patients unable to continue a minimum of 4 weeks of anticoagulation or with comorbidities for which risks of cardioversion outweigh benefits.

Successful maintenance of sinus rhythm is associated with reduced symptom burden and improved quality of life and is recommended for patients with persistent symptoms, failure of rate control, younger age, first episode of AF, or patient preference for rhythm control.³ Since AF progression results in irreversible cardiac remodeling, earlier rhythm control may prevent further atrial remodeling and atrial myopathy.

The EAST-AFNET 4 trial evaluated a rhythm-control strategy in patients with AF duration <12 months and who met two of the following: age > 65 years, female sex, heart failure, hypertension, diabetes, coronary artery disease, and chronic kidney disease.⁴ Maintenance of sinus rhythm was associated with a lower composite outcome of adverse cardiovascular outcomes and death from cardiovascular causes over 5 years compared to rate control (3.9/100 person-years vs 5.0/100 person-years, P = .005). Interestingly, roughly 20% of patients underwent CA and the remainder received AADs. The large proportion of patients treated with AADs raises the question of why the results differed from AFFIRM. There are four primary differences between these trials to consider. First, EAST-AFNET 4 used an early rhythm-control strategy (<12 months). Second, nearly all patients in EAST-AFNET 4 continued guideline-recommend anticoagulation compared to 70% receiving rhythm control in AFFIRM. Third, in AFFIRM, 62.8% of patients received amiodarone, which has significant long-term adverse effects compared to 11.8% by the end of EAST-AFNET 4. Finally, increased use of CA in EAST-AFNET 4 may have contributed to the success of rhythm control. In patients with cardiovascular disease or cardiovascular risk factors, a rhythm-control strategy will be best if implemented early (<12 months), before the development of long-standing persistent AF, and if clinicians adhere to anticoagulation recommendations.

Antiarrhythmic Drugs

Antiarrhythmic drug use prior to CA remains the cornerstone of a rhythm-control strategy for patients meeting EAST-AFNET 4 trial criteria or patient preference for medical management. Hospitalists’ knowledge of key differences between AADs used in EAST-AFNET 4 and AFFIRM as well as American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline recommendations help avoid harmful AAD prescribing. Notably, 21.9% of patients in AFFIRM received AADs no longer recommended to maintain sinus rhythm in the AHA/ACC/HRS guidelines (quinidine, disopyramide, procainamide, moricizine).³ For patients without structural heart disease, flecainide, propafenone, sotalol, or dronedarone are preferred. Dronedarone and sotalol remain an option for those with coronary artery disease. For patients with heart failure with reduced ejection fraction (HFrEF), amiodarone and dofetilide are preferred (Table).³

Catheter Ablation

The AHA/ACC/HRS guidelines offer a Ia recommendation for CA in patients with recurrent, symptomatic AF who failed AAD therapy. Initial CA is a IIa recommendation and is increasingly common for patients with paroxysmal AF who prefer this strategy to long-term AAD use.³ Recent trials evaluated CA as a primary treatment modality in patients with heart failure and as initial management before AADs.

Initial Catheter Ablation

The CABANA trial compared CA with AADs as an initial approach for maintaining sinus rhythm.⁵ In the intention-to-treat analysis, there was no difference in all death or disabling stroke between AAD therapy and CA at 5-year follow-up. The results are limited by a 27.5% crossover rate from drug therapy to CA. The per-protocol analysis based on the treatment received favored CA for the primary composite outcome of death, disabling stroke, serious bleeding, or cardiac arrest at 12 months. The STOP-AF and EARLY-AF trials found that initial CA was more successful in maintaining freedom from atrial arrhythmias (74.6% vs 45.0%, P < .001)⁶ and fewer symptomatic atrial arrhythmias among patients with paroxysmal AF compared to AADs, without significant CA-associated adverse events.^6,7

While hospitalists should interpret the per-protocol analysis cautiously when determining the clinical benefit, these trials indicate initial CA is as safe as AADs and improves freedom from AF. Duration of AF, knowledge of periprocedural anticoagulation recommendations, and CA procedural complications are important when recommending CA (Figure). Efficacy of CA is approximately 70% in paroxysmal AF and decreases for persistent and long-standing AF.⁶ Complications of CA include venous access site hematoma, cardiac tamponade, phrenic nerve injury, pulmonary vein stenosis, atrial-esophageal fistula, left atrial flutter, and stroke due to endothelial injury and intraprocedural thrombosis.³ Therapeutic anticoagulation is required before CA and for at least 2 months post ablation regardless of the CHA₂DS₂-VASc score.³

Catheter Ablation Plus Antiarrhythmics

Ongoing AADs following CA may suppress AF triggers, especially in patients with persistent AF or high-risk for recurrence post ablation (left atrial dilation). The AMIO-CAT trial found that 4 weeks of amiodarone after ablation reduced early AF recurrence at 3 months (34% vs 53%, P = .006), arrhythmia-related hospitalizations, and need for cardioversion in patients with paroxysmal and persistent AF.⁸ However, amiodarone did not reduce recurrent atrial tachyarrhythmias at 6 months. The POWDER-AF trial evaluated AAD use for 1 year after CA in patients with drug-refractory paroxysmal AF.⁹ Continuation of class IC (eg, flecainide) and III (eg, amiodarone) AADs resulted in a near 20% absolute risk reduction in recurrent atrial arrhythmias and reduced the need for repeat CA. These trials suggest that discharging patients on adjunctive AADs decreases early recurrence of AF and arrhythmia-related hospitalizations; however, studies evaluating additional clinical outcomes are needed.

Heart Failure

The AATAC trial found CA was superior to amiodarone therapy at maintaining freedom from AF and reducing unplanned hospitalizations and mortality among patients with persistent AF and HFrEF.¹⁰ The larger CASTLE-AF trial randomized patients with an ejection fraction below 35% and NYHA class II or greater symptoms with symptomatic paroxysmal AF or persistent AF in whom AAD therapy failed to CA or medical therapy.¹¹ The CA group experienced lower cardiovascular mortality (11.2% vs 22.3%, P = .009) and fewer heart failure hospitalizations (20.7% vs 35.9%, P = .004). The subsequent AMICA trial did not find a benefit of CA in patients with HFrEF and persistent or long-standing persistent AF; however, this trial was limited to 12 months, whereas the benefit of CA in CASTLE-AF was observed after 12 months.¹² Also, AMICA enrolled patients with higher NYHA class. Therefore, hospitalists should refer AF patients with left ventricular systolic dysfunction and NYHA II or III symptoms for CA. Comparing AMICA and CASTLE-AF suggests earlier referral for CA, prior to the development of worsening heart failure symptoms, may improve outcomes.

Data for patients with heart failure with preserved EF (HFpEF) is limited. One small trial showed reduced heart failure hospitalizations in HFpEF patients treated with CA compared to AADs or beta-blockers.¹³ It is reasonable to refer HFpEF patients with persisting symptoms or reduced quality of life for CA.

The AHA Scientific Statement on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation delineates risk factors that increase the incidence of AF, including alcohol consumption, obstructive sleep apnea, hypertension, and obesity.¹⁴ Among regular alcohol consumers with paroxysmal or persistent AF managed with a rhythm-control strategy, cessation of alcohol has been shown to significantly lower the incidence of recurrent AF (53.0% vs 73.0%, P = .005), and lead to a longer time until recurrence of AF compared to patients regularly consuming alcohol.¹⁵ Among patients with obstructive sleep apnea, a systematic review of nonrandomized studies showed continuous positive airway pressure is associated with maintenance of sinus rhythm.¹⁴ Control of these risk factors is associated with up to approximately 40% of patients maintaining sinus rhythm without intervention, and hospitalists should encourage lifestyle modification to maximize the probability of maintaining sinus rhythm. 

Hospitalists frequently determine the best initial management strategy for patients admitted with new-onset AF, and recent literature may shift more patients towards management with rhythm control. Based on the trials reviewed in this Progress Note, hospitalists should recommend a rhythm-control strategy for patients with symptomatic, paroxysmal, or persistent AF of <12 months’ duration and refer patients with HFrEF for CA. Adherence to guideline recommendations is essential when prescribing AADs to avoid adverse drug events. It is vital to ensure patients managed with a rhythm-control strategy receive anticoagulation for 4 weeks post cardioversion or 2 months post CA with long-term anticoagulation based on CHA₂DS₂-VASc score. Finally, admissions for AF should serve as a catalyst to communicate to patients the importance of addressing obstructive sleep apnea, obesity, and alcohol use disorders. Applying these evidence-based practices will enable hospitalists to make clinical decisions that improve symptom burden and survival for patients with AF.

It has been 19 years since the publication of the landmark AFFIRM trial.¹ At the time of publication, a “rhythm control” strategy was the preferred therapy, with a rate control approach an accepted alternative. AFFIRM showed no mortality benefit of rhythm control over rate control, and its result dramatically shifted the paradigm of atrial fibrillation (AF) management. However, the high crossover rate between treatment arms may have biased the study toward the null hypothesis. Post hoc analyses of AFFIRM and other observational studies indicate that sinus rhythm was associated with a lower risk of death.² Since AFFIRM, technical advances and procedural experience have improved the safety and efficacy of catheter ablation (CA), and recently published randomized trials have shown improved outcomes with rhythm control. This Progress Note summarizes the recent evidence, updating hospitalists on the management of AF, including inpatient cardioversion, patient selection for CA, use of antiarrhythmic drugs (AADs), and lifestyle modifications associated with maintenance of sinus rhythm.

A PubMed search for recent publications using combined the MeSH terms “atrial fibrillation” with “catheter ablation,” “antiarrhythmic drugs,” and “lifestyle modifications.” Our review filtered for randomized trials, guidelines, and selected reviews. 

Urgent cardioversion is recommended for those with hemodynamic instability, AF associated ischemia, or acute heart failure.³ Whether to perform elective cardioversion depends on AF duration, symptoms, and the initial evaluation for structural heart disease or reversible causes of AF. Evaluation for new-onset AF includes eliciting a history of AF-associated comorbidities (hypertension, alcohol use, obstructive sleep apnea) and an echocardiogram and thyroid, renal, and liver function tests.³ Stable patients with AF precipitated by high-catecholamine states (eg, postoperative AF, sepsis, hyperthyroidism, pulmonary embolism, substance use) require management of the underlying condition before considering rhythm control. Inpatient electrical or pharmacologic cardioversion may be considered for patients with stable, new-onset AF sufficiently symptomatic to require hospitalization. Pre-procedure anticoagulation and a transesophageal echocardiogram to rule out left atrial thrombus before cardioversion is preferred for a first episode of AF suspected of lasting longer than 48 hours but requires anesthesia and considerable resources. In resource-constrained settings, patients asymptomatic once rate controlled may be safely discharged with a referral for outpatient cardioversion.

For patients with structural heart disease (left atrial dilation), previously failed cardioversion, or recurrent AF, initiating AADs (eg, ibutilide, amiodarone) before electrical cardioversion can improve the success rate of cardioversion.³ Ibutilide infusion requires cardiology consultation and postinfusion hemodynamic and QTc monitoring. Defer immediate cardioversion among stable patients unable to continue a minimum of 4 weeks of anticoagulation or with comorbidities for which risks of cardioversion outweigh benefits.

Successful maintenance of sinus rhythm is associated with reduced symptom burden and improved quality of life and is recommended for patients with persistent symptoms, failure of rate control, younger age, first episode of AF, or patient preference for rhythm control.³ Since AF progression results in irreversible cardiac remodeling, earlier rhythm control may prevent further atrial remodeling and atrial myopathy.

The EAST-AFNET 4 trial evaluated a rhythm-control strategy in patients with AF duration <12 months and who met two of the following: age > 65 years, female sex, heart failure, hypertension, diabetes, coronary artery disease, and chronic kidney disease.⁴ Maintenance of sinus rhythm was associated with a lower composite outcome of adverse cardiovascular outcomes and death from cardiovascular causes over 5 years compared to rate control (3.9/100 person-years vs 5.0/100 person-years, P = .005). Interestingly, roughly 20% of patients underwent CA and the remainder received AADs. The large proportion of patients treated with AADs raises the question of why the results differed from AFFIRM. There are four primary differences between these trials to consider. First, EAST-AFNET 4 used an early rhythm-control strategy (<12 months). Second, nearly all patients in EAST-AFNET 4 continued guideline-recommend anticoagulation compared to 70% receiving rhythm control in AFFIRM. Third, in AFFIRM, 62.8% of patients received amiodarone, which has significant long-term adverse effects compared to 11.8% by the end of EAST-AFNET 4. Finally, increased use of CA in EAST-AFNET 4 may have contributed to the success of rhythm control. In patients with cardiovascular disease or cardiovascular risk factors, a rhythm-control strategy will be best if implemented early (<12 months), before the development of long-standing persistent AF, and if clinicians adhere to anticoagulation recommendations.

Antiarrhythmic Drugs

Antiarrhythmic drug use prior to CA remains the cornerstone of a rhythm-control strategy for patients meeting EAST-AFNET 4 trial criteria or patient preference for medical management. Hospitalists’ knowledge of key differences between AADs used in EAST-AFNET 4 and AFFIRM as well as American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline recommendations help avoid harmful AAD prescribing. Notably, 21.9% of patients in AFFIRM received AADs no longer recommended to maintain sinus rhythm in the AHA/ACC/HRS guidelines (quinidine, disopyramide, procainamide, moricizine).³ For patients without structural heart disease, flecainide, propafenone, sotalol, or dronedarone are preferred. Dronedarone and sotalol remain an option for those with coronary artery disease. For patients with heart failure with reduced ejection fraction (HFrEF), amiodarone and dofetilide are preferred (Table).³

Catheter Ablation

The AHA/ACC/HRS guidelines offer a Ia recommendation for CA in patients with recurrent, symptomatic AF who failed AAD therapy. Initial CA is a IIa recommendation and is increasingly common for patients with paroxysmal AF who prefer this strategy to long-term AAD use.³ Recent trials evaluated CA as a primary treatment modality in patients with heart failure and as initial management before AADs.

Initial Catheter Ablation

The CABANA trial compared CA with AADs as an initial approach for maintaining sinus rhythm.⁵ In the intention-to-treat analysis, there was no difference in all death or disabling stroke between AAD therapy and CA at 5-year follow-up. The results are limited by a 27.5% crossover rate from drug therapy to CA. The per-protocol analysis based on the treatment received favored CA for the primary composite outcome of death, disabling stroke, serious bleeding, or cardiac arrest at 12 months. The STOP-AF and EARLY-AF trials found that initial CA was more successful in maintaining freedom from atrial arrhythmias (74.6% vs 45.0%, P < .001)⁶ and fewer symptomatic atrial arrhythmias among patients with paroxysmal AF compared to AADs, without significant CA-associated adverse events.^6,7

While hospitalists should interpret the per-protocol analysis cautiously when determining the clinical benefit, these trials indicate initial CA is as safe as AADs and improves freedom from AF. Duration of AF, knowledge of periprocedural anticoagulation recommendations, and CA procedural complications are important when recommending CA (Figure). Efficacy of CA is approximately 70% in paroxysmal AF and decreases for persistent and long-standing AF.⁶ Complications of CA include venous access site hematoma, cardiac tamponade, phrenic nerve injury, pulmonary vein stenosis, atrial-esophageal fistula, left atrial flutter, and stroke due to endothelial injury and intraprocedural thrombosis.³ Therapeutic anticoagulation is required before CA and for at least 2 months post ablation regardless of the CHA₂DS₂-VASc score.³

Catheter Ablation Plus Antiarrhythmics

Ongoing AADs following CA may suppress AF triggers, especially in patients with persistent AF or high-risk for recurrence post ablation (left atrial dilation). The AMIO-CAT trial found that 4 weeks of amiodarone after ablation reduced early AF recurrence at 3 months (34% vs 53%, P = .006), arrhythmia-related hospitalizations, and need for cardioversion in patients with paroxysmal and persistent AF.⁸ However, amiodarone did not reduce recurrent atrial tachyarrhythmias at 6 months. The POWDER-AF trial evaluated AAD use for 1 year after CA in patients with drug-refractory paroxysmal AF.⁹ Continuation of class IC (eg, flecainide) and III (eg, amiodarone) AADs resulted in a near 20% absolute risk reduction in recurrent atrial arrhythmias and reduced the need for repeat CA. These trials suggest that discharging patients on adjunctive AADs decreases early recurrence of AF and arrhythmia-related hospitalizations; however, studies evaluating additional clinical outcomes are needed.

Heart Failure

The AATAC trial found CA was superior to amiodarone therapy at maintaining freedom from AF and reducing unplanned hospitalizations and mortality among patients with persistent AF and HFrEF.¹⁰ The larger CASTLE-AF trial randomized patients with an ejection fraction below 35% and NYHA class II or greater symptoms with symptomatic paroxysmal AF or persistent AF in whom AAD therapy failed to CA or medical therapy.¹¹ The CA group experienced lower cardiovascular mortality (11.2% vs 22.3%, P = .009) and fewer heart failure hospitalizations (20.7% vs 35.9%, P = .004). The subsequent AMICA trial did not find a benefit of CA in patients with HFrEF and persistent or long-standing persistent AF; however, this trial was limited to 12 months, whereas the benefit of CA in CASTLE-AF was observed after 12 months.¹² Also, AMICA enrolled patients with higher NYHA class. Therefore, hospitalists should refer AF patients with left ventricular systolic dysfunction and NYHA II or III symptoms for CA. Comparing AMICA and CASTLE-AF suggests earlier referral for CA, prior to the development of worsening heart failure symptoms, may improve outcomes.

Data for patients with heart failure with preserved EF (HFpEF) is limited. One small trial showed reduced heart failure hospitalizations in HFpEF patients treated with CA compared to AADs or beta-blockers.¹³ It is reasonable to refer HFpEF patients with persisting symptoms or reduced quality of life for CA.

The AHA Scientific Statement on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation delineates risk factors that increase the incidence of AF, including alcohol consumption, obstructive sleep apnea, hypertension, and obesity.¹⁴ Among regular alcohol consumers with paroxysmal or persistent AF managed with a rhythm-control strategy, cessation of alcohol has been shown to significantly lower the incidence of recurrent AF (53.0% vs 73.0%, P = .005), and lead to a longer time until recurrence of AF compared to patients regularly consuming alcohol.¹⁵ Among patients with obstructive sleep apnea, a systematic review of nonrandomized studies showed continuous positive airway pressure is associated with maintenance of sinus rhythm.¹⁴ Control of these risk factors is associated with up to approximately 40% of patients maintaining sinus rhythm without intervention, and hospitalists should encourage lifestyle modification to maximize the probability of maintaining sinus rhythm. 

Hospitalists frequently determine the best initial management strategy for patients admitted with new-onset AF, and recent literature may shift more patients towards management with rhythm control. Based on the trials reviewed in this Progress Note, hospitalists should recommend a rhythm-control strategy for patients with symptomatic, paroxysmal, or persistent AF of <12 months’ duration and refer patients with HFrEF for CA. Adherence to guideline recommendations is essential when prescribing AADs to avoid adverse drug events. It is vital to ensure patients managed with a rhythm-control strategy receive anticoagulation for 4 weeks post cardioversion or 2 months post CA with long-term anticoagulation based on CHA₂DS₂-VASc score. Finally, admissions for AF should serve as a catalyst to communicate to patients the importance of addressing obstructive sleep apnea, obesity, and alcohol use disorders. Applying these evidence-based practices will enable hospitalists to make clinical decisions that improve symptom burden and survival for patients with AF.

It has been 19 years since the publication of the landmark AFFIRM trial.¹ At the time of publication, a “rhythm control” strategy was the preferred therapy, with a rate control approach an accepted alternative. AFFIRM showed no mortality benefit of rhythm control over rate control, and its result dramatically shifted the paradigm of atrial fibrillation (AF) management. However, the high crossover rate between treatment arms may have biased the study toward the null hypothesis. Post hoc analyses of AFFIRM and other observational studies indicate that sinus rhythm was associated with a lower risk of death.² Since AFFIRM, technical advances and procedural experience have improved the safety and efficacy of catheter ablation (CA), and recently published randomized trials have shown improved outcomes with rhythm control. This Progress Note summarizes the recent evidence, updating hospitalists on the management of AF, including inpatient cardioversion, patient selection for CA, use of antiarrhythmic drugs (AADs), and lifestyle modifications associated with maintenance of sinus rhythm.

A PubMed search for recent publications using combined the MeSH terms “atrial fibrillation” with “catheter ablation,” “antiarrhythmic drugs,” and “lifestyle modifications.” Our review filtered for randomized trials, guidelines, and selected reviews. 

Urgent cardioversion is recommended for those with hemodynamic instability, AF associated ischemia, or acute heart failure.³ Whether to perform elective cardioversion depends on AF duration, symptoms, and the initial evaluation for structural heart disease or reversible causes of AF. Evaluation for new-onset AF includes eliciting a history of AF-associated comorbidities (hypertension, alcohol use, obstructive sleep apnea) and an echocardiogram and thyroid, renal, and liver function tests.³ Stable patients with AF precipitated by high-catecholamine states (eg, postoperative AF, sepsis, hyperthyroidism, pulmonary embolism, substance use) require management of the underlying condition before considering rhythm control. Inpatient electrical or pharmacologic cardioversion may be considered for patients with stable, new-onset AF sufficiently symptomatic to require hospitalization. Pre-procedure anticoagulation and a transesophageal echocardiogram to rule out left atrial thrombus before cardioversion is preferred for a first episode of AF suspected of lasting longer than 48 hours but requires anesthesia and considerable resources. In resource-constrained settings, patients asymptomatic once rate controlled may be safely discharged with a referral for outpatient cardioversion.

For patients with structural heart disease (left atrial dilation), previously failed cardioversion, or recurrent AF, initiating AADs (eg, ibutilide, amiodarone) before electrical cardioversion can improve the success rate of cardioversion.³ Ibutilide infusion requires cardiology consultation and postinfusion hemodynamic and QTc monitoring. Defer immediate cardioversion among stable patients unable to continue a minimum of 4 weeks of anticoagulation or with comorbidities for which risks of cardioversion outweigh benefits.

Successful maintenance of sinus rhythm is associated with reduced symptom burden and improved quality of life and is recommended for patients with persistent symptoms, failure of rate control, younger age, first episode of AF, or patient preference for rhythm control.³ Since AF progression results in irreversible cardiac remodeling, earlier rhythm control may prevent further atrial remodeling and atrial myopathy.

The EAST-AFNET 4 trial evaluated a rhythm-control strategy in patients with AF duration <12 months and who met two of the following: age > 65 years, female sex, heart failure, hypertension, diabetes, coronary artery disease, and chronic kidney disease.⁴ Maintenance of sinus rhythm was associated with a lower composite outcome of adverse cardiovascular outcomes and death from cardiovascular causes over 5 years compared to rate control (3.9/100 person-years vs 5.0/100 person-years, P = .005). Interestingly, roughly 20% of patients underwent CA and the remainder received AADs. The large proportion of patients treated with AADs raises the question of why the results differed from AFFIRM. There are four primary differences between these trials to consider. First, EAST-AFNET 4 used an early rhythm-control strategy (<12 months). Second, nearly all patients in EAST-AFNET 4 continued guideline-recommend anticoagulation compared to 70% receiving rhythm control in AFFIRM. Third, in AFFIRM, 62.8% of patients received amiodarone, which has significant long-term adverse effects compared to 11.8% by the end of EAST-AFNET 4. Finally, increased use of CA in EAST-AFNET 4 may have contributed to the success of rhythm control. In patients with cardiovascular disease or cardiovascular risk factors, a rhythm-control strategy will be best if implemented early (<12 months), before the development of long-standing persistent AF, and if clinicians adhere to anticoagulation recommendations.

Antiarrhythmic Drugs

Antiarrhythmic drug use prior to CA remains the cornerstone of a rhythm-control strategy for patients meeting EAST-AFNET 4 trial criteria or patient preference for medical management. Hospitalists’ knowledge of key differences between AADs used in EAST-AFNET 4 and AFFIRM as well as American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline recommendations help avoid harmful AAD prescribing. Notably, 21.9% of patients in AFFIRM received AADs no longer recommended to maintain sinus rhythm in the AHA/ACC/HRS guidelines (quinidine, disopyramide, procainamide, moricizine).³ For patients without structural heart disease, flecainide, propafenone, sotalol, or dronedarone are preferred. Dronedarone and sotalol remain an option for those with coronary artery disease. For patients with heart failure with reduced ejection fraction (HFrEF), amiodarone and dofetilide are preferred (Table).³

Catheter Ablation

The AHA/ACC/HRS guidelines offer a Ia recommendation for CA in patients with recurrent, symptomatic AF who failed AAD therapy. Initial CA is a IIa recommendation and is increasingly common for patients with paroxysmal AF who prefer this strategy to long-term AAD use.³ Recent trials evaluated CA as a primary treatment modality in patients with heart failure and as initial management before AADs.

Initial Catheter Ablation

The CABANA trial compared CA with AADs as an initial approach for maintaining sinus rhythm.⁵ In the intention-to-treat analysis, there was no difference in all death or disabling stroke between AAD therapy and CA at 5-year follow-up. The results are limited by a 27.5% crossover rate from drug therapy to CA. The per-protocol analysis based on the treatment received favored CA for the primary composite outcome of death, disabling stroke, serious bleeding, or cardiac arrest at 12 months. The STOP-AF and EARLY-AF trials found that initial CA was more successful in maintaining freedom from atrial arrhythmias (74.6% vs 45.0%, P < .001)⁶ and fewer symptomatic atrial arrhythmias among patients with paroxysmal AF compared to AADs, without significant CA-associated adverse events.^6,7

While hospitalists should interpret the per-protocol analysis cautiously when determining the clinical benefit, these trials indicate initial CA is as safe as AADs and improves freedom from AF. Duration of AF, knowledge of periprocedural anticoagulation recommendations, and CA procedural complications are important when recommending CA (Figure). Efficacy of CA is approximately 70% in paroxysmal AF and decreases for persistent and long-standing AF.⁶ Complications of CA include venous access site hematoma, cardiac tamponade, phrenic nerve injury, pulmonary vein stenosis, atrial-esophageal fistula, left atrial flutter, and stroke due to endothelial injury and intraprocedural thrombosis.³ Therapeutic anticoagulation is required before CA and for at least 2 months post ablation regardless of the CHA₂DS₂-VASc score.³

Catheter Ablation Plus Antiarrhythmics

Ongoing AADs following CA may suppress AF triggers, especially in patients with persistent AF or high-risk for recurrence post ablation (left atrial dilation). The AMIO-CAT trial found that 4 weeks of amiodarone after ablation reduced early AF recurrence at 3 months (34% vs 53%, P = .006), arrhythmia-related hospitalizations, and need for cardioversion in patients with paroxysmal and persistent AF.⁸ However, amiodarone did not reduce recurrent atrial tachyarrhythmias at 6 months. The POWDER-AF trial evaluated AAD use for 1 year after CA in patients with drug-refractory paroxysmal AF.⁹ Continuation of class IC (eg, flecainide) and III (eg, amiodarone) AADs resulted in a near 20% absolute risk reduction in recurrent atrial arrhythmias and reduced the need for repeat CA. These trials suggest that discharging patients on adjunctive AADs decreases early recurrence of AF and arrhythmia-related hospitalizations; however, studies evaluating additional clinical outcomes are needed.

Heart Failure

The AATAC trial found CA was superior to amiodarone therapy at maintaining freedom from AF and reducing unplanned hospitalizations and mortality among patients with persistent AF and HFrEF.¹⁰ The larger CASTLE-AF trial randomized patients with an ejection fraction below 35% and NYHA class II or greater symptoms with symptomatic paroxysmal AF or persistent AF in whom AAD therapy failed to CA or medical therapy.¹¹ The CA group experienced lower cardiovascular mortality (11.2% vs 22.3%, P = .009) and fewer heart failure hospitalizations (20.7% vs 35.9%, P = .004). The subsequent AMICA trial did not find a benefit of CA in patients with HFrEF and persistent or long-standing persistent AF; however, this trial was limited to 12 months, whereas the benefit of CA in CASTLE-AF was observed after 12 months.¹² Also, AMICA enrolled patients with higher NYHA class. Therefore, hospitalists should refer AF patients with left ventricular systolic dysfunction and NYHA II or III symptoms for CA. Comparing AMICA and CASTLE-AF suggests earlier referral for CA, prior to the development of worsening heart failure symptoms, may improve outcomes.

Data for patients with heart failure with preserved EF (HFpEF) is limited. One small trial showed reduced heart failure hospitalizations in HFpEF patients treated with CA compared to AADs or beta-blockers.¹³ It is reasonable to refer HFpEF patients with persisting symptoms or reduced quality of life for CA.

The AHA Scientific Statement on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation delineates risk factors that increase the incidence of AF, including alcohol consumption, obstructive sleep apnea, hypertension, and obesity.¹⁴ Among regular alcohol consumers with paroxysmal or persistent AF managed with a rhythm-control strategy, cessation of alcohol has been shown to significantly lower the incidence of recurrent AF (53.0% vs 73.0%, P = .005), and lead to a longer time until recurrence of AF compared to patients regularly consuming alcohol.¹⁵ Among patients with obstructive sleep apnea, a systematic review of nonrandomized studies showed continuous positive airway pressure is associated with maintenance of sinus rhythm.¹⁴ Control of these risk factors is associated with up to approximately 40% of patients maintaining sinus rhythm without intervention, and hospitalists should encourage lifestyle modification to maximize the probability of maintaining sinus rhythm. 

Hospitalists frequently determine the best initial management strategy for patients admitted with new-onset AF, and recent literature may shift more patients towards management with rhythm control. Based on the trials reviewed in this Progress Note, hospitalists should recommend a rhythm-control strategy for patients with symptomatic, paroxysmal, or persistent AF of <12 months’ duration and refer patients with HFrEF for CA. Adherence to guideline recommendations is essential when prescribing AADs to avoid adverse drug events. It is vital to ensure patients managed with a rhythm-control strategy receive anticoagulation for 4 weeks post cardioversion or 2 months post CA with long-term anticoagulation based on CHA₂DS₂-VASc score. Finally, admissions for AF should serve as a catalyst to communicate to patients the importance of addressing obstructive sleep apnea, obesity, and alcohol use disorders. Applying these evidence-based practices will enable hospitalists to make clinical decisions that improve symptom burden and survival for patients with AF.

Rosa* was one of my first patients as an intern rotating at the county hospital. Her marriage had disintegrated years earlier. To cope with depression, she hid a daily ritual of orange juice and vodka from her children. She worked as a cashier, until nausea and fatigue overwhelmed her.

The first time I met her she sat on the gurney: petite, tanned, and pregnant. Then I saw her yellow eyes and revised: temporal wasting, jaundiced, and swollen with ascites. Rosa didn’t know that alcohol could cause liver disease. Without insurance or access to primary care, her untreated alcohol use disorder (AUD) and depression had snowballed for years. 

Midway through my intern year, I’d taken care of many people with AUD. However, I’d barely learned anything about it as a medical student, though we’d spent weeks studying esoteric diseases, that now––9 years after medical school––I still have not encountered. 

Among the 28.3 million individuals in the United States with AUD, only 1% receive medication treatment.¹ In the United States, unhealthy alcohol use accounts for more than 95,000 deaths each year.² This number likely under-captures alcohol-related mortality and is higher now given recent reports of increasing alcohol-related deaths and prevalence of unhealthy alcohol use, especially among women, younger age groups, and marginalized populations.^3-5 

Rosa had alcohol-related hepatitis, which can cause severe inflammation and liver failure and quickly lead to death. As her liver failure progressed, I asked the gastroenterologists, “What other treatments can we offer? Is she a liver transplant candidate?” “Nothing” and “No” they answered.

Later, I emailed the hepatologist and transplant surgeon begging them to reevaluate her transplantation candidacy, but they told me there was no exception to the institution’s 6-month sobriety rule.

Maintaining a 6-month sobriety period is not an evidence-based criterion for transplantation. However, 50% of transplant centers do not perform transplantation prior to 6 months of alcohol abstinence for alcohol-related hepatitis due to concern for return to drinking after transplant.⁶ This practice may promote bias in patient selection for transplantation. A recent study found that individuals with alcohol-related liver disease transplanted before 6 months of abstinence had similar rates of survival and return to drinking compared to those who abstained from alcohol for 6 months and participated in AUD treatment before transplantation.⁷

There are other liver transplant practices that result in inequities for individuals with substance use disorders (SUD). Some liver transplant centers consider being on a medication for opioid use disorder a contraindication for transplantation—even if the individual is in recovery and abstaining from substances.⁸ Others mandate that individuals with alcohol-related liver disease attend Alcoholics Anonymous (AA) meetings prior to transplant. While mutual help groups, including AA, may benefit some individuals, different approaches work for different people.⁹ Other psychosocial interventions (eg, cognitive-behavioral therapy, contingency management, and residential treatment) and medications also help individuals reduce or stop drinking. Some meet their goals without any treatment. Addiction care works best when it respects autonomy and meets individuals where they are by allowing them to decide among options.

While organ allocations are a crystalized example of inequities in addiction care, they are also ethically complex. Many individuals—with and without SUD—die on waiting lists and must meet stringent transplantation criteria. However, we can at least remove the unnecessary biases that compound inequities in care people with SUD already face.

As Rosa’s liver succumbed, her kidneys failed too, and she required dialysis. She sensed what was coming. “I want everything…for now. I need to take care of my children.” I, too, wanted Rosa to live and see her youngest start kindergarten.

A few days before her discharge, I walked to the pharmacy and bought a purple journal. In a rare moment, I found Rosa alone in her room, without her ex-husband, sister, and mother, who rarely left her bedside. Together, we called AA and explored whether she could start participating in phone meetings from the hospital. I explained that one way to document a commitment to sobriety, as the transplant center’s rules dictated, was to attend and document AA meetings in this notebook. “In 5 months, you will be a liver transplant candidate,” I remember saying, wishing it to fruition.

I became Rosa’s primary care physician and saw her in clinic. Over the next few weeks, her skin took on an ashen tone. Sleep escaped her and her thoughts and speech blurred. Her walk slowed and she needed a wheelchair. The quiet fierceness that had defined her dissipated as encephalopathy took over. But until our last visit, she brought her purple journal, tracking the AA meetings she’d attended. Dialysis became intolerable, but not before Rosa made care arrangements for her girls. When that happened, she stopped dialysis and went to Mexico, where she died in her sleep after saying good-bye to her father. 

Earlier access to healthcare and effective depression and AUD treatment could have saved Rosa’s life. While it was too late for her, as hospitalists we care for many others with substance-related complications and may miss opportunities to discuss and offer evidence-based addiction treatment. For example, we initiate the most up-to-date management for a patient’s gastrointestinal bleed but may leave the alcohol discussion for someone else. It is similar for other SUD: we treat cellulitis, epidural abscesses, bacteremia, chronic obstructive pulmonary disease, heart failure exacerbations, and other complications of SUD without addressing the root cause of the hospitalization—other than to prescribe abstinence from substance use or, at our worst, scold individuals for continuing to use.

But what can we offer? Most healthcare professionals still do not receive addiction education during training. Without tools, we enact temporizing measures, until patients return to the hospital or die.

In addition to increasing alcohol-related morbidity, there have also been increases in drug-related overdoses, fueled by COVID-19, synthetic opioids like fentanyl, and stimulants.¹⁰ In the 12-month period ending April 2021, more than 100,000 individuals died of drug-related overdoses, the highest number of deaths ever recorded in a year.¹¹ Despite this, most healthcare systems remain unequipped to provide addiction services during hospitalization due to inadequate training, stigma, and lack of systems-based care.

Hospitalists and healthcare systems cannot be bystanders amid our worsening addiction crisis. We must empower clinicians with addiction education and ensure health systems offer evidence-based SUD services.

Educational efforts can close the knowledge gaps for both medical students and hospitalists. Medical schools should include foundational curricular content in screening, assessing, diagnosing, and treating SUD in alignment with standards set by the Liaison Committee on Medical Education, which accredits US medical schools. Residency programs can offer educational conferences, cased-based discussions, and addiction medicine rotations. Hospitalists can participate in educational didactics and review evidence-based addiction guidelines.^12,13 While the focus here is on hospitalists, clinicians across practice settings and specialties will encounter patients with SUD, and all need to be well-versed in the diagnosis and treatment of addiction given the all-hands-on deck approach necessary amidst our worsening addiction crisis.

With one in nine hospitalizations involving individuals with SUD, and this number quickly rising, and with an annual cost to US hospitals of $13.2 billion, healthcare system leaders must invest in addiction care.^14,15 Hospital-based addiction services could pay for themselves and save healthcare systems money while improving the patient and clinician experience.¹⁶One way to implement hospital-based addiction care is through an addiction consult team (ACT).¹⁷ While ACT compositions vary, most are interprofessional, offer evidence-based addiction treatment, and connect patients to community care.¹⁸ Our hospital’s ACT has nurses, patient navigators, and physicians who assess, diagnose, and treat SUD, and arrange follow-up addiction care.¹⁹ In addition to caring for individual patients, our ACT has led systems change. For example, we created order sets to guide clinicians, added medications to our hospital formulary to ensure access to evidence-based addiction treatment, and partnered with community stakeholders to streamline care transitions and access to psychosocial and medication treatment. Our team also worked with hospital leadership, nursing, and a syringe service program to integrate hospital harm reduction education and supply provision. Additionally, we are building capacity among staff, trainees, and clinicians through education and systems changes.

In hospitals without an ACT, leadership can finance SUD champions and integrate them into policy-level decision-making to implement best practices in addiction care and lead hospital-wide educational efforts. This will transform hospital culture and improve care as all clinicians develop essential addiction skills.

Addiction champions and ACTs could also advocate for equitable practices for patients with SUD to reduce the stigma that both prevents patients from seeking care and results in self-discharges.²⁰ For example, with interprofessional support, we revised our in-hospital substance use policy. It previously entailed hospital security responding to substance use concerns, which unintentionally harmed patients and perpetuated stigma. Our revised policy ensures we offer medications for cravings and withdrawal, adequate pain management, and other services that address patients’ reasons for in-hospital substance use.

With the increasing prevalence of SUD among hospitalized patients, escalating substance-related deaths, rising healthcare costs, and the impact of addiction on health and well-being, addiction care, including ACTs and champions, must be adequately funded. However, sustainable financing remains a challenge.¹⁸

Caring for Rosa and others with SUD sparked my desire to learn about addiction, obtain addiction medicine board certification as a practicing hospitalist, and create an ACT that offers evidence-based addiction treatment. While much remains to be done, by collaborating with addiction champions and engaging hospital leadership, we have transformed our hospital’s approach to substance use care.

With the knowledge and resources I now have as an addiction medicine physician, I reimagine the possibilities for patients like Rosa.

Rosa died when living was possible.

*Name has been changed for patient privacy.

Rosa* was one of my first patients as an intern rotating at the county hospital. Her marriage had disintegrated years earlier. To cope with depression, she hid a daily ritual of orange juice and vodka from her children. She worked as a cashier, until nausea and fatigue overwhelmed her.

The first time I met her she sat on the gurney: petite, tanned, and pregnant. Then I saw her yellow eyes and revised: temporal wasting, jaundiced, and swollen with ascites. Rosa didn’t know that alcohol could cause liver disease. Without insurance or access to primary care, her untreated alcohol use disorder (AUD) and depression had snowballed for years. 

Midway through my intern year, I’d taken care of many people with AUD. However, I’d barely learned anything about it as a medical student, though we’d spent weeks studying esoteric diseases, that now––9 years after medical school––I still have not encountered. 

Among the 28.3 million individuals in the United States with AUD, only 1% receive medication treatment.¹ In the United States, unhealthy alcohol use accounts for more than 95,000 deaths each year.² This number likely under-captures alcohol-related mortality and is higher now given recent reports of increasing alcohol-related deaths and prevalence of unhealthy alcohol use, especially among women, younger age groups, and marginalized populations.^3-5 

Rosa had alcohol-related hepatitis, which can cause severe inflammation and liver failure and quickly lead to death. As her liver failure progressed, I asked the gastroenterologists, “What other treatments can we offer? Is she a liver transplant candidate?” “Nothing” and “No” they answered.

Later, I emailed the hepatologist and transplant surgeon begging them to reevaluate her transplantation candidacy, but they told me there was no exception to the institution’s 6-month sobriety rule.

Maintaining a 6-month sobriety period is not an evidence-based criterion for transplantation. However, 50% of transplant centers do not perform transplantation prior to 6 months of alcohol abstinence for alcohol-related hepatitis due to concern for return to drinking after transplant.⁶ This practice may promote bias in patient selection for transplantation. A recent study found that individuals with alcohol-related liver disease transplanted before 6 months of abstinence had similar rates of survival and return to drinking compared to those who abstained from alcohol for 6 months and participated in AUD treatment before transplantation.⁷

There are other liver transplant practices that result in inequities for individuals with substance use disorders (SUD). Some liver transplant centers consider being on a medication for opioid use disorder a contraindication for transplantation—even if the individual is in recovery and abstaining from substances.⁸ Others mandate that individuals with alcohol-related liver disease attend Alcoholics Anonymous (AA) meetings prior to transplant. While mutual help groups, including AA, may benefit some individuals, different approaches work for different people.⁹ Other psychosocial interventions (eg, cognitive-behavioral therapy, contingency management, and residential treatment) and medications also help individuals reduce or stop drinking. Some meet their goals without any treatment. Addiction care works best when it respects autonomy and meets individuals where they are by allowing them to decide among options.

While organ allocations are a crystalized example of inequities in addiction care, they are also ethically complex. Many individuals—with and without SUD—die on waiting lists and must meet stringent transplantation criteria. However, we can at least remove the unnecessary biases that compound inequities in care people with SUD already face.

As Rosa’s liver succumbed, her kidneys failed too, and she required dialysis. She sensed what was coming. “I want everything…for now. I need to take care of my children.” I, too, wanted Rosa to live and see her youngest start kindergarten.

A few days before her discharge, I walked to the pharmacy and bought a purple journal. In a rare moment, I found Rosa alone in her room, without her ex-husband, sister, and mother, who rarely left her bedside. Together, we called AA and explored whether she could start participating in phone meetings from the hospital. I explained that one way to document a commitment to sobriety, as the transplant center’s rules dictated, was to attend and document AA meetings in this notebook. “In 5 months, you will be a liver transplant candidate,” I remember saying, wishing it to fruition.

I became Rosa’s primary care physician and saw her in clinic. Over the next few weeks, her skin took on an ashen tone. Sleep escaped her and her thoughts and speech blurred. Her walk slowed and she needed a wheelchair. The quiet fierceness that had defined her dissipated as encephalopathy took over. But until our last visit, she brought her purple journal, tracking the AA meetings she’d attended. Dialysis became intolerable, but not before Rosa made care arrangements for her girls. When that happened, she stopped dialysis and went to Mexico, where she died in her sleep after saying good-bye to her father. 

Earlier access to healthcare and effective depression and AUD treatment could have saved Rosa’s life. While it was too late for her, as hospitalists we care for many others with substance-related complications and may miss opportunities to discuss and offer evidence-based addiction treatment. For example, we initiate the most up-to-date management for a patient’s gastrointestinal bleed but may leave the alcohol discussion for someone else. It is similar for other SUD: we treat cellulitis, epidural abscesses, bacteremia, chronic obstructive pulmonary disease, heart failure exacerbations, and other complications of SUD without addressing the root cause of the hospitalization—other than to prescribe abstinence from substance use or, at our worst, scold individuals for continuing to use.

But what can we offer? Most healthcare professionals still do not receive addiction education during training. Without tools, we enact temporizing measures, until patients return to the hospital or die.

In addition to increasing alcohol-related morbidity, there have also been increases in drug-related overdoses, fueled by COVID-19, synthetic opioids like fentanyl, and stimulants.¹⁰ In the 12-month period ending April 2021, more than 100,000 individuals died of drug-related overdoses, the highest number of deaths ever recorded in a year.¹¹ Despite this, most healthcare systems remain unequipped to provide addiction services during hospitalization due to inadequate training, stigma, and lack of systems-based care.

Hospitalists and healthcare systems cannot be bystanders amid our worsening addiction crisis. We must empower clinicians with addiction education and ensure health systems offer evidence-based SUD services.

Educational efforts can close the knowledge gaps for both medical students and hospitalists. Medical schools should include foundational curricular content in screening, assessing, diagnosing, and treating SUD in alignment with standards set by the Liaison Committee on Medical Education, which accredits US medical schools. Residency programs can offer educational conferences, cased-based discussions, and addiction medicine rotations. Hospitalists can participate in educational didactics and review evidence-based addiction guidelines.^12,13 While the focus here is on hospitalists, clinicians across practice settings and specialties will encounter patients with SUD, and all need to be well-versed in the diagnosis and treatment of addiction given the all-hands-on deck approach necessary amidst our worsening addiction crisis.

With one in nine hospitalizations involving individuals with SUD, and this number quickly rising, and with an annual cost to US hospitals of $13.2 billion, healthcare system leaders must invest in addiction care.^14,15 Hospital-based addiction services could pay for themselves and save healthcare systems money while improving the patient and clinician experience.¹⁶One way to implement hospital-based addiction care is through an addiction consult team (ACT).¹⁷ While ACT compositions vary, most are interprofessional, offer evidence-based addiction treatment, and connect patients to community care.¹⁸ Our hospital’s ACT has nurses, patient navigators, and physicians who assess, diagnose, and treat SUD, and arrange follow-up addiction care.¹⁹ In addition to caring for individual patients, our ACT has led systems change. For example, we created order sets to guide clinicians, added medications to our hospital formulary to ensure access to evidence-based addiction treatment, and partnered with community stakeholders to streamline care transitions and access to psychosocial and medication treatment. Our team also worked with hospital leadership, nursing, and a syringe service program to integrate hospital harm reduction education and supply provision. Additionally, we are building capacity among staff, trainees, and clinicians through education and systems changes.

In hospitals without an ACT, leadership can finance SUD champions and integrate them into policy-level decision-making to implement best practices in addiction care and lead hospital-wide educational efforts. This will transform hospital culture and improve care as all clinicians develop essential addiction skills.

Addiction champions and ACTs could also advocate for equitable practices for patients with SUD to reduce the stigma that both prevents patients from seeking care and results in self-discharges.²⁰ For example, with interprofessional support, we revised our in-hospital substance use policy. It previously entailed hospital security responding to substance use concerns, which unintentionally harmed patients and perpetuated stigma. Our revised policy ensures we offer medications for cravings and withdrawal, adequate pain management, and other services that address patients’ reasons for in-hospital substance use.

With the increasing prevalence of SUD among hospitalized patients, escalating substance-related deaths, rising healthcare costs, and the impact of addiction on health and well-being, addiction care, including ACTs and champions, must be adequately funded. However, sustainable financing remains a challenge.¹⁸

Caring for Rosa and others with SUD sparked my desire to learn about addiction, obtain addiction medicine board certification as a practicing hospitalist, and create an ACT that offers evidence-based addiction treatment. While much remains to be done, by collaborating with addiction champions and engaging hospital leadership, we have transformed our hospital’s approach to substance use care.

With the knowledge and resources I now have as an addiction medicine physician, I reimagine the possibilities for patients like Rosa.

Rosa died when living was possible.

*Name has been changed for patient privacy.

Rosa* was one of my first patients as an intern rotating at the county hospital. Her marriage had disintegrated years earlier. To cope with depression, she hid a daily ritual of orange juice and vodka from her children. She worked as a cashier, until nausea and fatigue overwhelmed her.

The first time I met her she sat on the gurney: petite, tanned, and pregnant. Then I saw her yellow eyes and revised: temporal wasting, jaundiced, and swollen with ascites. Rosa didn’t know that alcohol could cause liver disease. Without insurance or access to primary care, her untreated alcohol use disorder (AUD) and depression had snowballed for years. 

Midway through my intern year, I’d taken care of many people with AUD. However, I’d barely learned anything about it as a medical student, though we’d spent weeks studying esoteric diseases, that now––9 years after medical school––I still have not encountered. 

Among the 28.3 million individuals in the United States with AUD, only 1% receive medication treatment.¹ In the United States, unhealthy alcohol use accounts for more than 95,000 deaths each year.² This number likely under-captures alcohol-related mortality and is higher now given recent reports of increasing alcohol-related deaths and prevalence of unhealthy alcohol use, especially among women, younger age groups, and marginalized populations.^3-5 

Rosa had alcohol-related hepatitis, which can cause severe inflammation and liver failure and quickly lead to death. As her liver failure progressed, I asked the gastroenterologists, “What other treatments can we offer? Is she a liver transplant candidate?” “Nothing” and “No” they answered.

Later, I emailed the hepatologist and transplant surgeon begging them to reevaluate her transplantation candidacy, but they told me there was no exception to the institution’s 6-month sobriety rule.

Maintaining a 6-month sobriety period is not an evidence-based criterion for transplantation. However, 50% of transplant centers do not perform transplantation prior to 6 months of alcohol abstinence for alcohol-related hepatitis due to concern for return to drinking after transplant.⁶ This practice may promote bias in patient selection for transplantation. A recent study found that individuals with alcohol-related liver disease transplanted before 6 months of abstinence had similar rates of survival and return to drinking compared to those who abstained from alcohol for 6 months and participated in AUD treatment before transplantation.⁷

There are other liver transplant practices that result in inequities for individuals with substance use disorders (SUD). Some liver transplant centers consider being on a medication for opioid use disorder a contraindication for transplantation—even if the individual is in recovery and abstaining from substances.⁸ Others mandate that individuals with alcohol-related liver disease attend Alcoholics Anonymous (AA) meetings prior to transplant. While mutual help groups, including AA, may benefit some individuals, different approaches work for different people.⁹ Other psychosocial interventions (eg, cognitive-behavioral therapy, contingency management, and residential treatment) and medications also help individuals reduce or stop drinking. Some meet their goals without any treatment. Addiction care works best when it respects autonomy and meets individuals where they are by allowing them to decide among options.

While organ allocations are a crystalized example of inequities in addiction care, they are also ethically complex. Many individuals—with and without SUD—die on waiting lists and must meet stringent transplantation criteria. However, we can at least remove the unnecessary biases that compound inequities in care people with SUD already face.

As Rosa’s liver succumbed, her kidneys failed too, and she required dialysis. She sensed what was coming. “I want everything…for now. I need to take care of my children.” I, too, wanted Rosa to live and see her youngest start kindergarten.

A few days before her discharge, I walked to the pharmacy and bought a purple journal. In a rare moment, I found Rosa alone in her room, without her ex-husband, sister, and mother, who rarely left her bedside. Together, we called AA and explored whether she could start participating in phone meetings from the hospital. I explained that one way to document a commitment to sobriety, as the transplant center’s rules dictated, was to attend and document AA meetings in this notebook. “In 5 months, you will be a liver transplant candidate,” I remember saying, wishing it to fruition.

I became Rosa’s primary care physician and saw her in clinic. Over the next few weeks, her skin took on an ashen tone. Sleep escaped her and her thoughts and speech blurred. Her walk slowed and she needed a wheelchair. The quiet fierceness that had defined her dissipated as encephalopathy took over. But until our last visit, she brought her purple journal, tracking the AA meetings she’d attended. Dialysis became intolerable, but not before Rosa made care arrangements for her girls. When that happened, she stopped dialysis and went to Mexico, where she died in her sleep after saying good-bye to her father. 

Earlier access to healthcare and effective depression and AUD treatment could have saved Rosa’s life. While it was too late for her, as hospitalists we care for many others with substance-related complications and may miss opportunities to discuss and offer evidence-based addiction treatment. For example, we initiate the most up-to-date management for a patient’s gastrointestinal bleed but may leave the alcohol discussion for someone else. It is similar for other SUD: we treat cellulitis, epidural abscesses, bacteremia, chronic obstructive pulmonary disease, heart failure exacerbations, and other complications of SUD without addressing the root cause of the hospitalization—other than to prescribe abstinence from substance use or, at our worst, scold individuals for continuing to use.

But what can we offer? Most healthcare professionals still do not receive addiction education during training. Without tools, we enact temporizing measures, until patients return to the hospital or die.

In addition to increasing alcohol-related morbidity, there have also been increases in drug-related overdoses, fueled by COVID-19, synthetic opioids like fentanyl, and stimulants.¹⁰ In the 12-month period ending April 2021, more than 100,000 individuals died of drug-related overdoses, the highest number of deaths ever recorded in a year.¹¹ Despite this, most healthcare systems remain unequipped to provide addiction services during hospitalization due to inadequate training, stigma, and lack of systems-based care.

Hospitalists and healthcare systems cannot be bystanders amid our worsening addiction crisis. We must empower clinicians with addiction education and ensure health systems offer evidence-based SUD services.

Educational efforts can close the knowledge gaps for both medical students and hospitalists. Medical schools should include foundational curricular content in screening, assessing, diagnosing, and treating SUD in alignment with standards set by the Liaison Committee on Medical Education, which accredits US medical schools. Residency programs can offer educational conferences, cased-based discussions, and addiction medicine rotations. Hospitalists can participate in educational didactics and review evidence-based addiction guidelines.^12,13 While the focus here is on hospitalists, clinicians across practice settings and specialties will encounter patients with SUD, and all need to be well-versed in the diagnosis and treatment of addiction given the all-hands-on deck approach necessary amidst our worsening addiction crisis.

With one in nine hospitalizations involving individuals with SUD, and this number quickly rising, and with an annual cost to US hospitals of $13.2 billion, healthcare system leaders must invest in addiction care.^14,15 Hospital-based addiction services could pay for themselves and save healthcare systems money while improving the patient and clinician experience.¹⁶One way to implement hospital-based addiction care is through an addiction consult team (ACT).¹⁷ While ACT compositions vary, most are interprofessional, offer evidence-based addiction treatment, and connect patients to community care.¹⁸ Our hospital’s ACT has nurses, patient navigators, and physicians who assess, diagnose, and treat SUD, and arrange follow-up addiction care.¹⁹ In addition to caring for individual patients, our ACT has led systems change. For example, we created order sets to guide clinicians, added medications to our hospital formulary to ensure access to evidence-based addiction treatment, and partnered with community stakeholders to streamline care transitions and access to psychosocial and medication treatment. Our team also worked with hospital leadership, nursing, and a syringe service program to integrate hospital harm reduction education and supply provision. Additionally, we are building capacity among staff, trainees, and clinicians through education and systems changes.

In hospitals without an ACT, leadership can finance SUD champions and integrate them into policy-level decision-making to implement best practices in addiction care and lead hospital-wide educational efforts. This will transform hospital culture and improve care as all clinicians develop essential addiction skills.

Addiction champions and ACTs could also advocate for equitable practices for patients with SUD to reduce the stigma that both prevents patients from seeking care and results in self-discharges.²⁰ For example, with interprofessional support, we revised our in-hospital substance use policy. It previously entailed hospital security responding to substance use concerns, which unintentionally harmed patients and perpetuated stigma. Our revised policy ensures we offer medications for cravings and withdrawal, adequate pain management, and other services that address patients’ reasons for in-hospital substance use.

With the increasing prevalence of SUD among hospitalized patients, escalating substance-related deaths, rising healthcare costs, and the impact of addiction on health and well-being, addiction care, including ACTs and champions, must be adequately funded. However, sustainable financing remains a challenge.¹⁸

Caring for Rosa and others with SUD sparked my desire to learn about addiction, obtain addiction medicine board certification as a practicing hospitalist, and create an ACT that offers evidence-based addiction treatment. While much remains to be done, by collaborating with addiction champions and engaging hospital leadership, we have transformed our hospital’s approach to substance use care.

With the knowledge and resources I now have as an addiction medicine physician, I reimagine the possibilities for patients like Rosa.

Rosa died when living was possible.

*Name has been changed for patient privacy.