Expert Interview

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.

Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.

Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview. His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.

Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.

Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.

Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
 

How did all this begin?

Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.

How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?

We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.

We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
 

Are you able to capture every Alzheimer’s drug in development globally?

If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.

Who are the report’s main readers?

Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.

It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
 

What about patients and families? Are they able to use the report as well?

One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.

Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?

My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.

What other approaches are interesting to you?

We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.

Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?

That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.

What about other therapy classes?

We aim to be more serious about devices.

What will you call the database?

The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.

The annual pipeline report is very much associated with you. Is the database going to be different?

Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.

Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.

We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.

Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

What is the value of considering noninvasive methods for the diagnosis of endometriosis?

Dr. Flores: There is great value in noninvasive diagnostics for endometriosis. This is because while surgical diagnosis is the “gold standard,” surgery is invasive, and waiting until a surgical diagnosis can be made further contributes to delays in diagnosis. However, more recently there has been a shift toward utilizing noninvasive approaches to the diagnosis of endometriosis, with the primary one focusing on clinically diagnosing endometriosis. 

One of the first things to remember is the importance of gathering a patient history and conducting a physical exam. We've all learned this in medical school, and it comes into play even more so with a condition such as endometriosis. Endometriosis is defined as a benign gynecologic disease characterized by endometrial-like tissue outside of the uterus, but this definition does not reflect the true scope and manifestations of endometriosis. Research over the years has demonstrated that endometriosis has systemic effects—affecting regions of the brain associated with anxiety/depression, altering pain sensitization, and having inflammatory effects that can not only affect the reproductive organs but also other organ systems. As such, our questions when evaluating patients for endometriosis need to focus on these various aspects of the disease. 

Endometriosis usually leads to cyclic pain. This is because just as the lining of the uterus (the endometrium) grows and sheds every month in response to hormones, endometriotic lesions—which are endometrial-like tissue outside of the uterus—also grow and shed each month. However, there is no outflow for this shed tissue and, as a result, there is an inflammatory response as well as pain. Depending on where those lesions implant, symptoms can include not only cyclic pelvic pain but also cyclic bowel/bladder pain. I’ve also had patients complain of cyclic sharp/shooting leg pain. 

Many times, patients present to us after having seen several different types of providers and having been diagnosed with conditions such as irritable bowel syndrome or painful bladder syndrome. However, if you talk to patients and ask them to tell you a little bit more about this bowel or bladder pain, they will frequently endorse that their symptoms are cyclic/most severe during their menses. With respect to pelvic pain, endometriosis-related pelvic pain is usually progressive—becoming progressively more painful over the years. These symptoms are strong indicators that endometriosis is the cause. A pelvic exam is also helpful as findings of nodularity or a fixed uterus may lend further support for endometriosis; a normal exam, however, does not rule out endometriosis. 

What are the primary imaging techniques used to diagnose endometriosis?

Dr. Flores: While history and physical exam are the primary components of the clinical diagnosis, imaging can also be helpful. The 2 techniques most often used are pelvic ultrasound and magnetic resonance imaging (MRI). 

While transvaginal ultrasound is sensitive and specific for diagnosing endometriomas (ovarian cysts of endometriotic tissue) and may also be able to accurately identify deep-infiltrating endometriosis, it is limited in its ability to visualize peritoneal disease. MRI can improve diagnosis of endometriosis and better estimate the depth of invasion of deep-infiltrating disease, as well as confirm diagnosis of an endometrioma. While MRI is an option for peritoneal endometriosis, superficial disease is usually not detected. Lastly, computed tomography imaging of the chest can be used when thoracic endometriosis is suspected but is otherwise not routinely recommended. Imaging is also helpful in ruling in/out other potential etiologies of pelvic pain such as fibroids and adenomyosis. It is important to recognize, however, that the absence of any findings of endometriosis on imaging does not rule out the disease. 

What other best practices do you implement in your day-to-day to aid in diagnosis?

Dr. Flores: Take the time to listen to your patient. Often, they’ve seen several providers before ultimately seeing a provider who can diagnosis their endometriosis without the need for surgical evaluation. We have to ask questions related to their pain and when the pain occurs, and we can’t forget to also ask about pain during intercourse, as well as non-menstrual pelvic pain. Additionally, it is important to recognize that, for patients who may have been suffering from endometriosis for several years before reaching a diagnosis, they may present with chronic pelvic pain. In this case, it is important to ask what their menstrual cycles were like before the pelvic pain became chronic, and usually patients note cyclic pelvic pain that became progressive. We also know that patients who have a first-degree relative with endometriosis are 7 times more likely to be affected by the disease, so asking about a family history of endometriosis is important. 

We have to think about endometriosis as a systemic disease. Previously, endometriosis was incorrectly thought of as solely a pelvic disease, but we've been learning more and more through research that it truly is a chronic, systemic disease with multifactorial effects throughout the body. For example, we have found that endometriosis affects regions of the brain associated with anxiety and depression, as well as causing changes in metabolism. For example, a common misconception is that women with a low body mass index (BMI) were at risk for endometriosis, when in fact it's just the opposite—it is the endometriosis that is causing changes in metabolism that lead to a decreased BMI. Patients with endometriosis also frequently struggle with mood disorders; therefore, we cannot dismiss this aspect of the disease process. It is imperative that we help patients feel heard and let them know that some of the mood symptoms they are experiencing may be related to their endometriosis. Expanding our view of endometriosis as a disease that extends beyond the pelvis and thinking about the systemic effects of endometriosis is key.

We have also identified small molecules (microRNAs) that are predictive of endometriosis. They are continuing to be investigated as a noninvasive biomarker of endometriosis.  

Can you talk a little more about these biomarkers?

Dr. Flores: In terms of biomarkers, this is actually some exciting work I was fortunate to be involved in with Dr. Hugh Taylor at Yale. We studied circulating molecules known as microRNAs—these are small, noncoding RNAs that can modify gene expression. In endometriosis, we've identified several that, when combined, have a high sensitivity and specificity for diagnosing endometriosis. These specific microRNAs are undergoing continued studies to ensure that they are reliable in predicting endometriosis. Hopefully they will be available soon for clinical use, as this would be of great value to help shorten the time to diagnosis of endometriosis and ultimately avoid delays in endometriosis treatment.

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

What is the significance of the recent TRIANGLE study on mantle cell lymphoma (MCL)?

Dr. LaCasce: The TRIANGLE study is extremely important in previously untreated, transplant-eligible patients with MCL. The cutoff age for transplants varies by center and is between 60 and 75 years. In the absence of a TP53 mutation, we have typically used induction chemotherapy followed by autologous stem-cell transplant (ASCT), followed by 3 years of maintenance rituximab. Obviously, this is a lot of therapy.

The TRIANGLE study was a 3-arm study in which ibrutinib-containing therapy was compared with standard RCHOP/RDHAP followed by ASCT. Maintenance rituximab became standard of care midway through the trial and was added. In the first experimental arm, ibrutinib was combined with RCHOP and then given as maintenance for 2 years following ASCT. The second experimental arm included the same schedule of ibrutinib and omitted the ASCT.

The results are early, but what has been presented thus far, ibrutinib induction and maintenance with ASCT is clearly superior to the standard arm with ASCT. Although the data are not statistically mature, the failure-free survival of the 2 ibrutinib arms was similar, suggesting that transplant may not be necessary. Longer follow-up is necessary to confirm this conclusion and assess overall survival in all 3 arms.

If the results hold, ASCT could become a thing of the past or perhaps used in the second line. With the favorable activity of chimeric antigen receptor (CAR) T-cell therapy, however, it is unclear whether ASCT would be used in second line. Avoiding the sequential use of ASCT and CAR T-cell therapy is appealing given the stem-cell damage that can result. It is appealing to think about not using ASCT upfront, because ASCT increases the risk of myelodysplastic syndrome.

The TRIANGLE data are likely to change the frontline management of MCL. Although ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved in MCL and has obviously changed the field dramatically, it is significantly less well-tolerated than the next generation of drugs—acalabrutinib and zanubrutinib. I suspect these will be substituted for ibrutinib and we will see even more tolerable upfront regimens for patients with newly diagnosed MCL.

Have there been any disparities that you found in patients newly diagnosed with MCL regarding age, sex, or ethnicity?

Dr. LaCasce: MCL typically affects patients in their 60s. It is rare in young patients, and approximately 75% of the cases are male. If you look at the demographics, it is more common in White patients and less common in Hispanic and African American patients. In addition, there is an association with farming, which likely contribute to the demographics of patients with MCL.

What is your recommended approach to managing patients newly diagnosed with MCL in your day-to-day practice?

Dr. LaCasce: Management is a bit tricky right now because the TRIANGLE study is not part of any guidelines thus far. Therefore, most would argue the standard treatment continues to include ASCT upfront. There is an important, large randomized  study (NCT03267433) going on in the United States that is assessing the role of ASCT in patients who are in MRD-negative complete remission at the end of induction therapy. These patients are randomized to ASCT plus maintenance rituximab versus maintenance rituximab alone.

We are still enrolling patients to participate in this study, which is addressing a different question than TRIANGLE. I think we will learn a lot from this study. For patients who are not interested in participating in this study, we talk about the risks and benefits of ASCT.

One or 2 years ago, I would have strongly encouraged patients who were appropriate candidates to consider transplant in first remission. With the TRIANGLE data, however, and now that we have CAR T-cell therapy, I think it is more important to tailor the recommendation to the individual patient. If a patient is reluctant about ASCT and the associated risks, I do not push it.

If patients want the most aggressive approach associated with the longest remissions, at this moment, before TRIANGLE findings have been adopted into guidelines, I continue to recommend ASCT. For patients who have TP53 mutation, however, we treat with typically less aggressive therapy, as this patient population does not benefit from ASCT. We look forward to more data incorporating BTK inhibitors upfront, particularly for this group of patients, who tend to have a more adverse prognosis.

Do you feel MCL data and clinical trials are important areas of focus for your colleagues?

Dr. LaCasce: Yes. I think it is a rapidly evolving field, which is really exciting. We are seeing data now from the bispecific antibodies in the relapsed/refractory setting. We also need more data using pirtobrutinib for patients who have had BTK inhibitors and compare pirtobrutinib (a non-covalent BTK inhibitor) with the covalent BTK inhibitors.

I would strongly encourage patients to participate in clinical trials so that we can better answer these important questions. When patients go online and read about MCL, they often see a median survival of 3 to 4 years, which is completely outdated. The overall prognosis of MCL has changed dramatically since I have been in the field. Hopefully, survival will continue to improve, and therapies will become more tolerable, as well.

What is the link between endometriosis and abnormal uterine bleeding?

Dr. Lager: This is an important question because when people first learn about endometriosis, common symptoms include pain with periods, pelvic pain, but not necessarily abnormal uterine bleeding. However, many patients do complain of abnormal uterine bleeding when presenting with endometriosis.

There are a couple of reasons why abnormal uterine bleeding is important to consider. Within the spectrum of endometriosis, vaginal endometriosis can contribute to abnormal vaginal bleeding, most commonly cyclic or postcoital. The bleeding could be rectal due to deeply infiltrative endometriosis, although gastrointestinal etiologies should be included in the differential. Another link is coexisting diagnoses such as fibroids, adenomyosis, and endometrial polyps. In fact, the rates for coexisting conditions with endometriosis can be high and vary from study to study.

As an example, some studies show rates between 7% and 11%, where adenomyosis coexists with endometriosis. Other studies look at magnetic resonance imaging for adenomyosis and deep infiltrative endometriosis and find that women younger than 36 years have rates as high as 90% for coexisting diagnoses, and 79% for all women, regardless of the diagnosis.

The overlap is high. When I think particularly about adenomyosis and endometriosis, in some ways, the conditions are along a spectrum where adenomyosis involves ectopic endometrial glands in the myometrium, whereas endometriosis involves ectopic tissue outside of the uterus, predominantly in reproductive organs, but can be anywhere outside of the endometrium. So, when I think about abnormal uterine bleeding particularly associated with dysmenorrhea or pelvic pain, this can often be included in the constellation of symptoms for endometriosis.

Furthermore, it is important to rule out other causes of abnormal uterine bleeding because they would potentially change the treatment.

What are the current treatment options for endometriosis and abnormal uterine bleeding?

Dr. Lager: Treatments for endometriosis are inclusive of any overlapping conditions and we use a multidisciplinary approach to address symptoms. Medical treatments include hormonal management, including birth control pills, etonogestrel implants (Nexplanon), levonorgestrel-releasing intrauterine devices, progestin-only pills, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and combination medications. Some medications do overlap and work for both, such as combined GnRH antagonists, estradiol, and progesterone.

Surgical management includes diagnostic laparoscopy with excision of endometriosis. If there is another coexisting diagnosis that is structural in nature, such as endometrial polyps, adenomyosis, or fibroids, surgical management may include hysteroscopy, myomectomy, or hysterectomy as indicated. When we consider surgical and nonsurgical approaches, it is important to be clear on the etiology of abnormal uterine bleeding to appropriately counsel patients for what the surgery could entail.

Have you found there to be any age or racial disparities in endometriosis treatment?

Dr. Lager: One of the things that is important about endometriosis, and in medicine in general, is to really think about how we approach race as a social construct. In the past, medicine has included race as a risk factor for certain medical conditions. And physicians in training were taught to use these risk factors to determine a differential diagnosis. However, this strategy has limited us in understanding how historical and structural racism affected patient diagnosis and treatment.

If we think back to literature that was published in the 1950s or the 1970s, Dr. Meeks was one of the physicians who described a set of characteristics of patients with endometriosis. He commented that typical patients were women who were goal-oriented, had private insurance, and experienced delayed marriage, among other traits.

The problem with this characterization was that patients would then present with symptoms of endometriosis who did not fit the original phenotype as historically described and they would be misdiagnosed and thus treated incorrectly. This incorrect treatment further reinforced incorrect stereotypes of patient presentations. These misdiagnoses could lead to unfortunate consequences in their activities of daily living as well as reproductive outcomes. We do not have data on how many patients may have been misdiagnosed and treated for pelvic inflammatory disease because they were not White, did not have private insurance, or had children early. This is an example of areas where we need to recognize systemic racism and classism and work hard to simply do better for our patients.

Although misdiagnosing based on stereotypes has decreased over time, I still think that original thinking can certainly affect patient referrals. When we look at the data of patients who are diagnosed with endometriosis, we find a higher rate of White patients (17%) compared to Black (10.1%), Asian (11.3%), and Hispanic patients (7.4%). Ensuring that all of our patients are getting appropriate referrals and diagnosis should be a priority.

When we think about the timing to initial diagnosis, globally, we know that there is a delay in diagnosis anywhere from 7 to 12 years, and then on top of that, those social constructs decrease the rate of diagnosis for certain patient populations. Misdiagnosis based on social constructs is unacceptable and one aspect that I think is very important to point out.

In a more recent study of 12,000 patients in 2022, the rate of surgical complications associated with endometriosis surgery was higher in women who were Black, Asian and Pacific Islander, and Native American/American Indian than in women who were White. These groups have a much higher rate of complications and higher rates of laparotomy—an open procedure—versus laparoscopy. In younger women, there is a higher rate of oophorectomy at the time of surgery for endometriosis than in older women.

Are there any best practices you would like to share with your peers?

Dr. Lager: For patients with abnormal uterine bleeding, it is important to consider other diagnoses and not assume that abnormal bleeding is solely related to endometriosis, while considering deeply infiltrative endometriosis in the differential.

When patients do present with cyclical bleeding, especially, for example, after hysterectomy, it is important to examine for either vaginal or vaginal cuff endometriosis because there can be other reasons that patients will have abnormal uterine bleeding related to atypical endometriosis.

It is important to know the patient’s history and focus on each patient’s level of pain, how it affects their day-to-day activities, and how they are experiencing that pain.

We all should be working to improve our understanding of social history and systemic racism as best as we can and make sure all patients are getting the right care that they deserve.

What is the link between endometriosis and abnormal uterine bleeding?

Dr. Lager: This is an important question because when people first learn about endometriosis, common symptoms include pain with periods, pelvic pain, but not necessarily abnormal uterine bleeding. However, many patients do complain of abnormal uterine bleeding when presenting with endometriosis.

There are a couple of reasons why abnormal uterine bleeding is important to consider. Within the spectrum of endometriosis, vaginal endometriosis can contribute to abnormal vaginal bleeding, most commonly cyclic or postcoital. The bleeding could be rectal due to deeply infiltrative endometriosis, although gastrointestinal etiologies should be included in the differential. Another link is coexisting diagnoses such as fibroids, adenomyosis, and endometrial polyps. In fact, the rates for coexisting conditions with endometriosis can be high and vary from study to study.

As an example, some studies show rates between 7% and 11%, where adenomyosis coexists with endometriosis. Other studies look at magnetic resonance imaging for adenomyosis and deep infiltrative endometriosis and find that women younger than 36 years have rates as high as 90% for coexisting diagnoses, and 79% for all women, regardless of the diagnosis.

The overlap is high. When I think particularly about adenomyosis and endometriosis, in some ways, the conditions are along a spectrum where adenomyosis involves ectopic endometrial glands in the myometrium, whereas endometriosis involves ectopic tissue outside of the uterus, predominantly in reproductive organs, but can be anywhere outside of the endometrium. So, when I think about abnormal uterine bleeding particularly associated with dysmenorrhea or pelvic pain, this can often be included in the constellation of symptoms for endometriosis.

Furthermore, it is important to rule out other causes of abnormal uterine bleeding because they would potentially change the treatment.

What are the current treatment options for endometriosis and abnormal uterine bleeding?

Dr. Lager: Treatments for endometriosis are inclusive of any overlapping conditions and we use a multidisciplinary approach to address symptoms. Medical treatments include hormonal management, including birth control pills, etonogestrel implants (Nexplanon), levonorgestrel-releasing intrauterine devices, progestin-only pills, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and combination medications. Some medications do overlap and work for both, such as combined GnRH antagonists, estradiol, and progesterone.

Surgical management includes diagnostic laparoscopy with excision of endometriosis. If there is another coexisting diagnosis that is structural in nature, such as endometrial polyps, adenomyosis, or fibroids, surgical management may include hysteroscopy, myomectomy, or hysterectomy as indicated. When we consider surgical and nonsurgical approaches, it is important to be clear on the etiology of abnormal uterine bleeding to appropriately counsel patients for what the surgery could entail.

Have you found there to be any age or racial disparities in endometriosis treatment?

Dr. Lager: One of the things that is important about endometriosis, and in medicine in general, is to really think about how we approach race as a social construct. In the past, medicine has included race as a risk factor for certain medical conditions. And physicians in training were taught to use these risk factors to determine a differential diagnosis. However, this strategy has limited us in understanding how historical and structural racism affected patient diagnosis and treatment.

If we think back to literature that was published in the 1950s or the 1970s, Dr. Meeks was one of the physicians who described a set of characteristics of patients with endometriosis. He commented that typical patients were women who were goal-oriented, had private insurance, and experienced delayed marriage, among other traits.

The problem with this characterization was that patients would then present with symptoms of endometriosis who did not fit the original phenotype as historically described and they would be misdiagnosed and thus treated incorrectly. This incorrect treatment further reinforced incorrect stereotypes of patient presentations. These misdiagnoses could lead to unfortunate consequences in their activities of daily living as well as reproductive outcomes. We do not have data on how many patients may have been misdiagnosed and treated for pelvic inflammatory disease because they were not White, did not have private insurance, or had children early. This is an example of areas where we need to recognize systemic racism and classism and work hard to simply do better for our patients.

Although misdiagnosing based on stereotypes has decreased over time, I still think that original thinking can certainly affect patient referrals. When we look at the data of patients who are diagnosed with endometriosis, we find a higher rate of White patients (17%) compared to Black (10.1%), Asian (11.3%), and Hispanic patients (7.4%). Ensuring that all of our patients are getting appropriate referrals and diagnosis should be a priority.

When we think about the timing to initial diagnosis, globally, we know that there is a delay in diagnosis anywhere from 7 to 12 years, and then on top of that, those social constructs decrease the rate of diagnosis for certain patient populations. Misdiagnosis based on social constructs is unacceptable and one aspect that I think is very important to point out.

In a more recent study of 12,000 patients in 2022, the rate of surgical complications associated with endometriosis surgery was higher in women who were Black, Asian and Pacific Islander, and Native American/American Indian than in women who were White. These groups have a much higher rate of complications and higher rates of laparotomy—an open procedure—versus laparoscopy. In younger women, there is a higher rate of oophorectomy at the time of surgery for endometriosis than in older women.

Are there any best practices you would like to share with your peers?

Dr. Lager: For patients with abnormal uterine bleeding, it is important to consider other diagnoses and not assume that abnormal bleeding is solely related to endometriosis, while considering deeply infiltrative endometriosis in the differential.

When patients do present with cyclical bleeding, especially, for example, after hysterectomy, it is important to examine for either vaginal or vaginal cuff endometriosis because there can be other reasons that patients will have abnormal uterine bleeding related to atypical endometriosis.

It is important to know the patient’s history and focus on each patient’s level of pain, how it affects their day-to-day activities, and how they are experiencing that pain.

We all should be working to improve our understanding of social history and systemic racism as best as we can and make sure all patients are getting the right care that they deserve.

What is the link between endometriosis and abnormal uterine bleeding?

Dr. Lager: This is an important question because when people first learn about endometriosis, common symptoms include pain with periods, pelvic pain, but not necessarily abnormal uterine bleeding. However, many patients do complain of abnormal uterine bleeding when presenting with endometriosis.

There are a couple of reasons why abnormal uterine bleeding is important to consider. Within the spectrum of endometriosis, vaginal endometriosis can contribute to abnormal vaginal bleeding, most commonly cyclic or postcoital. The bleeding could be rectal due to deeply infiltrative endometriosis, although gastrointestinal etiologies should be included in the differential. Another link is coexisting diagnoses such as fibroids, adenomyosis, and endometrial polyps. In fact, the rates for coexisting conditions with endometriosis can be high and vary from study to study.

As an example, some studies show rates between 7% and 11%, where adenomyosis coexists with endometriosis. Other studies look at magnetic resonance imaging for adenomyosis and deep infiltrative endometriosis and find that women younger than 36 years have rates as high as 90% for coexisting diagnoses, and 79% for all women, regardless of the diagnosis.

The overlap is high. When I think particularly about adenomyosis and endometriosis, in some ways, the conditions are along a spectrum where adenomyosis involves ectopic endometrial glands in the myometrium, whereas endometriosis involves ectopic tissue outside of the uterus, predominantly in reproductive organs, but can be anywhere outside of the endometrium. So, when I think about abnormal uterine bleeding particularly associated with dysmenorrhea or pelvic pain, this can often be included in the constellation of symptoms for endometriosis.

Furthermore, it is important to rule out other causes of abnormal uterine bleeding because they would potentially change the treatment.

What are the current treatment options for endometriosis and abnormal uterine bleeding?

Dr. Lager: Treatments for endometriosis are inclusive of any overlapping conditions and we use a multidisciplinary approach to address symptoms. Medical treatments include hormonal management, including birth control pills, etonogestrel implants (Nexplanon), levonorgestrel-releasing intrauterine devices, progestin-only pills, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and combination medications. Some medications do overlap and work for both, such as combined GnRH antagonists, estradiol, and progesterone.

Surgical management includes diagnostic laparoscopy with excision of endometriosis. If there is another coexisting diagnosis that is structural in nature, such as endometrial polyps, adenomyosis, or fibroids, surgical management may include hysteroscopy, myomectomy, or hysterectomy as indicated. When we consider surgical and nonsurgical approaches, it is important to be clear on the etiology of abnormal uterine bleeding to appropriately counsel patients for what the surgery could entail.

Have you found there to be any age or racial disparities in endometriosis treatment?

Dr. Lager: One of the things that is important about endometriosis, and in medicine in general, is to really think about how we approach race as a social construct. In the past, medicine has included race as a risk factor for certain medical conditions. And physicians in training were taught to use these risk factors to determine a differential diagnosis. However, this strategy has limited us in understanding how historical and structural racism affected patient diagnosis and treatment.

If we think back to literature that was published in the 1950s or the 1970s, Dr. Meeks was one of the physicians who described a set of characteristics of patients with endometriosis. He commented that typical patients were women who were goal-oriented, had private insurance, and experienced delayed marriage, among other traits.

The problem with this characterization was that patients would then present with symptoms of endometriosis who did not fit the original phenotype as historically described and they would be misdiagnosed and thus treated incorrectly. This incorrect treatment further reinforced incorrect stereotypes of patient presentations. These misdiagnoses could lead to unfortunate consequences in their activities of daily living as well as reproductive outcomes. We do not have data on how many patients may have been misdiagnosed and treated for pelvic inflammatory disease because they were not White, did not have private insurance, or had children early. This is an example of areas where we need to recognize systemic racism and classism and work hard to simply do better for our patients.

Although misdiagnosing based on stereotypes has decreased over time, I still think that original thinking can certainly affect patient referrals. When we look at the data of patients who are diagnosed with endometriosis, we find a higher rate of White patients (17%) compared to Black (10.1%), Asian (11.3%), and Hispanic patients (7.4%). Ensuring that all of our patients are getting appropriate referrals and diagnosis should be a priority.

When we think about the timing to initial diagnosis, globally, we know that there is a delay in diagnosis anywhere from 7 to 12 years, and then on top of that, those social constructs decrease the rate of diagnosis for certain patient populations. Misdiagnosis based on social constructs is unacceptable and one aspect that I think is very important to point out.

In a more recent study of 12,000 patients in 2022, the rate of surgical complications associated with endometriosis surgery was higher in women who were Black, Asian and Pacific Islander, and Native American/American Indian than in women who were White. These groups have a much higher rate of complications and higher rates of laparotomy—an open procedure—versus laparoscopy. In younger women, there is a higher rate of oophorectomy at the time of surgery for endometriosis than in older women.

Are there any best practices you would like to share with your peers?

Dr. Lager: For patients with abnormal uterine bleeding, it is important to consider other diagnoses and not assume that abnormal bleeding is solely related to endometriosis, while considering deeply infiltrative endometriosis in the differential.

When patients do present with cyclical bleeding, especially, for example, after hysterectomy, it is important to examine for either vaginal or vaginal cuff endometriosis because there can be other reasons that patients will have abnormal uterine bleeding related to atypical endometriosis.

It is important to know the patient’s history and focus on each patient’s level of pain, how it affects their day-to-day activities, and how they are experiencing that pain.

We all should be working to improve our understanding of social history and systemic racism as best as we can and make sure all patients are getting the right care that they deserve.

What is your outlook on the role of upfront autologous stem cell transplant (ASCT) for patients with mantle cell lymphoma (MCL)?

Dr. Barrientos: Most of the data that we have for upfront ASCT for young patients in frontline therapy come from the era when we did not use rituximab, and the data have not kept up with the pace of all the recent advances. Rituximab has changed the way we approach maintenance therapy after induction therapy. No randomized controlled trial data (in regimens that incorporate rituximab and cytarabine) have demonstrated a benefit in overall survival (OS) with ASCT in the modern era.

There is a lot to consider for every patient with MCL before we start therapy or discuss upfront transplant. MCL is one of these non-Hodgkin lymphomas that unfortunately can be aggressive in some patients depending on their prognostic markers and particular clinical features of the disease. Some patients have a more indolent form, whereas others have a more aggressive presentation at the time of diagnosis. The disease is heterogeneous and will respond differently to certain regimens. For example, patients with MCL who have a high proliferation rate, blastoid morphology, multiple chromosomal aberrations, complex karyotype, and/or the presence of tumor suppressor protein P53 (TP53) mutation will likely have a more aggressive course. Fitness for transplant is also an important consideration regardless of age; that is, a patient with comorbid end-stage chronic kidney or liver disease will not be able to tolerate a transplant.

Even with optimal therapy that incorporates rituximab and cytarabine, pursuing a transplant does not necessarily benefit survival in patients with a known TP53 mutation, as these patients typically experience increased toxicity without improved OS. We know they will not respond well, and we should discuss the available data so that the patients can make a sound decision and consider participation in a clinical trial that incorporates novel agents. Another type of mutation—cyclin-dependent kinase inhibitor 2A (CDKN2A)—also has lower OS. Concurrent deletion of CDKN2A and TP53 aberration (deletion and/or mutation) are known to be associated with lower OS given their chemoresistant nature. Patients with these genetic mutations should not be offered standard ASCT, but rather they should be identified early on and prioritized to participate in clinical trials.

Importantly, the role of upfront ASCT is changing right now, based on a recent trial that was presented at the latest American Society of Hematology meeting in 2022. The TRIANGLE trial demonstrated the addition of ibrutinib (a first-generation Bruton tyrosine kinase [BTK] inhibitor) to standard chemoimmunotherapy induction and 2 years of ibrutinib maintenance can improve outcomes vs standard chemoimmunotherapy induction and ASCT alone for younger patients with MCL. However, longer follow-up is needed to fully elucidate the role of ASCT in the era of BTK inhibitors when incorporated early on into the treatment paradigm.

The TRIANGLE trial was an international, randomized 3-arm phase 3 trial (EudraCT-no. 2014-001363-12) for young (up to 65 years) fit patients with histologically confirmed, untreated, advanced stage II-IV MCL. In the control arm A, patients received an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (ASCT). In arm A+I, ibrutinib was added to the R-CHOP cycles (560 mg day 1-19) and was applied as maintenance (continuous dosing) for 2 years. In arm I, the same induction and maintenance was applied but high-dose consolidation and ASCT was skipped. A rituximab maintenance (single doses every 2 months for up to 3 years) was allowed to be added in all study arms according to national clinical routine.

The study showed that failure-free survival at 3 years was 72% with chemotherapy alone, 86% with ibrutinib alone, and 88% with ibrutinib plus ASCT. However, the ibrutinib plus ASCT group seemed to have much more toxicity, comorbidities, and other complications from the transplant. The OS data are not mature yet, but looking at the available data, ibrutinib alone might be more beneficial to our patients— not only in terms of efficacy, but also in tolerability and response, with less toxicity over time.

To put things in perspective, we did not have good salvage therapies a decade ago. At the time ASCT was incorporated, it was a good option that allowed numerous patients to achieve a deep response with durable remission duration. Before ibrutinib was approved, the overall response rate for the best salvage therapies was not as encouraging as the initial therapy and, with each relapse, the duration of response shortened. When ibrutinib came along, the overall response rate improved significantly. But again, these patients had relapsed/refractory disease. Researchers have been investigating what would happen if we used such a drug in earlier lines of therapy. Can we get better outcomes? Can we get patients in remission longer, similar to what we have seen with ASCT, but without the ASCT?

There has never been a single modern trial that has demonstrated that transplant improves survival. Transplantation can improve progression-free survival, but not OS. For a disease for which we do not have a cure, if we can keep patients in remission with a good salvage therapy and give them a better quality of life, without subjecting them to an ASCT, then I might choose that. New targeted agents and novel therapies are in clinical development all the time, so the future is bright for patients with this diagnosis. Given the novel salvage therapies in the pipeline, we may be able to no longer recommend ASCT upfront for most patients soon.

Can you share more about the potential benefits of using salvage therapies over ASCT, and particularly any promising newer agents in the salvage therapy setting?

Dr. Barrientos: Recently we had the FDA approval of pirtobrutinib—a noncovalently bound BTK inhibitor—for patients with relapsed/refractory MCL in whom at least 2 lines of systemic therapy had failed, including another BTK inhibitor. In the trial that led to the accelerated approval, pirtobrutinib-treated patients showed an overall response rate of 50% in those who received the drug at 200 mg daily (n = 120); most of the responses were partial responses. The efficacy of other novel drugs are being studied in patients with MCL. For example, ROR1 (receptor tyrosine kinase–like orphan receptor 1) inhibitors and BTK degraders are currently in clinical trials. Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been approved for the treatment of adult patients with relapsed or refractory MCL, and this may be an option for some patients.

Multiple novel agents might be able to salvage our patients without subjecting them to an upfront transplant. My hope is to get away from using the intense chemotherapy regimens that might cause myelosuppression, infection risk, or other toxicities, and try to stay with the novel agents. We need to do better for our patients.

Based on the data we now have, until there is a trial that demonstrates a higher OS rate with ASCT, it is hard for me to tell a patient to blindly pursue ASCT without learning more about all the available options. If you have access to a good salvage therapy, especially with all these new promising agents, a patient might be able to stay in remission without having ASCT, which can still have an increased risk of morbidity.

Are there certain patient groups that should never be considered for ASCT?

Dr. Barrientos: Younger patients with the CDKN2A gene—which represents about 22% of patients—and those who have a TP53 mutation should not be considered for a standard transplant because they have a worse outcome independent of the treatment. I would also include complex karyotype patients because of the same nature of the chromosomal aberrations. The more genetic aberrations that a patient has, the more likelihood that any chemotherapy will damage the DNA further and create a more aggressive clone. Instead, I would recommend that young patients in this category participate in a clinical trial with novel agents.

With novel therapies in the pipeline, the availability of CAR T, and now the bispecific antibodies such as blinatumomab and HexAbs coming along, the number of patients who may opt out of ASCT may increase. I have a long discussion with my patients. The more educated they are, the better it is for the patient. At the end of the day, the most important thing for me, with any therapy, is: how does the patient feel? Because if we cannot cure a patient or provide a survival advantage, I do not want to give that patient something that will decrease their quality of life. I would rather keep the patient in some sort of stable disease remission, comfortable, and having a good quality of life. That is my goal for anyone who cannot be cured. Now if it is a curable disease, like a diffuse large cell lymphoma or a Burkitt’s lymphoma, then it is a different story. But for people with MCL, a disease that you cannot cure, or chronic lymphocytic leukemia or follicular lymphoma, then it becomes a different discussion. Undetectable minimal residual disease correlates with longer remission durations, but sometimes trying to achieve that, you can actually do a lot of harm to some patients.

Are there any other conversations you have with your patients in day-to-day practice?

Dr. Barrientos: I always tell my patients to be on top of the age-appropriate cancer screening recommendations. For example, they should see a dermatologist once a year. Men should make sure that their prostate is checked. I recommend women get breast mammograms, Pap smears, and most importantly to avoid smoking—and that includes vaping. It is important to lead a healthy life to minimize the risk of secondary malignancies.

For risk of infections, I recommend to all my patients to be up to date on their vaccinations, such as pneumonia if they are older than 65, Shingrix for prevention of reactivation of varicella or chickenpox, and the flu shot once a year. I also recommend the COVID-19 vaccine even now, as our patients with blood disorders might have a harder time fighting COVID-19 infection. I always tell my patients to please reach out to us because we can discuss the use of antivirals such as Paxlovid (nirmatrelvir/ritonavir), and if they are sick, then they can get remdesivir in the hospital.

I want to touch on health literacy and disparities for a moment. I have some younger patients who are Latin or Black with uncontrolled hypertension or diabetes, even at a young age, and do not realize that I can treat their cancer into remission, but if their blood glucose is in the 500 range, they could die from their diabetes. So talking with patients about their overall health is important. Survivorship issues are important, especially if patients are diagnosed at a young age. We have known for a long time that chemotherapy can create cardiac events, arrhythmias, and heart disease. Therefore, I always tell patients with metabolic syndrome to try to exercise and eat healthy. Patients should get an electrocardiogram and see an internist at least once a year to make sure their cholesterol is well controlled. I think now we are being more cognizant that many complications can happen even 10 years after cancer treatment.

What is your outlook on the role of upfront autologous stem cell transplant (ASCT) for patients with mantle cell lymphoma (MCL)?

Dr. Barrientos: Most of the data that we have for upfront ASCT for young patients in frontline therapy come from the era when we did not use rituximab, and the data have not kept up with the pace of all the recent advances. Rituximab has changed the way we approach maintenance therapy after induction therapy. No randomized controlled trial data (in regimens that incorporate rituximab and cytarabine) have demonstrated a benefit in overall survival (OS) with ASCT in the modern era.

There is a lot to consider for every patient with MCL before we start therapy or discuss upfront transplant. MCL is one of these non-Hodgkin lymphomas that unfortunately can be aggressive in some patients depending on their prognostic markers and particular clinical features of the disease. Some patients have a more indolent form, whereas others have a more aggressive presentation at the time of diagnosis. The disease is heterogeneous and will respond differently to certain regimens. For example, patients with MCL who have a high proliferation rate, blastoid morphology, multiple chromosomal aberrations, complex karyotype, and/or the presence of tumor suppressor protein P53 (TP53) mutation will likely have a more aggressive course. Fitness for transplant is also an important consideration regardless of age; that is, a patient with comorbid end-stage chronic kidney or liver disease will not be able to tolerate a transplant.

Even with optimal therapy that incorporates rituximab and cytarabine, pursuing a transplant does not necessarily benefit survival in patients with a known TP53 mutation, as these patients typically experience increased toxicity without improved OS. We know they will not respond well, and we should discuss the available data so that the patients can make a sound decision and consider participation in a clinical trial that incorporates novel agents. Another type of mutation—cyclin-dependent kinase inhibitor 2A (CDKN2A)—also has lower OS. Concurrent deletion of CDKN2A and TP53 aberration (deletion and/or mutation) are known to be associated with lower OS given their chemoresistant nature. Patients with these genetic mutations should not be offered standard ASCT, but rather they should be identified early on and prioritized to participate in clinical trials.

Importantly, the role of upfront ASCT is changing right now, based on a recent trial that was presented at the latest American Society of Hematology meeting in 2022. The TRIANGLE trial demonstrated the addition of ibrutinib (a first-generation Bruton tyrosine kinase [BTK] inhibitor) to standard chemoimmunotherapy induction and 2 years of ibrutinib maintenance can improve outcomes vs standard chemoimmunotherapy induction and ASCT alone for younger patients with MCL. However, longer follow-up is needed to fully elucidate the role of ASCT in the era of BTK inhibitors when incorporated early on into the treatment paradigm.

The TRIANGLE trial was an international, randomized 3-arm phase 3 trial (EudraCT-no. 2014-001363-12) for young (up to 65 years) fit patients with histologically confirmed, untreated, advanced stage II-IV MCL. In the control arm A, patients received an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (ASCT). In arm A+I, ibrutinib was added to the R-CHOP cycles (560 mg day 1-19) and was applied as maintenance (continuous dosing) for 2 years. In arm I, the same induction and maintenance was applied but high-dose consolidation and ASCT was skipped. A rituximab maintenance (single doses every 2 months for up to 3 years) was allowed to be added in all study arms according to national clinical routine.

The study showed that failure-free survival at 3 years was 72% with chemotherapy alone, 86% with ibrutinib alone, and 88% with ibrutinib plus ASCT. However, the ibrutinib plus ASCT group seemed to have much more toxicity, comorbidities, and other complications from the transplant. The OS data are not mature yet, but looking at the available data, ibrutinib alone might be more beneficial to our patients— not only in terms of efficacy, but also in tolerability and response, with less toxicity over time.

To put things in perspective, we did not have good salvage therapies a decade ago. At the time ASCT was incorporated, it was a good option that allowed numerous patients to achieve a deep response with durable remission duration. Before ibrutinib was approved, the overall response rate for the best salvage therapies was not as encouraging as the initial therapy and, with each relapse, the duration of response shortened. When ibrutinib came along, the overall response rate improved significantly. But again, these patients had relapsed/refractory disease. Researchers have been investigating what would happen if we used such a drug in earlier lines of therapy. Can we get better outcomes? Can we get patients in remission longer, similar to what we have seen with ASCT, but without the ASCT?

There has never been a single modern trial that has demonstrated that transplant improves survival. Transplantation can improve progression-free survival, but not OS. For a disease for which we do not have a cure, if we can keep patients in remission with a good salvage therapy and give them a better quality of life, without subjecting them to an ASCT, then I might choose that. New targeted agents and novel therapies are in clinical development all the time, so the future is bright for patients with this diagnosis. Given the novel salvage therapies in the pipeline, we may be able to no longer recommend ASCT upfront for most patients soon.

Can you share more about the potential benefits of using salvage therapies over ASCT, and particularly any promising newer agents in the salvage therapy setting?

Dr. Barrientos: Recently we had the FDA approval of pirtobrutinib—a noncovalently bound BTK inhibitor—for patients with relapsed/refractory MCL in whom at least 2 lines of systemic therapy had failed, including another BTK inhibitor. In the trial that led to the accelerated approval, pirtobrutinib-treated patients showed an overall response rate of 50% in those who received the drug at 200 mg daily (n = 120); most of the responses were partial responses. The efficacy of other novel drugs are being studied in patients with MCL. For example, ROR1 (receptor tyrosine kinase–like orphan receptor 1) inhibitors and BTK degraders are currently in clinical trials. Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been approved for the treatment of adult patients with relapsed or refractory MCL, and this may be an option for some patients.

Multiple novel agents might be able to salvage our patients without subjecting them to an upfront transplant. My hope is to get away from using the intense chemotherapy regimens that might cause myelosuppression, infection risk, or other toxicities, and try to stay with the novel agents. We need to do better for our patients.

Based on the data we now have, until there is a trial that demonstrates a higher OS rate with ASCT, it is hard for me to tell a patient to blindly pursue ASCT without learning more about all the available options. If you have access to a good salvage therapy, especially with all these new promising agents, a patient might be able to stay in remission without having ASCT, which can still have an increased risk of morbidity.

Are there certain patient groups that should never be considered for ASCT?

Dr. Barrientos: Younger patients with the CDKN2A gene—which represents about 22% of patients—and those who have a TP53 mutation should not be considered for a standard transplant because they have a worse outcome independent of the treatment. I would also include complex karyotype patients because of the same nature of the chromosomal aberrations. The more genetic aberrations that a patient has, the more likelihood that any chemotherapy will damage the DNA further and create a more aggressive clone. Instead, I would recommend that young patients in this category participate in a clinical trial with novel agents.

With novel therapies in the pipeline, the availability of CAR T, and now the bispecific antibodies such as blinatumomab and HexAbs coming along, the number of patients who may opt out of ASCT may increase. I have a long discussion with my patients. The more educated they are, the better it is for the patient. At the end of the day, the most important thing for me, with any therapy, is: how does the patient feel? Because if we cannot cure a patient or provide a survival advantage, I do not want to give that patient something that will decrease their quality of life. I would rather keep the patient in some sort of stable disease remission, comfortable, and having a good quality of life. That is my goal for anyone who cannot be cured. Now if it is a curable disease, like a diffuse large cell lymphoma or a Burkitt’s lymphoma, then it is a different story. But for people with MCL, a disease that you cannot cure, or chronic lymphocytic leukemia or follicular lymphoma, then it becomes a different discussion. Undetectable minimal residual disease correlates with longer remission durations, but sometimes trying to achieve that, you can actually do a lot of harm to some patients.

Are there any other conversations you have with your patients in day-to-day practice?

Dr. Barrientos: I always tell my patients to be on top of the age-appropriate cancer screening recommendations. For example, they should see a dermatologist once a year. Men should make sure that their prostate is checked. I recommend women get breast mammograms, Pap smears, and most importantly to avoid smoking—and that includes vaping. It is important to lead a healthy life to minimize the risk of secondary malignancies.

For risk of infections, I recommend to all my patients to be up to date on their vaccinations, such as pneumonia if they are older than 65, Shingrix for prevention of reactivation of varicella or chickenpox, and the flu shot once a year. I also recommend the COVID-19 vaccine even now, as our patients with blood disorders might have a harder time fighting COVID-19 infection. I always tell my patients to please reach out to us because we can discuss the use of antivirals such as Paxlovid (nirmatrelvir/ritonavir), and if they are sick, then they can get remdesivir in the hospital.

I want to touch on health literacy and disparities for a moment. I have some younger patients who are Latin or Black with uncontrolled hypertension or diabetes, even at a young age, and do not realize that I can treat their cancer into remission, but if their blood glucose is in the 500 range, they could die from their diabetes. So talking with patients about their overall health is important. Survivorship issues are important, especially if patients are diagnosed at a young age. We have known for a long time that chemotherapy can create cardiac events, arrhythmias, and heart disease. Therefore, I always tell patients with metabolic syndrome to try to exercise and eat healthy. Patients should get an electrocardiogram and see an internist at least once a year to make sure their cholesterol is well controlled. I think now we are being more cognizant that many complications can happen even 10 years after cancer treatment.

What is your outlook on the role of upfront autologous stem cell transplant (ASCT) for patients with mantle cell lymphoma (MCL)?

Dr. Barrientos: Most of the data that we have for upfront ASCT for young patients in frontline therapy come from the era when we did not use rituximab, and the data have not kept up with the pace of all the recent advances. Rituximab has changed the way we approach maintenance therapy after induction therapy. No randomized controlled trial data (in regimens that incorporate rituximab and cytarabine) have demonstrated a benefit in overall survival (OS) with ASCT in the modern era.

There is a lot to consider for every patient with MCL before we start therapy or discuss upfront transplant. MCL is one of these non-Hodgkin lymphomas that unfortunately can be aggressive in some patients depending on their prognostic markers and particular clinical features of the disease. Some patients have a more indolent form, whereas others have a more aggressive presentation at the time of diagnosis. The disease is heterogeneous and will respond differently to certain regimens. For example, patients with MCL who have a high proliferation rate, blastoid morphology, multiple chromosomal aberrations, complex karyotype, and/or the presence of tumor suppressor protein P53 (TP53) mutation will likely have a more aggressive course. Fitness for transplant is also an important consideration regardless of age; that is, a patient with comorbid end-stage chronic kidney or liver disease will not be able to tolerate a transplant.

Even with optimal therapy that incorporates rituximab and cytarabine, pursuing a transplant does not necessarily benefit survival in patients with a known TP53 mutation, as these patients typically experience increased toxicity without improved OS. We know they will not respond well, and we should discuss the available data so that the patients can make a sound decision and consider participation in a clinical trial that incorporates novel agents. Another type of mutation—cyclin-dependent kinase inhibitor 2A (CDKN2A)—also has lower OS. Concurrent deletion of CDKN2A and TP53 aberration (deletion and/or mutation) are known to be associated with lower OS given their chemoresistant nature. Patients with these genetic mutations should not be offered standard ASCT, but rather they should be identified early on and prioritized to participate in clinical trials.

Importantly, the role of upfront ASCT is changing right now, based on a recent trial that was presented at the latest American Society of Hematology meeting in 2022. The TRIANGLE trial demonstrated the addition of ibrutinib (a first-generation Bruton tyrosine kinase [BTK] inhibitor) to standard chemoimmunotherapy induction and 2 years of ibrutinib maintenance can improve outcomes vs standard chemoimmunotherapy induction and ASCT alone for younger patients with MCL. However, longer follow-up is needed to fully elucidate the role of ASCT in the era of BTK inhibitors when incorporated early on into the treatment paradigm.

The TRIANGLE trial was an international, randomized 3-arm phase 3 trial (EudraCT-no. 2014-001363-12) for young (up to 65 years) fit patients with histologically confirmed, untreated, advanced stage II-IV MCL. In the control arm A, patients received an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (ASCT). In arm A+I, ibrutinib was added to the R-CHOP cycles (560 mg day 1-19) and was applied as maintenance (continuous dosing) for 2 years. In arm I, the same induction and maintenance was applied but high-dose consolidation and ASCT was skipped. A rituximab maintenance (single doses every 2 months for up to 3 years) was allowed to be added in all study arms according to national clinical routine.

The study showed that failure-free survival at 3 years was 72% with chemotherapy alone, 86% with ibrutinib alone, and 88% with ibrutinib plus ASCT. However, the ibrutinib plus ASCT group seemed to have much more toxicity, comorbidities, and other complications from the transplant. The OS data are not mature yet, but looking at the available data, ibrutinib alone might be more beneficial to our patients— not only in terms of efficacy, but also in tolerability and response, with less toxicity over time.

To put things in perspective, we did not have good salvage therapies a decade ago. At the time ASCT was incorporated, it was a good option that allowed numerous patients to achieve a deep response with durable remission duration. Before ibrutinib was approved, the overall response rate for the best salvage therapies was not as encouraging as the initial therapy and, with each relapse, the duration of response shortened. When ibrutinib came along, the overall response rate improved significantly. But again, these patients had relapsed/refractory disease. Researchers have been investigating what would happen if we used such a drug in earlier lines of therapy. Can we get better outcomes? Can we get patients in remission longer, similar to what we have seen with ASCT, but without the ASCT?

There has never been a single modern trial that has demonstrated that transplant improves survival. Transplantation can improve progression-free survival, but not OS. For a disease for which we do not have a cure, if we can keep patients in remission with a good salvage therapy and give them a better quality of life, without subjecting them to an ASCT, then I might choose that. New targeted agents and novel therapies are in clinical development all the time, so the future is bright for patients with this diagnosis. Given the novel salvage therapies in the pipeline, we may be able to no longer recommend ASCT upfront for most patients soon.

Can you share more about the potential benefits of using salvage therapies over ASCT, and particularly any promising newer agents in the salvage therapy setting?

Dr. Barrientos: Recently we had the FDA approval of pirtobrutinib—a noncovalently bound BTK inhibitor—for patients with relapsed/refractory MCL in whom at least 2 lines of systemic therapy had failed, including another BTK inhibitor. In the trial that led to the accelerated approval, pirtobrutinib-treated patients showed an overall response rate of 50% in those who received the drug at 200 mg daily (n = 120); most of the responses were partial responses. The efficacy of other novel drugs are being studied in patients with MCL. For example, ROR1 (receptor tyrosine kinase–like orphan receptor 1) inhibitors and BTK degraders are currently in clinical trials. Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been approved for the treatment of adult patients with relapsed or refractory MCL, and this may be an option for some patients.

Multiple novel agents might be able to salvage our patients without subjecting them to an upfront transplant. My hope is to get away from using the intense chemotherapy regimens that might cause myelosuppression, infection risk, or other toxicities, and try to stay with the novel agents. We need to do better for our patients.

Based on the data we now have, until there is a trial that demonstrates a higher OS rate with ASCT, it is hard for me to tell a patient to blindly pursue ASCT without learning more about all the available options. If you have access to a good salvage therapy, especially with all these new promising agents, a patient might be able to stay in remission without having ASCT, which can still have an increased risk of morbidity.

Are there certain patient groups that should never be considered for ASCT?

Dr. Barrientos: Younger patients with the CDKN2A gene—which represents about 22% of patients—and those who have a TP53 mutation should not be considered for a standard transplant because they have a worse outcome independent of the treatment. I would also include complex karyotype patients because of the same nature of the chromosomal aberrations. The more genetic aberrations that a patient has, the more likelihood that any chemotherapy will damage the DNA further and create a more aggressive clone. Instead, I would recommend that young patients in this category participate in a clinical trial with novel agents.

With novel therapies in the pipeline, the availability of CAR T, and now the bispecific antibodies such as blinatumomab and HexAbs coming along, the number of patients who may opt out of ASCT may increase. I have a long discussion with my patients. The more educated they are, the better it is for the patient. At the end of the day, the most important thing for me, with any therapy, is: how does the patient feel? Because if we cannot cure a patient or provide a survival advantage, I do not want to give that patient something that will decrease their quality of life. I would rather keep the patient in some sort of stable disease remission, comfortable, and having a good quality of life. That is my goal for anyone who cannot be cured. Now if it is a curable disease, like a diffuse large cell lymphoma or a Burkitt’s lymphoma, then it is a different story. But for people with MCL, a disease that you cannot cure, or chronic lymphocytic leukemia or follicular lymphoma, then it becomes a different discussion. Undetectable minimal residual disease correlates with longer remission durations, but sometimes trying to achieve that, you can actually do a lot of harm to some patients.

Are there any other conversations you have with your patients in day-to-day practice?

Dr. Barrientos: I always tell my patients to be on top of the age-appropriate cancer screening recommendations. For example, they should see a dermatologist once a year. Men should make sure that their prostate is checked. I recommend women get breast mammograms, Pap smears, and most importantly to avoid smoking—and that includes vaping. It is important to lead a healthy life to minimize the risk of secondary malignancies.

For risk of infections, I recommend to all my patients to be up to date on their vaccinations, such as pneumonia if they are older than 65, Shingrix for prevention of reactivation of varicella or chickenpox, and the flu shot once a year. I also recommend the COVID-19 vaccine even now, as our patients with blood disorders might have a harder time fighting COVID-19 infection. I always tell my patients to please reach out to us because we can discuss the use of antivirals such as Paxlovid (nirmatrelvir/ritonavir), and if they are sick, then they can get remdesivir in the hospital.

I want to touch on health literacy and disparities for a moment. I have some younger patients who are Latin or Black with uncontrolled hypertension or diabetes, even at a young age, and do not realize that I can treat their cancer into remission, but if their blood glucose is in the 500 range, they could die from their diabetes. So talking with patients about their overall health is important. Survivorship issues are important, especially if patients are diagnosed at a young age. We have known for a long time that chemotherapy can create cardiac events, arrhythmias, and heart disease. Therefore, I always tell patients with metabolic syndrome to try to exercise and eat healthy. Patients should get an electrocardiogram and see an internist at least once a year to make sure their cholesterol is well controlled. I think now we are being more cognizant that many complications can happen even 10 years after cancer treatment.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

How does endometriosis affect the whole body, and how often is it misunderstood for another condition?

Dr. Taylor: Far too often, we think about endometriosis as just a cause of bad menstrual cramps. So many times, we miss the signs and falsely attribute symptoms to other diseases. I cannot tell you the number of people who have seen multiple practitioners for other conditions, when the underlying problem was actually endometriosis.

Endometriosis affects the whole body. It can affect the intestines, the bladder, and body weight, and the brain and mood. Endometriosis causes fatigue and inflammation, and in the long run it can lead to an increased risk for cardiovascular disease. When we as physicians do surgery or laparoscopy, we find these little blue and brown lesions in the pelvis, and they certainly do cause pain, but that is not the whole disease.

Endometriosis heightens pain and nerve sensitivity for patients, and we should not dismiss the debilitating effect of these symptoms. Things actually do hurt more. In fact, the pain can spread from beyond the time of the menstrual period and spread to other areas besides the uterus.

We cannot ignore the totality of the effects of the disease and only focus on one part of the problem. More importantly, we cannot be distracted and discount endometriosis or mistake it for another condition. I have seen many patients who went to a gastroenterologist first and may even have had a colonoscopy because of some bowel symptoms, but then we come to find out it was endometriosis irritating the bowels at the time of their period and not another primary disease.

Another example is that the patient may see a urologist and have a cystoscopy to assess bladder pain, especially if the pain comes on around the time of menses. However, that pain is probably due to endometriosis irritating the bladder, not a primary bladder problem.

I have even had patients who were sent to a psychiatrist first because of anxiety that was actually being caused by the endometriosis. It is important to understand that treating the primary problem—endometriosis—should be our focus.

Which effects of this chronic disease can have the most long-term impact?

Dr. Taylor: It is important to understand that endometriosis has long-term effects on the entire body. For example, it affects the brain, increasing anxiety and depression. It causes pain sensitization, fatigue, and body inflammation. Endometriosis can also damage blood vessels or cause atherosclerosis.

A quick diagnosis is crucial because often this disease affects women at the most critical points in their life—either when they are in school, or in the early part of their career, when they need to be able to focus. It is important to get their endometriosis under control early and prevent long-term complications. Unfortunately, the long-term impacts are an aspect we do not focus on enough.

Infertility is another common long-term consequence of endometriosis. The sooner we can diagnose endometriosis, the sooner we can begin treatment and the more likely we can preserve someone's fertility. Our goal is to catch endometriosis early enough, preserve the patient’s fertility, and prevent any damage, so they hopefully will not have trouble getting pregnant or need medical intervention to get pregnant.

What methods do you use to diagnose endometriosis as quickly as possible?

Dr. Taylor: The sooner we can pinpoint the correct diagnosis and begin treatment, the more we can not only relieve patients of pain, but also stop that inflammation and all of these other manifestations of endometriosis so that they are not saddled with this for life.

We used to say you needed a laparoscopy to accurately diagnose endometriosis, and that statement is still true. You cannot see the most common types of endometriosis on an ultrasound or MRI. The endometriosis has to be pretty bad before you see it on an MRI or an ultrasound, and at that point it is often a big cyst in the ovary or a big nodule that is invasive.

However, you can diagnose endometriosis just by listening to your patients. If they have extremely painful menstrual cycles, dysmenorrhea, or painful menstrual cramps that get worse over the years, the problem is most likely endometriosis. You can rule out a few other things, and you can make that empiric clinical diagnosis of endometriosis. You can know with confidence that somebody likely has endometriosis. The treatments are benign. The first-line therapy would be to try a birth control pill. If we had to perform a laparoscopy before beginning endometriosis treatment, I think we would be doing our patients a huge disservice.

In addition to birth control pills, what are the most common therapeutic treatments you use in day-to-day practice?

Dr. Taylor: Birth control pills are still the first-line therapy. We use birth control pills because they are easy, well-tolerated, and inexpensive, but about a third of women will be resistant. Birth control pills are a great option when they work, but they do not always work 100% of the time.

We have a couple of other hormonal treatment options. Rarely, but occasionally, we use something called danazol, which is a mild male hormone. Side effects can be acne or hair growth, but it works well and is inexpensive. We used to give injectable agents, like leuprolide. Leuprolide is a harsh medication with once-a-month injections, and it puts someone in a temporary menopausal state with hot flashes and the possibility of decreased bone mineral density.

Today, we have the new class of GnRH antagonists that are a milder, gentler version of those injectable medications. They are oral, and you do not have to fully suppress estrogen levels all the way down to menopause. Patients can take the GnRH antagonists, stop treatment, and try to get pregnant at their next cycle.

Occasionally, we find that someone does not respond to any medical therapies, so surgery still has an important role. The usual reason for surgery is that you may suppress the active disease with medications, but the old damage is still there causing some pain, which can only be removed with surgery. Surgery is a good way to relieve that pain and it helps improve pregnancy rates for people with endometriosis wishing to conceive.

What does the future look like for endometriosis-related infertility, particularly related to in vitro fertilization (IVF)?

Dr. Taylor: We currently have an IVF trial in the works, in which we are using a hormone-suppressing GnRH (gonadotropin-releasing hormone) antagonist, elagolix, which suppresses endometriosis. The medication is administered before IVF. The goal is to determine if this approach leads to a better pregnancy rate in IVF cycles.

We are also working on nonhormonal medications in the laboratory, but these strategies are not yet ready for human clinical trials. These laboratory trials are investigating the basic biology of endometriosis, with the goal of learning what makes endometrial tissue grow in the wrong place, what makes it grow aggressively, and how it signals to other organs to cause damage.

We are looking at some additional nonhormonal medications that may possibly be used in someone trying to conceive, so that we can increase their chances of becoming pregnant. We are testing these medications in mice, but eventually we hope they progress to human clinical trials. The future for endometriosis therapy is nonhormonal treatments that can be used in somebody trying to conceive. That is what we have on the horizon.

Unfortunately for people with endometriosis wishing to conceive, all the classic first-line medications used to treat the condition are reproductive hormones that interfere with the ability to become pregnant. When we stop these medications, many women with endometriosis get pregnant spontaneously always suggest patients with endometriosis wishing to conceive try this approach, unless we know the endometriosis is very extensive. However, IVF is a good way to correct even the worst cases of endometriosis. As long as somebody has not waited until they are in their 40s and they have run out of eggs, IVF will usually correct endometriosis-related infertility.

Overall, how we treat endometriosis has been revolutionized and we have much better options than we had just 5 years ago. In my day-to-day practice, I recognize the importance of talking more openly about endometriosis, understanding the different symptoms, and not dismissing those connections. We should be able to talk about this important medical problem and all of its manifestations. I published a paper in The Lancet at the end of 2021 about the concept of endometriosis as a systemic whole-body disease and its effects. I think open conversations with patients about endometriosis is making a world of difference for the women with this disease.

This transcript has been edited for clarity.

Hello. I’m Dr Sandra Fryhofer. Welcome to Medicine Matters. The topic is highlights from ACIP’s new adult schedule for 2023, published in the Annals of Internal Medicine, and why this new schedule may be a collector’s item.

It’s a new year, which means a new ACIP adult immunization schedule – a valuable resource collating ACIP’s most up-to-date vaccination recommendations.

Here are this year’s five most important changes:

• COVID vaccines now front and center
• New emphasis on polio vaccination
• Inclusion of some nonvaccine products (such as monoclonal antibody products)
• Pharmacists group has approved the schedule for the first time
• New shared clinical decision-making option for pneumococcal vaccines

The schedule’s organization remains the same. It still has four sections:

• Table 1: vaccinations by age
• Table 2: vaccinations by medical condition and other indications
• The Notes section (alphabetically ordered by vaccine type)
• Appendix listing of vaccine-specific contraindications and precautions

But what’s unique this year is that some of the abbreviations have historical implications. The first change is no big surprise in light of what we’ve gone through in the past few years. COVID vaccines are listed first on the cover page by brand name for those authorized and by company name for those still under US emergency use authorization. They’re also listed first on the graphics and in the notes.

COVID and mRNA and protein-based vaccines have now been assigned official abbreviations based on vaccine platform and valency.

• 1vCOV-mRNA: Comirnaty/Pfizer-BioNTech and Spikevax Moderna COVID-19 vaccines
• 2vCOV-mRNA: Pfizer-BioNTech and Moderna bivalent COVID-19 vaccines
• 1vCOV-aPS: Novavax COVID-19 vaccine

Also remarkable is the absence of COVID viral vector vaccines on the list. However, the viral vector COVID vaccine (which has been available but is not preferred) does have a CDC website link in the Notes section.

A sad but necessary inclusion was triggered by recent polio cases in New York. Polio was believed to be eradicated, and we thought adults no longer needed to be vaccinated against polio. In the new schedule, the polio vaccine is listed on the cover page but is not included in the tables. Current polio vaccination recommendations are now in the Notes section.

Also of historical significance and something that may set a precedent is the inclusion of nonvaccine products. The value of COVID preexposure prophylaxis with products including monoclonal antibodies (such as Evusheld) for people who are moderately or severely immunocompromised is mentioned in the Notes section.

For the first time ever, the schedule has been approved by the American Pharmacists Association, which validates pharmacists as established partners in vaccine administration.
 

Color-code key

One aspect of the schedule that has not changed is the color-code key:

• Yellow: Recommended if the patient meets the age requirement
• Purple: Indicated for those with additional risk factors or another indication
• Blue: Recommended based on shared clinical decision-making
• Orange: Precaution
• Red: Contraindicated or not recommended; the vaccine should not be administered. Overlays on the red more precisely clarify whether a vaccine is really contraindicated or just not recommended. An asterisk on red means vaccinate after pregnancy if indicated.
• Gray: No recommendation or not applicable

Vaccinations by age

Table 1 lists recommended vaccinations by age. There is one major change. COVID vaccines are on the first row of the graphic, with the need for both a primary series and boosters emphasized on the overlay. The notes have hyperlinks to the most up-to-date COVID vaccination recommendations.

Pneumococcal vaccination. Pneumococcal vaccination is routinely recommended starting at age 65. Current recommendations for those not previously vaccinated have not changed since last year. But on Table 1, the bottom half of the row for those 65 or older is now blue (and that’s new). This new color blue means shared clinical decision-making and applies to people who were previously considered fully vaccinated with the now extinct combination of PCV13 and PPSV23. These patients now have the option of getting a dose of PCV20 five years after completing their PCV13-PPSV23 combo series. This option is blue because the decision is up to you and your patient.

Check the notes for more pneumococcal vaccination details. For example, for those partially vaccinated using lower valency vaccines, there’s an option of substituting PCV20 for PPSV23 to broaden and increase durability of protection.

The pneumococcal vaccination recommendation options are complicated. A new pneumococcal vaccination app can help.

Hepatitis B. For adults under age 60, the color code for the hepatitis B vaccine is yellow, meaning it’s indicated for all. For older patients, the color code is purple. If a patient who is age 60 or older wants the hepatitis B vaccine, they can have it even in the absence of additional risk indications.
 

Vaccinations by medical condition or other indications

Other than a few minor word changes on the overlay, the only thing that’s new is the COVID vaccine row.

This table is helpful for matching vaccine recommendations with specific medical conditions, including pregnancy, immunocompromise, HIV (with specifics according to CD4 count), asplenia, complement deficiencies, heart disease, lung disease, alcoholism, chronic liver disease, diabetes, health care personnel, and men who have sex with men.

Use this table to dot the i’s and cross the t’s when it comes to vaccination recommendations. For example, take a look at the pregnancy column. Live virus vaccines, including LAIV, MMR, and varicella, are contraindicated and color-coded red. MMR and varicella also have an asterisk, meaning vaccinate after pregnancy if indicated. HPV vaccines are not live virus vaccines, but the overlay says they are not recommended during pregnancy. The asterisk indicates that you can vaccinate after pregnancy.
 

Vaccine notes

The notes are in alphabetical order, and their organization (routine, special situations, and shared clinical decision-making when indicated) has not changed. They are concise and succinct, but sometimes they’re not enough. That’s why vaccine-specific links to more complete recommendations are so convenient.

Notes for hepatitis B contain nuances on specific dosing for vaccinating patients on dialysis, as well as a reminder that newer hepatitis C vaccines such as Heplisav and PreHevbrio are not recommended during pregnancy due to lack of safety data.

For influenza, everyone 6 months or older still needs yearly flu vaccination with an age- and health-appropriate flu vaccine. But for those aged 65 or older, the notes specify the three vaccine versions now preferred: high-dose, recombinant, or adjuvanted versions. However, if these aren’t available, it’s better to get any flu vaccine than to go without.

Under meningococcal vaccines, the notes for MenACWY and MenB are combined. For MenB, trade names Bexsero and Trumenba are specified because the products are not interchangeable. Booster intervals for those still at risk are different for each vaccine type: every 5 years for MenACWY boosters, and every 2-3 years for boosts of MenB.

The recent polio cases in New York have put polio vaccination in the spotlight. ACIP has now reinstated its Polio Vaccine Work Group. The new schedule lists polio vaccines on the cover page. Current recommendations have been added to the notes section. Routine vaccination for adults is not necessary, at least for now. However, those at increased risk for exposure to polio fall in the special-situation category. For those at increased risk who have completed a polio vaccine series, a single lifetime IPV booster can be given. For those at increased risk who have not completed their polio vaccine series, now would be the time to finish the series.
 

Appendix

The final step in using the new schedule is checking the appendix and its list of vaccine-specific contraindications and precautions.

I hope this review of the new ACIP adult immunization schedule has been helpful. For Medicine Matters, I’m Dr. Sandra Fryhofer.

Dr. Fryhofer is clinical associate professor of medicine, Emory University, Atlanta. She reported numerous conflicts of interest.

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

This transcript has been edited for clarity.

Hello. I’m Dr Sandra Fryhofer. Welcome to Medicine Matters. The topic is highlights from ACIP’s new adult schedule for 2023, published in the Annals of Internal Medicine, and why this new schedule may be a collector’s item.

It’s a new year, which means a new ACIP adult immunization schedule – a valuable resource collating ACIP’s most up-to-date vaccination recommendations.

Here are this year’s five most important changes:

• COVID vaccines now front and center
• New emphasis on polio vaccination
• Inclusion of some nonvaccine products (such as monoclonal antibody products)
• Pharmacists group has approved the schedule for the first time
• New shared clinical decision-making option for pneumococcal vaccines

The schedule’s organization remains the same. It still has four sections:

• Table 1: vaccinations by age
• Table 2: vaccinations by medical condition and other indications
• The Notes section (alphabetically ordered by vaccine type)
• Appendix listing of vaccine-specific contraindications and precautions

But what’s unique this year is that some of the abbreviations have historical implications. The first change is no big surprise in light of what we’ve gone through in the past few years. COVID vaccines are listed first on the cover page by brand name for those authorized and by company name for those still under US emergency use authorization. They’re also listed first on the graphics and in the notes.

COVID and mRNA and protein-based vaccines have now been assigned official abbreviations based on vaccine platform and valency.

• 1vCOV-mRNA: Comirnaty/Pfizer-BioNTech and Spikevax Moderna COVID-19 vaccines
• 2vCOV-mRNA: Pfizer-BioNTech and Moderna bivalent COVID-19 vaccines
• 1vCOV-aPS: Novavax COVID-19 vaccine

Also remarkable is the absence of COVID viral vector vaccines on the list. However, the viral vector COVID vaccine (which has been available but is not preferred) does have a CDC website link in the Notes section.

A sad but necessary inclusion was triggered by recent polio cases in New York. Polio was believed to be eradicated, and we thought adults no longer needed to be vaccinated against polio. In the new schedule, the polio vaccine is listed on the cover page but is not included in the tables. Current polio vaccination recommendations are now in the Notes section.

Also of historical significance and something that may set a precedent is the inclusion of nonvaccine products. The value of COVID preexposure prophylaxis with products including monoclonal antibodies (such as Evusheld) for people who are moderately or severely immunocompromised is mentioned in the Notes section.

For the first time ever, the schedule has been approved by the American Pharmacists Association, which validates pharmacists as established partners in vaccine administration.
 

Color-code key

One aspect of the schedule that has not changed is the color-code key:

• Yellow: Recommended if the patient meets the age requirement
• Purple: Indicated for those with additional risk factors or another indication
• Blue: Recommended based on shared clinical decision-making
• Orange: Precaution
• Red: Contraindicated or not recommended; the vaccine should not be administered. Overlays on the red more precisely clarify whether a vaccine is really contraindicated or just not recommended. An asterisk on red means vaccinate after pregnancy if indicated.
• Gray: No recommendation or not applicable

Vaccinations by age

Table 1 lists recommended vaccinations by age. There is one major change. COVID vaccines are on the first row of the graphic, with the need for both a primary series and boosters emphasized on the overlay. The notes have hyperlinks to the most up-to-date COVID vaccination recommendations.

Pneumococcal vaccination. Pneumococcal vaccination is routinely recommended starting at age 65. Current recommendations for those not previously vaccinated have not changed since last year. But on Table 1, the bottom half of the row for those 65 or older is now blue (and that’s new). This new color blue means shared clinical decision-making and applies to people who were previously considered fully vaccinated with the now extinct combination of PCV13 and PPSV23. These patients now have the option of getting a dose of PCV20 five years after completing their PCV13-PPSV23 combo series. This option is blue because the decision is up to you and your patient.

Check the notes for more pneumococcal vaccination details. For example, for those partially vaccinated using lower valency vaccines, there’s an option of substituting PCV20 for PPSV23 to broaden and increase durability of protection.

The pneumococcal vaccination recommendation options are complicated. A new pneumococcal vaccination app can help.

Hepatitis B. For adults under age 60, the color code for the hepatitis B vaccine is yellow, meaning it’s indicated for all. For older patients, the color code is purple. If a patient who is age 60 or older wants the hepatitis B vaccine, they can have it even in the absence of additional risk indications.
 

Vaccinations by medical condition or other indications

Other than a few minor word changes on the overlay, the only thing that’s new is the COVID vaccine row.

This table is helpful for matching vaccine recommendations with specific medical conditions, including pregnancy, immunocompromise, HIV (with specifics according to CD4 count), asplenia, complement deficiencies, heart disease, lung disease, alcoholism, chronic liver disease, diabetes, health care personnel, and men who have sex with men.

Use this table to dot the i’s and cross the t’s when it comes to vaccination recommendations. For example, take a look at the pregnancy column. Live virus vaccines, including LAIV, MMR, and varicella, are contraindicated and color-coded red. MMR and varicella also have an asterisk, meaning vaccinate after pregnancy if indicated. HPV vaccines are not live virus vaccines, but the overlay says they are not recommended during pregnancy. The asterisk indicates that you can vaccinate after pregnancy.
 

Vaccine notes

The notes are in alphabetical order, and their organization (routine, special situations, and shared clinical decision-making when indicated) has not changed. They are concise and succinct, but sometimes they’re not enough. That’s why vaccine-specific links to more complete recommendations are so convenient.

Notes for hepatitis B contain nuances on specific dosing for vaccinating patients on dialysis, as well as a reminder that newer hepatitis C vaccines such as Heplisav and PreHevbrio are not recommended during pregnancy due to lack of safety data.

For influenza, everyone 6 months or older still needs yearly flu vaccination with an age- and health-appropriate flu vaccine. But for those aged 65 or older, the notes specify the three vaccine versions now preferred: high-dose, recombinant, or adjuvanted versions. However, if these aren’t available, it’s better to get any flu vaccine than to go without.

Under meningococcal vaccines, the notes for MenACWY and MenB are combined. For MenB, trade names Bexsero and Trumenba are specified because the products are not interchangeable. Booster intervals for those still at risk are different for each vaccine type: every 5 years for MenACWY boosters, and every 2-3 years for boosts of MenB.

The recent polio cases in New York have put polio vaccination in the spotlight. ACIP has now reinstated its Polio Vaccine Work Group. The new schedule lists polio vaccines on the cover page. Current recommendations have been added to the notes section. Routine vaccination for adults is not necessary, at least for now. However, those at increased risk for exposure to polio fall in the special-situation category. For those at increased risk who have completed a polio vaccine series, a single lifetime IPV booster can be given. For those at increased risk who have not completed their polio vaccine series, now would be the time to finish the series.
 

Appendix

The final step in using the new schedule is checking the appendix and its list of vaccine-specific contraindications and precautions.

I hope this review of the new ACIP adult immunization schedule has been helpful. For Medicine Matters, I’m Dr. Sandra Fryhofer.

Dr. Fryhofer is clinical associate professor of medicine, Emory University, Atlanta. She reported numerous conflicts of interest.

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

This transcript has been edited for clarity.

Hello. I’m Dr Sandra Fryhofer. Welcome to Medicine Matters. The topic is highlights from ACIP’s new adult schedule for 2023, published in the Annals of Internal Medicine, and why this new schedule may be a collector’s item.

It’s a new year, which means a new ACIP adult immunization schedule – a valuable resource collating ACIP’s most up-to-date vaccination recommendations.

Here are this year’s five most important changes:

• COVID vaccines now front and center
• New emphasis on polio vaccination
• Inclusion of some nonvaccine products (such as monoclonal antibody products)
• Pharmacists group has approved the schedule for the first time
• New shared clinical decision-making option for pneumococcal vaccines

The schedule’s organization remains the same. It still has four sections:

• Table 1: vaccinations by age
• Table 2: vaccinations by medical condition and other indications
• The Notes section (alphabetically ordered by vaccine type)
• Appendix listing of vaccine-specific contraindications and precautions

But what’s unique this year is that some of the abbreviations have historical implications. The first change is no big surprise in light of what we’ve gone through in the past few years. COVID vaccines are listed first on the cover page by brand name for those authorized and by company name for those still under US emergency use authorization. They’re also listed first on the graphics and in the notes.

COVID and mRNA and protein-based vaccines have now been assigned official abbreviations based on vaccine platform and valency.

• 1vCOV-mRNA: Comirnaty/Pfizer-BioNTech and Spikevax Moderna COVID-19 vaccines
• 2vCOV-mRNA: Pfizer-BioNTech and Moderna bivalent COVID-19 vaccines
• 1vCOV-aPS: Novavax COVID-19 vaccine

Also remarkable is the absence of COVID viral vector vaccines on the list. However, the viral vector COVID vaccine (which has been available but is not preferred) does have a CDC website link in the Notes section.

A sad but necessary inclusion was triggered by recent polio cases in New York. Polio was believed to be eradicated, and we thought adults no longer needed to be vaccinated against polio. In the new schedule, the polio vaccine is listed on the cover page but is not included in the tables. Current polio vaccination recommendations are now in the Notes section.

Also of historical significance and something that may set a precedent is the inclusion of nonvaccine products. The value of COVID preexposure prophylaxis with products including monoclonal antibodies (such as Evusheld) for people who are moderately or severely immunocompromised is mentioned in the Notes section.

For the first time ever, the schedule has been approved by the American Pharmacists Association, which validates pharmacists as established partners in vaccine administration.
 

Color-code key

One aspect of the schedule that has not changed is the color-code key:

• Yellow: Recommended if the patient meets the age requirement
• Purple: Indicated for those with additional risk factors or another indication
• Blue: Recommended based on shared clinical decision-making
• Orange: Precaution
• Red: Contraindicated or not recommended; the vaccine should not be administered. Overlays on the red more precisely clarify whether a vaccine is really contraindicated or just not recommended. An asterisk on red means vaccinate after pregnancy if indicated.
• Gray: No recommendation or not applicable

Vaccinations by age

Table 1 lists recommended vaccinations by age. There is one major change. COVID vaccines are on the first row of the graphic, with the need for both a primary series and boosters emphasized on the overlay. The notes have hyperlinks to the most up-to-date COVID vaccination recommendations.

Pneumococcal vaccination. Pneumococcal vaccination is routinely recommended starting at age 65. Current recommendations for those not previously vaccinated have not changed since last year. But on Table 1, the bottom half of the row for those 65 or older is now blue (and that’s new). This new color blue means shared clinical decision-making and applies to people who were previously considered fully vaccinated with the now extinct combination of PCV13 and PPSV23. These patients now have the option of getting a dose of PCV20 five years after completing their PCV13-PPSV23 combo series. This option is blue because the decision is up to you and your patient.

Check the notes for more pneumococcal vaccination details. For example, for those partially vaccinated using lower valency vaccines, there’s an option of substituting PCV20 for PPSV23 to broaden and increase durability of protection.

The pneumococcal vaccination recommendation options are complicated. A new pneumococcal vaccination app can help.

Hepatitis B. For adults under age 60, the color code for the hepatitis B vaccine is yellow, meaning it’s indicated for all. For older patients, the color code is purple. If a patient who is age 60 or older wants the hepatitis B vaccine, they can have it even in the absence of additional risk indications.
 

Vaccinations by medical condition or other indications

Other than a few minor word changes on the overlay, the only thing that’s new is the COVID vaccine row.

This table is helpful for matching vaccine recommendations with specific medical conditions, including pregnancy, immunocompromise, HIV (with specifics according to CD4 count), asplenia, complement deficiencies, heart disease, lung disease, alcoholism, chronic liver disease, diabetes, health care personnel, and men who have sex with men.

Use this table to dot the i’s and cross the t’s when it comes to vaccination recommendations. For example, take a look at the pregnancy column. Live virus vaccines, including LAIV, MMR, and varicella, are contraindicated and color-coded red. MMR and varicella also have an asterisk, meaning vaccinate after pregnancy if indicated. HPV vaccines are not live virus vaccines, but the overlay says they are not recommended during pregnancy. The asterisk indicates that you can vaccinate after pregnancy.
 

Vaccine notes

The notes are in alphabetical order, and their organization (routine, special situations, and shared clinical decision-making when indicated) has not changed. They are concise and succinct, but sometimes they’re not enough. That’s why vaccine-specific links to more complete recommendations are so convenient.

Notes for hepatitis B contain nuances on specific dosing for vaccinating patients on dialysis, as well as a reminder that newer hepatitis C vaccines such as Heplisav and PreHevbrio are not recommended during pregnancy due to lack of safety data.

For influenza, everyone 6 months or older still needs yearly flu vaccination with an age- and health-appropriate flu vaccine. But for those aged 65 or older, the notes specify the three vaccine versions now preferred: high-dose, recombinant, or adjuvanted versions. However, if these aren’t available, it’s better to get any flu vaccine than to go without.

Under meningococcal vaccines, the notes for MenACWY and MenB are combined. For MenB, trade names Bexsero and Trumenba are specified because the products are not interchangeable. Booster intervals for those still at risk are different for each vaccine type: every 5 years for MenACWY boosters, and every 2-3 years for boosts of MenB.

The recent polio cases in New York have put polio vaccination in the spotlight. ACIP has now reinstated its Polio Vaccine Work Group. The new schedule lists polio vaccines on the cover page. Current recommendations have been added to the notes section. Routine vaccination for adults is not necessary, at least for now. However, those at increased risk for exposure to polio fall in the special-situation category. For those at increased risk who have completed a polio vaccine series, a single lifetime IPV booster can be given. For those at increased risk who have not completed their polio vaccine series, now would be the time to finish the series.
 

Appendix

The final step in using the new schedule is checking the appendix and its list of vaccine-specific contraindications and precautions.

I hope this review of the new ACIP adult immunization schedule has been helpful. For Medicine Matters, I’m Dr. Sandra Fryhofer.

Dr. Fryhofer is clinical associate professor of medicine, Emory University, Atlanta. She reported numerous conflicts of interest.

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

What were the most exciting mantle cell lymphoma (MCL) updates from the recent meeting of the American Society of Hematology (ASH)?

Dr. Martin: The 2022 ASH meeting reported mostly about MCL research, which is great for the MCL community, because clearly, there is a lot of room for improvement. One of the big trials presented at a plenary session—one which we have been eager to see the results from, but maybe did not expect to see quite so soon—was the European MCL Network TRIANGLE trial. This is a 3-arm trial in which 870 patients were randomized. They had treatment-naive MCL and were younger than 66 years, so they were eligible for more intensive chemotherapy.

Arm A was the standard-of-care arm, defined by the prior European MCL Network TRIANGLE Trial. This was 6 alternating cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride [doxorubicin hydrochloride], vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) – 3 of each followed by autologous stem cell transplant. Arm B was the same regimen with the addition of the first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib to induction followed by 2 years of ibrutinib maintenance. Arm C was the same induction regimen (6 alternating cycles of R-CHOP and R-DHAP plus ibrutinib during induction and maintenance) with no autologous stem cell transplant. Roughly half the patients in the trial, all equally distributed across all arms, received 3 years of maintenance rituximab.

The primary outcome was failure-free survival (FFS). After only 31 months of median follow-up, the trial reported a significant difference in FFS between patients receiving ibrutinib (Arms B and C) and patients who underwent autologous stem cell transplant and did not receive ibrutinib (Arm A).

This clearly shows that 2 years of ibrutinib maintenance significantly improves FFS. FFS was 88% versus 72% (Arm B vs Arm A) at 3 years with a hazard ratio of 0.5. That is a striking hazard ratio, highly statistically significant. Importantly, patients in Arms B and C fared similarly, suggesting that transplant was unnecessary in patients receiving ibrutinib.

What these findings suggest is that in the patient population treated with intensive induction, we are moving beyond autologous stem cell transplant. These results were similar across all subgroups. In fact, outcomes were most striking for patients with higher risk features like high Ki-67 and overexpression of p53.

The patients who need ibrutinib most were those who were most likely to benefit, and that is really encouraging for all of us. There is a clear trend toward an improvement in overall survival with ibrutinib maintenance and there clearly is less toxicity and less treatment-related mortality from avoiding transplant.

It will be important to see this trial published in a peer-reviewed journal with more granular data. But to me, these trial results are groundbreaking. It is a practice-changing trial for sure.

Is there anything else from an investigational approach on the horizon for MCL?

Dr. Martin: Yes. I would like to highlight 2 trials that stand out to me.

First, my colleague Dr. Ruan from Cornell presented on a phase 2 trial of a triplet of acalabrutinib plus lenalidomide plus rituximab with real-time monitoring of minimal residual disease (MRD) in patients with treatment-naive MCL.

This was a small trial with just 24 patients. It was fairly evenly split between low-, medium-, and high-risk MCL international prognostic index (MIPI) scores. All of these patients received the triplet for 1 year of induction followed by an additional year of maintenance with a slightly lower dose of lenalidomide. At the end of 2 years, patients who were in a durable MRD-negative state could stop the oral therapy and just continue with rituximab maintenance.

In a prior trial published in The New England Journal of Medicine, we showed that the lenalidomide plus rituximab regimen has a complete response rate of about 60%. In this new ongoing trial regimen of acalabrutinib plus lenalidomide plus rituximab, we found that at the end of just 1 year of induction treatment, the complete response rate was 83%. With all of the caveats and comparing across trials, this new regimen was clearly active and potentially more active than the prior regimen. It also appeared to be well tolerated without any real significant issues.

I think what this trial plus the TRIANGLE showed us is that BTK inhibitors belong in the front-line setting. That is what patients want. That is what physicians want.

The other trial that I wanted to highlight is an update of something that we saw last year at ASH, specifically a phase 1/2 trial of glofitamab in people with previously treated MCL. The overall response rate was 83% and the complete response rate was 73%. The complete response rate at the first assessment was already almost 50%. These are among patients who have had prior treatment for MCL, including BTK inhibitors.

We are not accustomed to seeing treatments that are so active in the relapsed/refractory MCL patient population, particularly, if they have had a prior BTK inhibitor. So, these results are exciting and promising.

This compares to the ZUMA-2 trial with CAR T-cells. CAR T-cells are also strikingly active in this patient population, but they do have some drawbacks. They have to be administered in a specialized facility and they are associated with fairly high rates of cytokine release syndrome and neurotoxicity.

The rates of grade 3 to 4 cytokine release syndrome and neurotoxicity with glofitamab were low, but not negligible. All cytokine release syndrome events were manageable, and no patients discontinued treatment because of adverse events. This is, potentially, attractive, because it offers an active therapy to a broader subset of patients with MCL who may not be able to access CAR T-cell therapy as easily. A phase 3 trial is in the planning stages, and it is likely that if that trial has positive results, we will see glofitamab approved in the not-too-distant future for people with MCL, and having more options is always great.

Based on these developments, do you see any shifts in your day-to-day practice in the future?

Dr. Martin: I think what has been interesting to me about MCL over the past decade is this idea that not everybody is the same. That should not come as a surprise statement, but MCL does behave differently in different people.

As a physician who treats a lot of patients with MCL, I have seen all of the different ways in which MCL can behave; combine that with the heterogeneity of humanity as a whole. Having guidelines from the NCCN (National Comprehensive Care Network) are helpful, but those guidelines are broad.

Learning how to take all that heterogeneity and variety into account and match the appropriate treatment to each patient is important. What these front-line trials are telling us is that it is OK to do research that does not involve chemotherapy.

In the past, it might have been considered unethical to give a younger patient a treatment without autologous stem cell transplant. But that is clearly not the case now. I think that in real-life practice in the near future, guidelines may actually start to get a little bit easier to follow as we come up with options that are less intensive.

It may be that patients can access treatments that are a little bit easier, that do not involve a transplant. That would be good for people with MCL from all across the country.

What were the most exciting mantle cell lymphoma (MCL) updates from the recent meeting of the American Society of Hematology (ASH)?

Dr. Martin: The 2022 ASH meeting reported mostly about MCL research, which is great for the MCL community, because clearly, there is a lot of room for improvement. One of the big trials presented at a plenary session—one which we have been eager to see the results from, but maybe did not expect to see quite so soon—was the European MCL Network TRIANGLE trial. This is a 3-arm trial in which 870 patients were randomized. They had treatment-naive MCL and were younger than 66 years, so they were eligible for more intensive chemotherapy.

Arm A was the standard-of-care arm, defined by the prior European MCL Network TRIANGLE Trial. This was 6 alternating cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride [doxorubicin hydrochloride], vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) – 3 of each followed by autologous stem cell transplant. Arm B was the same regimen with the addition of the first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib to induction followed by 2 years of ibrutinib maintenance. Arm C was the same induction regimen (6 alternating cycles of R-CHOP and R-DHAP plus ibrutinib during induction and maintenance) with no autologous stem cell transplant. Roughly half the patients in the trial, all equally distributed across all arms, received 3 years of maintenance rituximab.

The primary outcome was failure-free survival (FFS). After only 31 months of median follow-up, the trial reported a significant difference in FFS between patients receiving ibrutinib (Arms B and C) and patients who underwent autologous stem cell transplant and did not receive ibrutinib (Arm A).

This clearly shows that 2 years of ibrutinib maintenance significantly improves FFS. FFS was 88% versus 72% (Arm B vs Arm A) at 3 years with a hazard ratio of 0.5. That is a striking hazard ratio, highly statistically significant. Importantly, patients in Arms B and C fared similarly, suggesting that transplant was unnecessary in patients receiving ibrutinib.

What these findings suggest is that in the patient population treated with intensive induction, we are moving beyond autologous stem cell transplant. These results were similar across all subgroups. In fact, outcomes were most striking for patients with higher risk features like high Ki-67 and overexpression of p53.

The patients who need ibrutinib most were those who were most likely to benefit, and that is really encouraging for all of us. There is a clear trend toward an improvement in overall survival with ibrutinib maintenance and there clearly is less toxicity and less treatment-related mortality from avoiding transplant.

It will be important to see this trial published in a peer-reviewed journal with more granular data. But to me, these trial results are groundbreaking. It is a practice-changing trial for sure.

Is there anything else from an investigational approach on the horizon for MCL?

Dr. Martin: Yes. I would like to highlight 2 trials that stand out to me.

First, my colleague Dr. Ruan from Cornell presented on a phase 2 trial of a triplet of acalabrutinib plus lenalidomide plus rituximab with real-time monitoring of minimal residual disease (MRD) in patients with treatment-naive MCL.

This was a small trial with just 24 patients. It was fairly evenly split between low-, medium-, and high-risk MCL international prognostic index (MIPI) scores. All of these patients received the triplet for 1 year of induction followed by an additional year of maintenance with a slightly lower dose of lenalidomide. At the end of 2 years, patients who were in a durable MRD-negative state could stop the oral therapy and just continue with rituximab maintenance.

In a prior trial published in The New England Journal of Medicine, we showed that the lenalidomide plus rituximab regimen has a complete response rate of about 60%. In this new ongoing trial regimen of acalabrutinib plus lenalidomide plus rituximab, we found that at the end of just 1 year of induction treatment, the complete response rate was 83%. With all of the caveats and comparing across trials, this new regimen was clearly active and potentially more active than the prior regimen. It also appeared to be well tolerated without any real significant issues.

I think what this trial plus the TRIANGLE showed us is that BTK inhibitors belong in the front-line setting. That is what patients want. That is what physicians want.

The other trial that I wanted to highlight is an update of something that we saw last year at ASH, specifically a phase 1/2 trial of glofitamab in people with previously treated MCL. The overall response rate was 83% and the complete response rate was 73%. The complete response rate at the first assessment was already almost 50%. These are among patients who have had prior treatment for MCL, including BTK inhibitors.

We are not accustomed to seeing treatments that are so active in the relapsed/refractory MCL patient population, particularly, if they have had a prior BTK inhibitor. So, these results are exciting and promising.

This compares to the ZUMA-2 trial with CAR T-cells. CAR T-cells are also strikingly active in this patient population, but they do have some drawbacks. They have to be administered in a specialized facility and they are associated with fairly high rates of cytokine release syndrome and neurotoxicity.

The rates of grade 3 to 4 cytokine release syndrome and neurotoxicity with glofitamab were low, but not negligible. All cytokine release syndrome events were manageable, and no patients discontinued treatment because of adverse events. This is, potentially, attractive, because it offers an active therapy to a broader subset of patients with MCL who may not be able to access CAR T-cell therapy as easily. A phase 3 trial is in the planning stages, and it is likely that if that trial has positive results, we will see glofitamab approved in the not-too-distant future for people with MCL, and having more options is always great.

Based on these developments, do you see any shifts in your day-to-day practice in the future?

Dr. Martin: I think what has been interesting to me about MCL over the past decade is this idea that not everybody is the same. That should not come as a surprise statement, but MCL does behave differently in different people.

As a physician who treats a lot of patients with MCL, I have seen all of the different ways in which MCL can behave; combine that with the heterogeneity of humanity as a whole. Having guidelines from the NCCN (National Comprehensive Care Network) are helpful, but those guidelines are broad.

Learning how to take all that heterogeneity and variety into account and match the appropriate treatment to each patient is important. What these front-line trials are telling us is that it is OK to do research that does not involve chemotherapy.

In the past, it might have been considered unethical to give a younger patient a treatment without autologous stem cell transplant. But that is clearly not the case now. I think that in real-life practice in the near future, guidelines may actually start to get a little bit easier to follow as we come up with options that are less intensive.

It may be that patients can access treatments that are a little bit easier, that do not involve a transplant. That would be good for people with MCL from all across the country.

What were the most exciting mantle cell lymphoma (MCL) updates from the recent meeting of the American Society of Hematology (ASH)?

Dr. Martin: The 2022 ASH meeting reported mostly about MCL research, which is great for the MCL community, because clearly, there is a lot of room for improvement. One of the big trials presented at a plenary session—one which we have been eager to see the results from, but maybe did not expect to see quite so soon—was the European MCL Network TRIANGLE trial. This is a 3-arm trial in which 870 patients were randomized. They had treatment-naive MCL and were younger than 66 years, so they were eligible for more intensive chemotherapy.

Arm A was the standard-of-care arm, defined by the prior European MCL Network TRIANGLE Trial. This was 6 alternating cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride [doxorubicin hydrochloride], vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) – 3 of each followed by autologous stem cell transplant. Arm B was the same regimen with the addition of the first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib to induction followed by 2 years of ibrutinib maintenance. Arm C was the same induction regimen (6 alternating cycles of R-CHOP and R-DHAP plus ibrutinib during induction and maintenance) with no autologous stem cell transplant. Roughly half the patients in the trial, all equally distributed across all arms, received 3 years of maintenance rituximab.

The primary outcome was failure-free survival (FFS). After only 31 months of median follow-up, the trial reported a significant difference in FFS between patients receiving ibrutinib (Arms B and C) and patients who underwent autologous stem cell transplant and did not receive ibrutinib (Arm A).

This clearly shows that 2 years of ibrutinib maintenance significantly improves FFS. FFS was 88% versus 72% (Arm B vs Arm A) at 3 years with a hazard ratio of 0.5. That is a striking hazard ratio, highly statistically significant. Importantly, patients in Arms B and C fared similarly, suggesting that transplant was unnecessary in patients receiving ibrutinib.

What these findings suggest is that in the patient population treated with intensive induction, we are moving beyond autologous stem cell transplant. These results were similar across all subgroups. In fact, outcomes were most striking for patients with higher risk features like high Ki-67 and overexpression of p53.

The patients who need ibrutinib most were those who were most likely to benefit, and that is really encouraging for all of us. There is a clear trend toward an improvement in overall survival with ibrutinib maintenance and there clearly is less toxicity and less treatment-related mortality from avoiding transplant.

It will be important to see this trial published in a peer-reviewed journal with more granular data. But to me, these trial results are groundbreaking. It is a practice-changing trial for sure.

Is there anything else from an investigational approach on the horizon for MCL?

Dr. Martin: Yes. I would like to highlight 2 trials that stand out to me.

First, my colleague Dr. Ruan from Cornell presented on a phase 2 trial of a triplet of acalabrutinib plus lenalidomide plus rituximab with real-time monitoring of minimal residual disease (MRD) in patients with treatment-naive MCL.

This was a small trial with just 24 patients. It was fairly evenly split between low-, medium-, and high-risk MCL international prognostic index (MIPI) scores. All of these patients received the triplet for 1 year of induction followed by an additional year of maintenance with a slightly lower dose of lenalidomide. At the end of 2 years, patients who were in a durable MRD-negative state could stop the oral therapy and just continue with rituximab maintenance.

In a prior trial published in The New England Journal of Medicine, we showed that the lenalidomide plus rituximab regimen has a complete response rate of about 60%. In this new ongoing trial regimen of acalabrutinib plus lenalidomide plus rituximab, we found that at the end of just 1 year of induction treatment, the complete response rate was 83%. With all of the caveats and comparing across trials, this new regimen was clearly active and potentially more active than the prior regimen. It also appeared to be well tolerated without any real significant issues.

I think what this trial plus the TRIANGLE showed us is that BTK inhibitors belong in the front-line setting. That is what patients want. That is what physicians want.

The other trial that I wanted to highlight is an update of something that we saw last year at ASH, specifically a phase 1/2 trial of glofitamab in people with previously treated MCL. The overall response rate was 83% and the complete response rate was 73%. The complete response rate at the first assessment was already almost 50%. These are among patients who have had prior treatment for MCL, including BTK inhibitors.

We are not accustomed to seeing treatments that are so active in the relapsed/refractory MCL patient population, particularly, if they have had a prior BTK inhibitor. So, these results are exciting and promising.

This compares to the ZUMA-2 trial with CAR T-cells. CAR T-cells are also strikingly active in this patient population, but they do have some drawbacks. They have to be administered in a specialized facility and they are associated with fairly high rates of cytokine release syndrome and neurotoxicity.

The rates of grade 3 to 4 cytokine release syndrome and neurotoxicity with glofitamab were low, but not negligible. All cytokine release syndrome events were manageable, and no patients discontinued treatment because of adverse events. This is, potentially, attractive, because it offers an active therapy to a broader subset of patients with MCL who may not be able to access CAR T-cell therapy as easily. A phase 3 trial is in the planning stages, and it is likely that if that trial has positive results, we will see glofitamab approved in the not-too-distant future for people with MCL, and having more options is always great.

Based on these developments, do you see any shifts in your day-to-day practice in the future?

Dr. Martin: I think what has been interesting to me about MCL over the past decade is this idea that not everybody is the same. That should not come as a surprise statement, but MCL does behave differently in different people.

As a physician who treats a lot of patients with MCL, I have seen all of the different ways in which MCL can behave; combine that with the heterogeneity of humanity as a whole. Having guidelines from the NCCN (National Comprehensive Care Network) are helpful, but those guidelines are broad.

Learning how to take all that heterogeneity and variety into account and match the appropriate treatment to each patient is important. What these front-line trials are telling us is that it is OK to do research that does not involve chemotherapy.

In the past, it might have been considered unethical to give a younger patient a treatment without autologous stem cell transplant. But that is clearly not the case now. I think that in real-life practice in the near future, guidelines may actually start to get a little bit easier to follow as we come up with options that are less intensive.

It may be that patients can access treatments that are a little bit easier, that do not involve a transplant. That would be good for people with MCL from all across the country.

Can you talk about the evolution and treatment of human epidermal growth factor receptor 2 (HER2)-low breast cancer?

Dr. Abdou: Until recently, HER2 status had been defined as a positive or negative result, but this convention has evolved, and now a newly defined population with low levels of HER2 expression has been identified. This HER2-low population accounts for about 55% of all breast cancers. Previously, low HER2 expression levels were considered HER2-negative in clinical practice because HER2-targeted therapies had been considered ineffective in this setting. Patients with HER2-low disease therefore had limited targeted treatment options after progression on their primary therapy.

Now, new studies and clinical trials have opened the door to effective treatments for this cohort of patients. The clinical trial DESTINY-Breast04, which was presented at ASCO 2022, led to the first FDA approval in August 2022 of a targeted therapy option for patients with HER2-low breast cancer subtypes, reclassifying this cohort as a new targetable subset in breast cancer.

DESTINY-Breast04 was the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefits for patients with HER2-low metastatic breast cancer, not only patients with HER2-positive disease. The phase 3 study enrolled about 557 patients with hormone receptor (HR)-negative or -positive breast cancer and centrally confirmed HER2-low expression who were previously treated with 1 or 2 prior lines of chemotherapy. Patients were randomized to receive either the antibody–drug conjugate trastuzumab deruxtecan or physician’s choice of standard chemotherapy. The risk of disease progression was about 50% lower and the risk of death was about 36% lower with trastuzumab deruxtecan compared with chemotherapy.¹

These impressive and practice-changing results opened the door to a new treatment option for a substantial group of patients with HER2-low disease and significantly expanded the population of patients who can benefit from HER2-targeted therapy.

What molecular characteristics do you take into consideration to help determine whether patients are eligible for these targeted treatment options?

Dr. Abdou: As we said earlier, HER2 status should no longer be recorded as a binary result of either HER2-positive or HER2-negative. It is important to start routinely testing for the level of HER2 expression in the tumor. Obtaining these levels is done through commonly used immunohistochemical (IHC) assays that allow direct visualization of the HER2 protein. Breast tumors considered to be HER2-low are classified as IHC1+ or as IHC2+ with in situ hybridization or FISH-negative status.

HER2-low breast cancer consists of a heterogeneous group of breast cancers, most of which are HR-positive tumors, whereas about 20% are HR-negative tumors. While these tumors may have distinct molecular profiles leading to clinicopathological and prognostic differences within these groups—HR-positive tumors represent more luminal subtypes and HR-negative tumors tend to be predominantly basal-like subtypes—these distinctions do not necessarily affect patient eligibility for targeted therapy. The benefit of trastuzumab deruxtecan was seen in both subgroups, although the HR-positive population was much more well represented in the DESTINY-Breast04 study.

Other than the HER2 expression status, I also take into consideration the presence of clinical comorbidities, particularly pulmonary comorbidities or prior lung injuries. Trastuzumab deruxtecan can cause a potentially serious type of lung toxicity called interstitial lung disease (ILD). In DESTINY-Breast04, ILD developed in about 12% of patients in the trastuzumab deruxtecan group, with 3 deaths as a result.

Therefore, it’s important for us to carefully select these patients and closely monitor them while they’re on treatment.

What is next in the treatment of HER2-low breast cancer, and what would you like to see in the future?

Dr. Abdou: The exciting new field of HER2-low breast cancer has really opened the door to novel studies and clinical trials, several of which are exploring the role of antibody–drug conjugates in patients with metastatic HER2-low disease and others that are studying early-stage HER2-low breast cancer. In early-stage HER2-low breast cancer, we may potentially see an even greater benefit with these drugs because the disease has not yet developed resistance to therapy. Other studies are examining the role of combination therapy in metastatic breast cancer, such as antibody–drug conjugates in combination with immunotherapy and other targeted agents. I look forward to results from those studies.

Also, importantly, as we start using these therapies more widely, I would like to see more accurate and sensitive ways of assessing the HER2 expression status. The current IHC assay, although widely available, fails to identify many women who have HER2 expression in their tumors. I think more sensitive tests may be able to identify even more women who can benefit from these targeted therapies.

Can you talk about the evolution and treatment of human epidermal growth factor receptor 2 (HER2)-low breast cancer?

Dr. Abdou: Until recently, HER2 status had been defined as a positive or negative result, but this convention has evolved, and now a newly defined population with low levels of HER2 expression has been identified. This HER2-low population accounts for about 55% of all breast cancers. Previously, low HER2 expression levels were considered HER2-negative in clinical practice because HER2-targeted therapies had been considered ineffective in this setting. Patients with HER2-low disease therefore had limited targeted treatment options after progression on their primary therapy.

Now, new studies and clinical trials have opened the door to effective treatments for this cohort of patients. The clinical trial DESTINY-Breast04, which was presented at ASCO 2022, led to the first FDA approval in August 2022 of a targeted therapy option for patients with HER2-low breast cancer subtypes, reclassifying this cohort as a new targetable subset in breast cancer.

DESTINY-Breast04 was the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefits for patients with HER2-low metastatic breast cancer, not only patients with HER2-positive disease. The phase 3 study enrolled about 557 patients with hormone receptor (HR)-negative or -positive breast cancer and centrally confirmed HER2-low expression who were previously treated with 1 or 2 prior lines of chemotherapy. Patients were randomized to receive either the antibody–drug conjugate trastuzumab deruxtecan or physician’s choice of standard chemotherapy. The risk of disease progression was about 50% lower and the risk of death was about 36% lower with trastuzumab deruxtecan compared with chemotherapy.¹

These impressive and practice-changing results opened the door to a new treatment option for a substantial group of patients with HER2-low disease and significantly expanded the population of patients who can benefit from HER2-targeted therapy.

What molecular characteristics do you take into consideration to help determine whether patients are eligible for these targeted treatment options?

Dr. Abdou: As we said earlier, HER2 status should no longer be recorded as a binary result of either HER2-positive or HER2-negative. It is important to start routinely testing for the level of HER2 expression in the tumor. Obtaining these levels is done through commonly used immunohistochemical (IHC) assays that allow direct visualization of the HER2 protein. Breast tumors considered to be HER2-low are classified as IHC1+ or as IHC2+ with in situ hybridization or FISH-negative status.

HER2-low breast cancer consists of a heterogeneous group of breast cancers, most of which are HR-positive tumors, whereas about 20% are HR-negative tumors. While these tumors may have distinct molecular profiles leading to clinicopathological and prognostic differences within these groups—HR-positive tumors represent more luminal subtypes and HR-negative tumors tend to be predominantly basal-like subtypes—these distinctions do not necessarily affect patient eligibility for targeted therapy. The benefit of trastuzumab deruxtecan was seen in both subgroups, although the HR-positive population was much more well represented in the DESTINY-Breast04 study.

Other than the HER2 expression status, I also take into consideration the presence of clinical comorbidities, particularly pulmonary comorbidities or prior lung injuries. Trastuzumab deruxtecan can cause a potentially serious type of lung toxicity called interstitial lung disease (ILD). In DESTINY-Breast04, ILD developed in about 12% of patients in the trastuzumab deruxtecan group, with 3 deaths as a result.

Therefore, it’s important for us to carefully select these patients and closely monitor them while they’re on treatment.

What is next in the treatment of HER2-low breast cancer, and what would you like to see in the future?

Dr. Abdou: The exciting new field of HER2-low breast cancer has really opened the door to novel studies and clinical trials, several of which are exploring the role of antibody–drug conjugates in patients with metastatic HER2-low disease and others that are studying early-stage HER2-low breast cancer. In early-stage HER2-low breast cancer, we may potentially see an even greater benefit with these drugs because the disease has not yet developed resistance to therapy. Other studies are examining the role of combination therapy in metastatic breast cancer, such as antibody–drug conjugates in combination with immunotherapy and other targeted agents. I look forward to results from those studies.

Also, importantly, as we start using these therapies more widely, I would like to see more accurate and sensitive ways of assessing the HER2 expression status. The current IHC assay, although widely available, fails to identify many women who have HER2 expression in their tumors. I think more sensitive tests may be able to identify even more women who can benefit from these targeted therapies.

Can you talk about the evolution and treatment of human epidermal growth factor receptor 2 (HER2)-low breast cancer?

Dr. Abdou: Until recently, HER2 status had been defined as a positive or negative result, but this convention has evolved, and now a newly defined population with low levels of HER2 expression has been identified. This HER2-low population accounts for about 55% of all breast cancers. Previously, low HER2 expression levels were considered HER2-negative in clinical practice because HER2-targeted therapies had been considered ineffective in this setting. Patients with HER2-low disease therefore had limited targeted treatment options after progression on their primary therapy.

Now, new studies and clinical trials have opened the door to effective treatments for this cohort of patients. The clinical trial DESTINY-Breast04, which was presented at ASCO 2022, led to the first FDA approval in August 2022 of a targeted therapy option for patients with HER2-low breast cancer subtypes, reclassifying this cohort as a new targetable subset in breast cancer.

DESTINY-Breast04 was the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefits for patients with HER2-low metastatic breast cancer, not only patients with HER2-positive disease. The phase 3 study enrolled about 557 patients with hormone receptor (HR)-negative or -positive breast cancer and centrally confirmed HER2-low expression who were previously treated with 1 or 2 prior lines of chemotherapy. Patients were randomized to receive either the antibody–drug conjugate trastuzumab deruxtecan or physician’s choice of standard chemotherapy. The risk of disease progression was about 50% lower and the risk of death was about 36% lower with trastuzumab deruxtecan compared with chemotherapy.¹

These impressive and practice-changing results opened the door to a new treatment option for a substantial group of patients with HER2-low disease and significantly expanded the population of patients who can benefit from HER2-targeted therapy.

What molecular characteristics do you take into consideration to help determine whether patients are eligible for these targeted treatment options?

Dr. Abdou: As we said earlier, HER2 status should no longer be recorded as a binary result of either HER2-positive or HER2-negative. It is important to start routinely testing for the level of HER2 expression in the tumor. Obtaining these levels is done through commonly used immunohistochemical (IHC) assays that allow direct visualization of the HER2 protein. Breast tumors considered to be HER2-low are classified as IHC1+ or as IHC2+ with in situ hybridization or FISH-negative status.

HER2-low breast cancer consists of a heterogeneous group of breast cancers, most of which are HR-positive tumors, whereas about 20% are HR-negative tumors. While these tumors may have distinct molecular profiles leading to clinicopathological and prognostic differences within these groups—HR-positive tumors represent more luminal subtypes and HR-negative tumors tend to be predominantly basal-like subtypes—these distinctions do not necessarily affect patient eligibility for targeted therapy. The benefit of trastuzumab deruxtecan was seen in both subgroups, although the HR-positive population was much more well represented in the DESTINY-Breast04 study.

Other than the HER2 expression status, I also take into consideration the presence of clinical comorbidities, particularly pulmonary comorbidities or prior lung injuries. Trastuzumab deruxtecan can cause a potentially serious type of lung toxicity called interstitial lung disease (ILD). In DESTINY-Breast04, ILD developed in about 12% of patients in the trastuzumab deruxtecan group, with 3 deaths as a result.

Therefore, it’s important for us to carefully select these patients and closely monitor them while they’re on treatment.

What is next in the treatment of HER2-low breast cancer, and what would you like to see in the future?

Dr. Abdou: The exciting new field of HER2-low breast cancer has really opened the door to novel studies and clinical trials, several of which are exploring the role of antibody–drug conjugates in patients with metastatic HER2-low disease and others that are studying early-stage HER2-low breast cancer. In early-stage HER2-low breast cancer, we may potentially see an even greater benefit with these drugs because the disease has not yet developed resistance to therapy. Other studies are examining the role of combination therapy in metastatic breast cancer, such as antibody–drug conjugates in combination with immunotherapy and other targeted agents. I look forward to results from those studies.

Also, importantly, as we start using these therapies more widely, I would like to see more accurate and sensitive ways of assessing the HER2 expression status. The current IHC assay, although widely available, fails to identify many women who have HER2 expression in their tumors. I think more sensitive tests may be able to identify even more women who can benefit from these targeted therapies.