Neil Osterweil

A newly identified circulating cell type may be a reliable marker for impending RA flares. The discovery and description of the cells, which bear a “striking” similarity to synovial fibroblasts, provide important clues to the origins of RA and progressive joint inflammation, investigators say.

By studying longitudinally collected blood samples from four patients with RA over 4 years, Dana E. Orange, MD and colleagues at Rockefeller University, New York, identified a pattern of B-cell activation and expansion of circulating cells that are negative for CD45 and CD31 expression, and positive for PDPN, dubbed preinflammatory mesenchymal or “PRIME” cells.

Expansion of PRIME cells in circulation increased dramatically in the weeks leading up to a flare and decreased during a flare, suggesting the possibility of a serum assay for predicting flares and allowing for early intervention to ameliorate or prevent disabling consequences, the investigators wrote in a study published in the New England Journal of Medicine.

“Our hope is that this will be a diagnostic in the future, but we need to study it in more patients to see how it will perform,” Dr. Orange said in an interview, adding that the cells, if shown to be pathogenic, could also be targets for new therapeutic strategies.
 

RNA sequencing

Dr. Orange and colleagues discovered the PRIME cells through a novel clinical and technical protocol involving home collection of blood by patients and longitudinal RNA sequencing to study gene expression profiles during times of both disease quiescence and flares, and noticed a distinct pattern of PRIME cell expansion, depletion, and gene expression.

“Looking at their gene expression profiles, they overlapped with fibroblasts that reside in inflamed rheumatoid arthritis synovium, and in an animal model those types of fibroblasts were important for allowing entry of inflammatory infiltrates around the joint,” she said.

PRIME cells may be a precursor of synovial fibroblasts, which have been implicated by some researchers in the spread of RA between joints, Dr. Orange added.

Patients do homework

The investigators began by enrolling four patients, followed for 1-4 years, who met 2010 American College of Rheumatology–European League Against Rheumatism criteria and who were seropositive for anti–cyclic citrullinated peptide antibodies.

They assessed disease activity from patient homes weekly or during escalation of flares up to four times daily, with the Routine Assessment of Patient Index Data 3 (RAPID3) questionnaire, as well as monthly clinic visits. At clinic visits during flares, disease activity was assessed using both the RAPID3 and 28-joint Disease Activity Score.

The patients performed fingerstick blood collection and mailed the samples overnight each week to Rockefeller University, where RNA was extracted and sequenced. The investigators identified gene transcripts that were differentially expressed in blood prior to flares, and compared them with data profiles derived from synovial single-cell RNA sequencing.

To validate the findings, the researchers used flow cytometry and sorted blood-cell RNA sequencing of samples from an additional 19 patients with RA.

They found that a total of 2,613 genes were differentially expressed during a flare, compared with baseline, and that expression of 1,437 of these genes was increased during a flare, with the remaining 1,176 decreased during flares.
 

Before the storm

Focusing on two flare-antecedent clusters of genes, they identified one cluster of transcripts that increased 2 weeks before a flare, enriched with genes coding for developmental pathways for naive B cells (that is, not yet exposed to antigens) and leukocytes.

The second cluster included gene transcripts that increased during the week before a flare, then decreased over the duration of the flare. Genes in this cluster were enriched for pathways that were unexpected in typical blood specimens, including genes involved in cartilage morphogenesis, endochondral bone growth, and extracellular matrix organization. The gene activity suggested the presence of a mesenchymal cell, they wrote.

The RNA expression profiles of these newly identified PRIME cells were very similar to those of synovial fibroblasts, and the investigators speculated that PRIME cells may be synovial fibroblast precursors.

They proposed a model of RA exacerbation in which PRIME cells become activated by B cells in the weeks immediately preceding a flare, and then migrate out of blood into the synovium.

The investigators are currently investigating “how reproducible this signature is in different flares in patients on different types of background therapy, and then we’re very interested in looking at the upstream triggers of the B cell and the PRIME cell,” Dr. Orange said.

“One of the reasons this is very exciting is that there are these signatures that can be found when patients are clearly asymptomatic but about to flare, and if we can intervene at that time, then the patients won’t have to live through a flare, they won’t have to have that experience,” she said.
 

Pros and cons

In an editorial accompanying the study, Ellen M. Gravallese, MD, from Brigham and Women’s Hospital in Boston and William H. Robinson, MD, PhD, from Stanford (Calif.) University and the Veterans Affairs Palo Alto (Calif.) Health Care System wrote that the study demonstrates an important method for identifying genetic contributions to many different types of disease.

“Orange and colleagues show that intensively collected longitudinal data from a small sample of patients can be used to identify dysregulated transcriptional signatures that are not recognized by classical cross-sectional studies. This study illustrates the exciting potential of longitudinal genomics to identify key antecedents of disease flares in an approach that may be applicable to the investigation of pathogenic and protective immune responses in a wide range of human diseases,” they wrote.

Rheumatology researcher Christopher D. Buckley, MBBS, DPhil, from the University of Birmingham (England), who was not involved in the study, said that the use of blood samples is both a strength and a weakness of the study.

“Blood is much easier to get than synovial tissue, but synovial tissue is important. If I’m trying to look at the blood and trying to make an inference about what’s going on in the synovium, if I don’t look at the synovium I don’t know what the link between the blood and synovium is,” he said in an interview.

On the plus side, “the big advantage about looking at blood is that you do multiple time points, which is really cool,” he said.

Dr. Buckley is a coauthor of a recent paper in Nature Medicine – published after the study by Dr. Orange and colleagues was accepted by the New England Journal of Medicine – showing that a population of macrophages in synovium was highly predictive of remission in patients with RA, and that therapeutic modulation of these macrophages has the potential as a treatment strategy for RA.

“We are very keen to understand the cellular basis of disease. We’re very good at understanding genes, but genes have to work in cells, and cells make organs, so the cells are critical,” he said.

The paper adds fuel to a controversy that has been raging among rheumatology researchers for more than a decade: the “flying fibroblast” hypothesis, which suggests that fibroblasts can migrate from one joint to another, hence spreading the disease in a manner akin to cancer metastases.

“It’s been quite controversial whether these cells like fibroblasts can exist in the blood, or whether they’re found in sufficient number in the blood,” Dr. Buckley said. “The fact that they have identified these PRIME cells is fascinating, because that’s going to cause us to go back and reinvestigate the whole flying fibroblast story.”

His colleague John Isaacs, MBBS, PhD, from Newcastle (England) University, is principal investigator for the BIO-FLARE study, in which participants with RA stop taking their disease-modifying antirheumatic drugs under close supervision of researchers. The investigators then study the patients looking for flare signals as well as the biology of flares themselves.

“As it happens, our protocols would not pick up this particular cell, because we have not been focusing on the stroma, at least not in peripheral blood. We’ve all been looking at synovium as part of BIO-FLARE,” he said in an interview. “We will be looking for this cell now that we have seen this research, and certainly we would want to replicate.”

He agreed with Dr. Buckley’s observation that the PRIME cell data may revive the flying fibroblast hypothesis. “This is a great paper in a top clinical journal. What isn’t there is mechanism. That’s the thing we’re all going to want to understand now: Where do the cells come from, how do they actually trigger flares, and how do they go down as flare starts?”

Both Dr. Buckley and Dr. Isaacs agreed that the study findings point to important new avenues of research, but also noted that the study was small, involving a total of only 23 patients, and that replication of the findings and elucidation of the mechanism of PRIME cell generation and disposition will be required.

The study was supported by grants from the National Institutes of Health, Simons Foundation, Robertson Foundation, Rheumatology Research Foundation, Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and Rockefeller University. Dr. Orange disclosed a provisional patent for the discovery of the PRIME cells. Dr. Buckley and Dr. Isaacs reported no relevant conflicts of interest.

SOURCE: Orange DE et al. N Engl J Med. 2020 Jul 15. doi: 10.1056/NEJMoa2004114.

A newly identified circulating cell type may be a reliable marker for impending RA flares. The discovery and description of the cells, which bear a “striking” similarity to synovial fibroblasts, provide important clues to the origins of RA and progressive joint inflammation, investigators say.

By studying longitudinally collected blood samples from four patients with RA over 4 years, Dana E. Orange, MD and colleagues at Rockefeller University, New York, identified a pattern of B-cell activation and expansion of circulating cells that are negative for CD45 and CD31 expression, and positive for PDPN, dubbed preinflammatory mesenchymal or “PRIME” cells.

Expansion of PRIME cells in circulation increased dramatically in the weeks leading up to a flare and decreased during a flare, suggesting the possibility of a serum assay for predicting flares and allowing for early intervention to ameliorate or prevent disabling consequences, the investigators wrote in a study published in the New England Journal of Medicine.

“Our hope is that this will be a diagnostic in the future, but we need to study it in more patients to see how it will perform,” Dr. Orange said in an interview, adding that the cells, if shown to be pathogenic, could also be targets for new therapeutic strategies.
 

RNA sequencing

Dr. Orange and colleagues discovered the PRIME cells through a novel clinical and technical protocol involving home collection of blood by patients and longitudinal RNA sequencing to study gene expression profiles during times of both disease quiescence and flares, and noticed a distinct pattern of PRIME cell expansion, depletion, and gene expression.

“Looking at their gene expression profiles, they overlapped with fibroblasts that reside in inflamed rheumatoid arthritis synovium, and in an animal model those types of fibroblasts were important for allowing entry of inflammatory infiltrates around the joint,” she said.

PRIME cells may be a precursor of synovial fibroblasts, which have been implicated by some researchers in the spread of RA between joints, Dr. Orange added.

Patients do homework

The investigators began by enrolling four patients, followed for 1-4 years, who met 2010 American College of Rheumatology–European League Against Rheumatism criteria and who were seropositive for anti–cyclic citrullinated peptide antibodies.

They assessed disease activity from patient homes weekly or during escalation of flares up to four times daily, with the Routine Assessment of Patient Index Data 3 (RAPID3) questionnaire, as well as monthly clinic visits. At clinic visits during flares, disease activity was assessed using both the RAPID3 and 28-joint Disease Activity Score.

The patients performed fingerstick blood collection and mailed the samples overnight each week to Rockefeller University, where RNA was extracted and sequenced. The investigators identified gene transcripts that were differentially expressed in blood prior to flares, and compared them with data profiles derived from synovial single-cell RNA sequencing.

To validate the findings, the researchers used flow cytometry and sorted blood-cell RNA sequencing of samples from an additional 19 patients with RA.

They found that a total of 2,613 genes were differentially expressed during a flare, compared with baseline, and that expression of 1,437 of these genes was increased during a flare, with the remaining 1,176 decreased during flares.
 

Before the storm

Focusing on two flare-antecedent clusters of genes, they identified one cluster of transcripts that increased 2 weeks before a flare, enriched with genes coding for developmental pathways for naive B cells (that is, not yet exposed to antigens) and leukocytes.

The second cluster included gene transcripts that increased during the week before a flare, then decreased over the duration of the flare. Genes in this cluster were enriched for pathways that were unexpected in typical blood specimens, including genes involved in cartilage morphogenesis, endochondral bone growth, and extracellular matrix organization. The gene activity suggested the presence of a mesenchymal cell, they wrote.

The RNA expression profiles of these newly identified PRIME cells were very similar to those of synovial fibroblasts, and the investigators speculated that PRIME cells may be synovial fibroblast precursors.

They proposed a model of RA exacerbation in which PRIME cells become activated by B cells in the weeks immediately preceding a flare, and then migrate out of blood into the synovium.

The investigators are currently investigating “how reproducible this signature is in different flares in patients on different types of background therapy, and then we’re very interested in looking at the upstream triggers of the B cell and the PRIME cell,” Dr. Orange said.

“One of the reasons this is very exciting is that there are these signatures that can be found when patients are clearly asymptomatic but about to flare, and if we can intervene at that time, then the patients won’t have to live through a flare, they won’t have to have that experience,” she said.
 

Pros and cons

In an editorial accompanying the study, Ellen M. Gravallese, MD, from Brigham and Women’s Hospital in Boston and William H. Robinson, MD, PhD, from Stanford (Calif.) University and the Veterans Affairs Palo Alto (Calif.) Health Care System wrote that the study demonstrates an important method for identifying genetic contributions to many different types of disease.

“Orange and colleagues show that intensively collected longitudinal data from a small sample of patients can be used to identify dysregulated transcriptional signatures that are not recognized by classical cross-sectional studies. This study illustrates the exciting potential of longitudinal genomics to identify key antecedents of disease flares in an approach that may be applicable to the investigation of pathogenic and protective immune responses in a wide range of human diseases,” they wrote.

Rheumatology researcher Christopher D. Buckley, MBBS, DPhil, from the University of Birmingham (England), who was not involved in the study, said that the use of blood samples is both a strength and a weakness of the study.

“Blood is much easier to get than synovial tissue, but synovial tissue is important. If I’m trying to look at the blood and trying to make an inference about what’s going on in the synovium, if I don’t look at the synovium I don’t know what the link between the blood and synovium is,” he said in an interview.

On the plus side, “the big advantage about looking at blood is that you do multiple time points, which is really cool,” he said.

Dr. Buckley is a coauthor of a recent paper in Nature Medicine – published after the study by Dr. Orange and colleagues was accepted by the New England Journal of Medicine – showing that a population of macrophages in synovium was highly predictive of remission in patients with RA, and that therapeutic modulation of these macrophages has the potential as a treatment strategy for RA.

“We are very keen to understand the cellular basis of disease. We’re very good at understanding genes, but genes have to work in cells, and cells make organs, so the cells are critical,” he said.

The paper adds fuel to a controversy that has been raging among rheumatology researchers for more than a decade: the “flying fibroblast” hypothesis, which suggests that fibroblasts can migrate from one joint to another, hence spreading the disease in a manner akin to cancer metastases.

“It’s been quite controversial whether these cells like fibroblasts can exist in the blood, or whether they’re found in sufficient number in the blood,” Dr. Buckley said. “The fact that they have identified these PRIME cells is fascinating, because that’s going to cause us to go back and reinvestigate the whole flying fibroblast story.”

His colleague John Isaacs, MBBS, PhD, from Newcastle (England) University, is principal investigator for the BIO-FLARE study, in which participants with RA stop taking their disease-modifying antirheumatic drugs under close supervision of researchers. The investigators then study the patients looking for flare signals as well as the biology of flares themselves.

“As it happens, our protocols would not pick up this particular cell, because we have not been focusing on the stroma, at least not in peripheral blood. We’ve all been looking at synovium as part of BIO-FLARE,” he said in an interview. “We will be looking for this cell now that we have seen this research, and certainly we would want to replicate.”

He agreed with Dr. Buckley’s observation that the PRIME cell data may revive the flying fibroblast hypothesis. “This is a great paper in a top clinical journal. What isn’t there is mechanism. That’s the thing we’re all going to want to understand now: Where do the cells come from, how do they actually trigger flares, and how do they go down as flare starts?”

Both Dr. Buckley and Dr. Isaacs agreed that the study findings point to important new avenues of research, but also noted that the study was small, involving a total of only 23 patients, and that replication of the findings and elucidation of the mechanism of PRIME cell generation and disposition will be required.

The study was supported by grants from the National Institutes of Health, Simons Foundation, Robertson Foundation, Rheumatology Research Foundation, Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and Rockefeller University. Dr. Orange disclosed a provisional patent for the discovery of the PRIME cells. Dr. Buckley and Dr. Isaacs reported no relevant conflicts of interest.

SOURCE: Orange DE et al. N Engl J Med. 2020 Jul 15. doi: 10.1056/NEJMoa2004114.

A newly identified circulating cell type may be a reliable marker for impending RA flares. The discovery and description of the cells, which bear a “striking” similarity to synovial fibroblasts, provide important clues to the origins of RA and progressive joint inflammation, investigators say.

By studying longitudinally collected blood samples from four patients with RA over 4 years, Dana E. Orange, MD and colleagues at Rockefeller University, New York, identified a pattern of B-cell activation and expansion of circulating cells that are negative for CD45 and CD31 expression, and positive for PDPN, dubbed preinflammatory mesenchymal or “PRIME” cells.

Expansion of PRIME cells in circulation increased dramatically in the weeks leading up to a flare and decreased during a flare, suggesting the possibility of a serum assay for predicting flares and allowing for early intervention to ameliorate or prevent disabling consequences, the investigators wrote in a study published in the New England Journal of Medicine.

“Our hope is that this will be a diagnostic in the future, but we need to study it in more patients to see how it will perform,” Dr. Orange said in an interview, adding that the cells, if shown to be pathogenic, could also be targets for new therapeutic strategies.
 

RNA sequencing

Dr. Orange and colleagues discovered the PRIME cells through a novel clinical and technical protocol involving home collection of blood by patients and longitudinal RNA sequencing to study gene expression profiles during times of both disease quiescence and flares, and noticed a distinct pattern of PRIME cell expansion, depletion, and gene expression.

“Looking at their gene expression profiles, they overlapped with fibroblasts that reside in inflamed rheumatoid arthritis synovium, and in an animal model those types of fibroblasts were important for allowing entry of inflammatory infiltrates around the joint,” she said.

PRIME cells may be a precursor of synovial fibroblasts, which have been implicated by some researchers in the spread of RA between joints, Dr. Orange added.

Patients do homework

The investigators began by enrolling four patients, followed for 1-4 years, who met 2010 American College of Rheumatology–European League Against Rheumatism criteria and who were seropositive for anti–cyclic citrullinated peptide antibodies.

They assessed disease activity from patient homes weekly or during escalation of flares up to four times daily, with the Routine Assessment of Patient Index Data 3 (RAPID3) questionnaire, as well as monthly clinic visits. At clinic visits during flares, disease activity was assessed using both the RAPID3 and 28-joint Disease Activity Score.

The patients performed fingerstick blood collection and mailed the samples overnight each week to Rockefeller University, where RNA was extracted and sequenced. The investigators identified gene transcripts that were differentially expressed in blood prior to flares, and compared them with data profiles derived from synovial single-cell RNA sequencing.

To validate the findings, the researchers used flow cytometry and sorted blood-cell RNA sequencing of samples from an additional 19 patients with RA.

They found that a total of 2,613 genes were differentially expressed during a flare, compared with baseline, and that expression of 1,437 of these genes was increased during a flare, with the remaining 1,176 decreased during flares.
 

Before the storm

Focusing on two flare-antecedent clusters of genes, they identified one cluster of transcripts that increased 2 weeks before a flare, enriched with genes coding for developmental pathways for naive B cells (that is, not yet exposed to antigens) and leukocytes.

The second cluster included gene transcripts that increased during the week before a flare, then decreased over the duration of the flare. Genes in this cluster were enriched for pathways that were unexpected in typical blood specimens, including genes involved in cartilage morphogenesis, endochondral bone growth, and extracellular matrix organization. The gene activity suggested the presence of a mesenchymal cell, they wrote.

The RNA expression profiles of these newly identified PRIME cells were very similar to those of synovial fibroblasts, and the investigators speculated that PRIME cells may be synovial fibroblast precursors.

They proposed a model of RA exacerbation in which PRIME cells become activated by B cells in the weeks immediately preceding a flare, and then migrate out of blood into the synovium.

The investigators are currently investigating “how reproducible this signature is in different flares in patients on different types of background therapy, and then we’re very interested in looking at the upstream triggers of the B cell and the PRIME cell,” Dr. Orange said.

“One of the reasons this is very exciting is that there are these signatures that can be found when patients are clearly asymptomatic but about to flare, and if we can intervene at that time, then the patients won’t have to live through a flare, they won’t have to have that experience,” she said.
 

Pros and cons

In an editorial accompanying the study, Ellen M. Gravallese, MD, from Brigham and Women’s Hospital in Boston and William H. Robinson, MD, PhD, from Stanford (Calif.) University and the Veterans Affairs Palo Alto (Calif.) Health Care System wrote that the study demonstrates an important method for identifying genetic contributions to many different types of disease.

“Orange and colleagues show that intensively collected longitudinal data from a small sample of patients can be used to identify dysregulated transcriptional signatures that are not recognized by classical cross-sectional studies. This study illustrates the exciting potential of longitudinal genomics to identify key antecedents of disease flares in an approach that may be applicable to the investigation of pathogenic and protective immune responses in a wide range of human diseases,” they wrote.

Rheumatology researcher Christopher D. Buckley, MBBS, DPhil, from the University of Birmingham (England), who was not involved in the study, said that the use of blood samples is both a strength and a weakness of the study.

“Blood is much easier to get than synovial tissue, but synovial tissue is important. If I’m trying to look at the blood and trying to make an inference about what’s going on in the synovium, if I don’t look at the synovium I don’t know what the link between the blood and synovium is,” he said in an interview.

On the plus side, “the big advantage about looking at blood is that you do multiple time points, which is really cool,” he said.

Dr. Buckley is a coauthor of a recent paper in Nature Medicine – published after the study by Dr. Orange and colleagues was accepted by the New England Journal of Medicine – showing that a population of macrophages in synovium was highly predictive of remission in patients with RA, and that therapeutic modulation of these macrophages has the potential as a treatment strategy for RA.

“We are very keen to understand the cellular basis of disease. We’re very good at understanding genes, but genes have to work in cells, and cells make organs, so the cells are critical,” he said.

The paper adds fuel to a controversy that has been raging among rheumatology researchers for more than a decade: the “flying fibroblast” hypothesis, which suggests that fibroblasts can migrate from one joint to another, hence spreading the disease in a manner akin to cancer metastases.

“It’s been quite controversial whether these cells like fibroblasts can exist in the blood, or whether they’re found in sufficient number in the blood,” Dr. Buckley said. “The fact that they have identified these PRIME cells is fascinating, because that’s going to cause us to go back and reinvestigate the whole flying fibroblast story.”

His colleague John Isaacs, MBBS, PhD, from Newcastle (England) University, is principal investigator for the BIO-FLARE study, in which participants with RA stop taking their disease-modifying antirheumatic drugs under close supervision of researchers. The investigators then study the patients looking for flare signals as well as the biology of flares themselves.

“As it happens, our protocols would not pick up this particular cell, because we have not been focusing on the stroma, at least not in peripheral blood. We’ve all been looking at synovium as part of BIO-FLARE,” he said in an interview. “We will be looking for this cell now that we have seen this research, and certainly we would want to replicate.”

He agreed with Dr. Buckley’s observation that the PRIME cell data may revive the flying fibroblast hypothesis. “This is a great paper in a top clinical journal. What isn’t there is mechanism. That’s the thing we’re all going to want to understand now: Where do the cells come from, how do they actually trigger flares, and how do they go down as flare starts?”

Both Dr. Buckley and Dr. Isaacs agreed that the study findings point to important new avenues of research, but also noted that the study was small, involving a total of only 23 patients, and that replication of the findings and elucidation of the mechanism of PRIME cell generation and disposition will be required.

The study was supported by grants from the National Institutes of Health, Simons Foundation, Robertson Foundation, Rheumatology Research Foundation, Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and Rockefeller University. Dr. Orange disclosed a provisional patent for the discovery of the PRIME cells. Dr. Buckley and Dr. Isaacs reported no relevant conflicts of interest.

SOURCE: Orange DE et al. N Engl J Med. 2020 Jul 15. doi: 10.1056/NEJMoa2004114.

A bus converted into a mobile CT screening unit has been reaching high-risk individuals in underserved rural counties in Appalachian areas who may have otherwise not had a chance to be screened for lung cancer.

Results from a pilot study, published online July 13 in The Annals of Thoracic Surgery, show that the scheme is both practical and financially sustainable.

During a 10-month test run, the mobile unit screened 548 individuals at 104 sites. Five lung cancers (four of which were early stage) and a type B thymoma were discovered, and all of these individuals went on to have treatment.

Significant pulmonary findings were also discovered in 52 individuals, who were advised to undergo further testing, as well as significant nonpulmonary findings in 152 individuals (of whom 13 required further testing, but none went on to have treatment). These findings included severe coronary disease and thyroid abnormalities.

The bus reached the estimated financial break-even point of 428 scans, but future economic viability of such a program will likely rely on additional revenue from the treatment of patients with incidental findings from low-dose CT screens, acknowledged the authors, led by James R. Headrick Jr, MD, MBA, from the University of Tennessee College of Medicine in Chattanooga.

The real value of the Breathe Easy program, however, comes from bringing both patient education and lung cancer screening services to a high-risk population who might otherwise be overlooked, Headrick said in an interview with Medscape Medical News.

“We were all excited when lung screening was approved, and we got the recommendation from the United States Preventive Services Task Force [USPSTF], and the Centers for Medicare & Medicaid Services signed off on it, and we sat in our offices and clinics and hospitals — and nobody showed up. We were thinking, ‘Wow, we have this simple test, the easiest screening tool in the world, and nobody’s coming,’ “ he said.

“There was certainly an educational issue that needed to be solved,” he continued, “but we were also dealing with a population that had been told that if they smoked and didn’t live life well, there was a 100% chance they were going to get lung cancer and die,” he said.

The individuals screened in the program were very heavy smokers.

The mean pack-years of smoking was 41 — 11 pack-years higher than the minimum recommended under current lung cancer screening guidelines, and 21 pack-years higher than that recently recommended under proposed low-dose CT screening guidelines by the USPSTF.  

Albert Rizzo, MD, chief medical officer for the American Lung Association, who was not involved in the study, told Medscape Medical News any initiative that can expand lung cancer screening is welcome, particularly when a program may be self-sustaining.

“The interesting part of this article included the downstream revenue to help make something like this viable,” Rizzo said. “Just doing the scans is probably not going to cover the cost of the mobile unit itself, but if you take into account that other things are being found in addition to lung cancer, such as coronary abnormalities, then it becomes more cost-effective, especially if those patients are then treated at the site where the mobile unit is coming from,” he said.
 

Starting at square one

The first mobile CT scanner was launched in Nagano Prefecture, a rural area in Japan, in 1996. Since then, mobile screening units, primarily mounted on tractor trailers, have brought screening to centralized areas, such as shopping mall parking lots. The Levine Cancer Institute in Charlotte, North Carolina, also has a mobile CT-screening unit mounted in a modified box truck.

For Headrick and colleagues the goal was not to reinvent the wheel, but to see if a mobile lung cancer screening program could improve access and also pay for itself in a time of parsimonious support for preventive medicine.

Their first challenge was the mobile unit itself.

“CT scanners are sensitive, complex electrical machines that require climate control and a level environment to operate. Historically, they have been placed in tractor trailers and parked on level concrete slabs connected to external power supplies. We needed mobility, self-leveling, independent power, climate control, patient comfort, and drivability,” they wrote.

They assembled a team of engineers from CT and vehicle makers, and input was also provided by a thoracic surgeon, pulmonologist, radiologist, CT technician, and driver with a commercial driver’s license. Together, they designed and built the bus over 8 months. Funds for the total cost of the prototype vehicle ($650,000) came from two local nonprofit foundations. The estimated cost for a commercial version of the same vehicle was $850,000.

The Breathe Easy pilot began operation in early 2018, with the initial plan to drive the bus within a 2-hour radius of CHI Memorial Hospital, Chattanooga, Tennessee, to avoid overnight trips. The radius was later shortened to 1.5 hours when operators realized it was a burden for patients with significant screening findings to travel to as much as 4 hours (round trip) to Chattanooga for further testing.

Each screening visit takes about 15 minutes.
 

Cancer and other significant findings

As noted before, the bus traveled to 104 sites over 10 months, and 548 patients with a mean age of 62 were screened. Five lung cancers were identified, including two stage 1A, one stage 1A2, one stage 1B, and one stage 3A.

Two patients with early stage disease underwent stereotactic body radiation therapy, and two underwent minimally invasive surgery (a segmentectomy and a lobectomy). The patient with stage 3A disease underwent curative chemotherapy and radiation therapy. One patient with a type B1 thymoma underwent robotic-assisted thoracoscopic resection with en bloc pericardial resection and reconstruction.

A total of 51 patients had a significant pulmonary finding of Lung CT Screening Reporting and Data System (Lung-RADS) 3 or 4 and were advised to follow up with further testing, but 17 patients in this group did not pursue further testing. Of these 17 patients, 15 had been screened in a health clinic for the homeless at a rural site.

Significant nonpulmonary findings included moderate to severe coronary artery disease in 101 patients, abdominal findings in 15, thyroid abnormalities in 14, other thoracic findings in 10, and ascending aortic dilatation in 9. Of the 152 patients with nonpulmonary findings, only 13 required further testing and none required treatment.
 

Revisions, improvements, and priorities

The Breathe Easy bus has been in operation for more than 2 years, performing an average of approximately 100 screenings per month, with a goal of 200. The bus continued to operate throughout the COVID-19 pandemic because many patients viewed it as a safer alternative to a hospital visit, Headrick said.

Design changes planned to improve performance of the bus include a stronger chassis and structural components, as well as swapping out the 16-slice CT unit for a specially designed 64-slice mobile unit that can be operated with an iPad and provide gated coronary calcium scores.

When challenged about whether the cost of lung cancer screening is the best use of limited resources, Headrick said, “if it’s not, then when we need to go back to the drawing board and jump-start lung cancer screening.”

“When I spent a year in 2014-2015 trying to talk to radio stations, news stations, media, nobody really cared about lung cancer screening,” he said. “But as soon as I had this shiny object, which is the bus, which we labeled as the easiest and most valuable doctor visit, people had an interest.”

The pilot study was supported by local nonprofit foundations through the CHI Memorial Foundation.

This article first appeared on Medscape.com.

A bus converted into a mobile CT screening unit has been reaching high-risk individuals in underserved rural counties in Appalachian areas who may have otherwise not had a chance to be screened for lung cancer.

Results from a pilot study, published online July 13 in The Annals of Thoracic Surgery, show that the scheme is both practical and financially sustainable.

During a 10-month test run, the mobile unit screened 548 individuals at 104 sites. Five lung cancers (four of which were early stage) and a type B thymoma were discovered, and all of these individuals went on to have treatment.

Significant pulmonary findings were also discovered in 52 individuals, who were advised to undergo further testing, as well as significant nonpulmonary findings in 152 individuals (of whom 13 required further testing, but none went on to have treatment). These findings included severe coronary disease and thyroid abnormalities.

The bus reached the estimated financial break-even point of 428 scans, but future economic viability of such a program will likely rely on additional revenue from the treatment of patients with incidental findings from low-dose CT screens, acknowledged the authors, led by James R. Headrick Jr, MD, MBA, from the University of Tennessee College of Medicine in Chattanooga.

The real value of the Breathe Easy program, however, comes from bringing both patient education and lung cancer screening services to a high-risk population who might otherwise be overlooked, Headrick said in an interview with Medscape Medical News.

“We were all excited when lung screening was approved, and we got the recommendation from the United States Preventive Services Task Force [USPSTF], and the Centers for Medicare & Medicaid Services signed off on it, and we sat in our offices and clinics and hospitals — and nobody showed up. We were thinking, ‘Wow, we have this simple test, the easiest screening tool in the world, and nobody’s coming,’ “ he said.

“There was certainly an educational issue that needed to be solved,” he continued, “but we were also dealing with a population that had been told that if they smoked and didn’t live life well, there was a 100% chance they were going to get lung cancer and die,” he said.

The individuals screened in the program were very heavy smokers.

The mean pack-years of smoking was 41 — 11 pack-years higher than the minimum recommended under current lung cancer screening guidelines, and 21 pack-years higher than that recently recommended under proposed low-dose CT screening guidelines by the USPSTF.  

Albert Rizzo, MD, chief medical officer for the American Lung Association, who was not involved in the study, told Medscape Medical News any initiative that can expand lung cancer screening is welcome, particularly when a program may be self-sustaining.

“The interesting part of this article included the downstream revenue to help make something like this viable,” Rizzo said. “Just doing the scans is probably not going to cover the cost of the mobile unit itself, but if you take into account that other things are being found in addition to lung cancer, such as coronary abnormalities, then it becomes more cost-effective, especially if those patients are then treated at the site where the mobile unit is coming from,” he said.
 

Starting at square one

The first mobile CT scanner was launched in Nagano Prefecture, a rural area in Japan, in 1996. Since then, mobile screening units, primarily mounted on tractor trailers, have brought screening to centralized areas, such as shopping mall parking lots. The Levine Cancer Institute in Charlotte, North Carolina, also has a mobile CT-screening unit mounted in a modified box truck.

For Headrick and colleagues the goal was not to reinvent the wheel, but to see if a mobile lung cancer screening program could improve access and also pay for itself in a time of parsimonious support for preventive medicine.

Their first challenge was the mobile unit itself.

“CT scanners are sensitive, complex electrical machines that require climate control and a level environment to operate. Historically, they have been placed in tractor trailers and parked on level concrete slabs connected to external power supplies. We needed mobility, self-leveling, independent power, climate control, patient comfort, and drivability,” they wrote.

They assembled a team of engineers from CT and vehicle makers, and input was also provided by a thoracic surgeon, pulmonologist, radiologist, CT technician, and driver with a commercial driver’s license. Together, they designed and built the bus over 8 months. Funds for the total cost of the prototype vehicle ($650,000) came from two local nonprofit foundations. The estimated cost for a commercial version of the same vehicle was $850,000.

The Breathe Easy pilot began operation in early 2018, with the initial plan to drive the bus within a 2-hour radius of CHI Memorial Hospital, Chattanooga, Tennessee, to avoid overnight trips. The radius was later shortened to 1.5 hours when operators realized it was a burden for patients with significant screening findings to travel to as much as 4 hours (round trip) to Chattanooga for further testing.

Each screening visit takes about 15 minutes.
 

Cancer and other significant findings

As noted before, the bus traveled to 104 sites over 10 months, and 548 patients with a mean age of 62 were screened. Five lung cancers were identified, including two stage 1A, one stage 1A2, one stage 1B, and one stage 3A.

Two patients with early stage disease underwent stereotactic body radiation therapy, and two underwent minimally invasive surgery (a segmentectomy and a lobectomy). The patient with stage 3A disease underwent curative chemotherapy and radiation therapy. One patient with a type B1 thymoma underwent robotic-assisted thoracoscopic resection with en bloc pericardial resection and reconstruction.

A total of 51 patients had a significant pulmonary finding of Lung CT Screening Reporting and Data System (Lung-RADS) 3 or 4 and were advised to follow up with further testing, but 17 patients in this group did not pursue further testing. Of these 17 patients, 15 had been screened in a health clinic for the homeless at a rural site.

Significant nonpulmonary findings included moderate to severe coronary artery disease in 101 patients, abdominal findings in 15, thyroid abnormalities in 14, other thoracic findings in 10, and ascending aortic dilatation in 9. Of the 152 patients with nonpulmonary findings, only 13 required further testing and none required treatment.
 

Revisions, improvements, and priorities

The Breathe Easy bus has been in operation for more than 2 years, performing an average of approximately 100 screenings per month, with a goal of 200. The bus continued to operate throughout the COVID-19 pandemic because many patients viewed it as a safer alternative to a hospital visit, Headrick said.

Design changes planned to improve performance of the bus include a stronger chassis and structural components, as well as swapping out the 16-slice CT unit for a specially designed 64-slice mobile unit that can be operated with an iPad and provide gated coronary calcium scores.

When challenged about whether the cost of lung cancer screening is the best use of limited resources, Headrick said, “if it’s not, then when we need to go back to the drawing board and jump-start lung cancer screening.”

“When I spent a year in 2014-2015 trying to talk to radio stations, news stations, media, nobody really cared about lung cancer screening,” he said. “But as soon as I had this shiny object, which is the bus, which we labeled as the easiest and most valuable doctor visit, people had an interest.”

The pilot study was supported by local nonprofit foundations through the CHI Memorial Foundation.

This article first appeared on Medscape.com.

A bus converted into a mobile CT screening unit has been reaching high-risk individuals in underserved rural counties in Appalachian areas who may have otherwise not had a chance to be screened for lung cancer.

Results from a pilot study, published online July 13 in The Annals of Thoracic Surgery, show that the scheme is both practical and financially sustainable.

During a 10-month test run, the mobile unit screened 548 individuals at 104 sites. Five lung cancers (four of which were early stage) and a type B thymoma were discovered, and all of these individuals went on to have treatment.

Significant pulmonary findings were also discovered in 52 individuals, who were advised to undergo further testing, as well as significant nonpulmonary findings in 152 individuals (of whom 13 required further testing, but none went on to have treatment). These findings included severe coronary disease and thyroid abnormalities.

The bus reached the estimated financial break-even point of 428 scans, but future economic viability of such a program will likely rely on additional revenue from the treatment of patients with incidental findings from low-dose CT screens, acknowledged the authors, led by James R. Headrick Jr, MD, MBA, from the University of Tennessee College of Medicine in Chattanooga.

The real value of the Breathe Easy program, however, comes from bringing both patient education and lung cancer screening services to a high-risk population who might otherwise be overlooked, Headrick said in an interview with Medscape Medical News.

“We were all excited when lung screening was approved, and we got the recommendation from the United States Preventive Services Task Force [USPSTF], and the Centers for Medicare & Medicaid Services signed off on it, and we sat in our offices and clinics and hospitals — and nobody showed up. We were thinking, ‘Wow, we have this simple test, the easiest screening tool in the world, and nobody’s coming,’ “ he said.

“There was certainly an educational issue that needed to be solved,” he continued, “but we were also dealing with a population that had been told that if they smoked and didn’t live life well, there was a 100% chance they were going to get lung cancer and die,” he said.

The individuals screened in the program were very heavy smokers.

The mean pack-years of smoking was 41 — 11 pack-years higher than the minimum recommended under current lung cancer screening guidelines, and 21 pack-years higher than that recently recommended under proposed low-dose CT screening guidelines by the USPSTF.  

Albert Rizzo, MD, chief medical officer for the American Lung Association, who was not involved in the study, told Medscape Medical News any initiative that can expand lung cancer screening is welcome, particularly when a program may be self-sustaining.

“The interesting part of this article included the downstream revenue to help make something like this viable,” Rizzo said. “Just doing the scans is probably not going to cover the cost of the mobile unit itself, but if you take into account that other things are being found in addition to lung cancer, such as coronary abnormalities, then it becomes more cost-effective, especially if those patients are then treated at the site where the mobile unit is coming from,” he said.
 

Starting at square one

The first mobile CT scanner was launched in Nagano Prefecture, a rural area in Japan, in 1996. Since then, mobile screening units, primarily mounted on tractor trailers, have brought screening to centralized areas, such as shopping mall parking lots. The Levine Cancer Institute in Charlotte, North Carolina, also has a mobile CT-screening unit mounted in a modified box truck.

For Headrick and colleagues the goal was not to reinvent the wheel, but to see if a mobile lung cancer screening program could improve access and also pay for itself in a time of parsimonious support for preventive medicine.

Their first challenge was the mobile unit itself.

“CT scanners are sensitive, complex electrical machines that require climate control and a level environment to operate. Historically, they have been placed in tractor trailers and parked on level concrete slabs connected to external power supplies. We needed mobility, self-leveling, independent power, climate control, patient comfort, and drivability,” they wrote.

They assembled a team of engineers from CT and vehicle makers, and input was also provided by a thoracic surgeon, pulmonologist, radiologist, CT technician, and driver with a commercial driver’s license. Together, they designed and built the bus over 8 months. Funds for the total cost of the prototype vehicle ($650,000) came from two local nonprofit foundations. The estimated cost for a commercial version of the same vehicle was $850,000.

The Breathe Easy pilot began operation in early 2018, with the initial plan to drive the bus within a 2-hour radius of CHI Memorial Hospital, Chattanooga, Tennessee, to avoid overnight trips. The radius was later shortened to 1.5 hours when operators realized it was a burden for patients with significant screening findings to travel to as much as 4 hours (round trip) to Chattanooga for further testing.

Each screening visit takes about 15 minutes.
 

Cancer and other significant findings

As noted before, the bus traveled to 104 sites over 10 months, and 548 patients with a mean age of 62 were screened. Five lung cancers were identified, including two stage 1A, one stage 1A2, one stage 1B, and one stage 3A.

Two patients with early stage disease underwent stereotactic body radiation therapy, and two underwent minimally invasive surgery (a segmentectomy and a lobectomy). The patient with stage 3A disease underwent curative chemotherapy and radiation therapy. One patient with a type B1 thymoma underwent robotic-assisted thoracoscopic resection with en bloc pericardial resection and reconstruction.

A total of 51 patients had a significant pulmonary finding of Lung CT Screening Reporting and Data System (Lung-RADS) 3 or 4 and were advised to follow up with further testing, but 17 patients in this group did not pursue further testing. Of these 17 patients, 15 had been screened in a health clinic for the homeless at a rural site.

Significant nonpulmonary findings included moderate to severe coronary artery disease in 101 patients, abdominal findings in 15, thyroid abnormalities in 14, other thoracic findings in 10, and ascending aortic dilatation in 9. Of the 152 patients with nonpulmonary findings, only 13 required further testing and none required treatment.
 

Revisions, improvements, and priorities

The Breathe Easy bus has been in operation for more than 2 years, performing an average of approximately 100 screenings per month, with a goal of 200. The bus continued to operate throughout the COVID-19 pandemic because many patients viewed it as a safer alternative to a hospital visit, Headrick said.

Design changes planned to improve performance of the bus include a stronger chassis and structural components, as well as swapping out the 16-slice CT unit for a specially designed 64-slice mobile unit that can be operated with an iPad and provide gated coronary calcium scores.

When challenged about whether the cost of lung cancer screening is the best use of limited resources, Headrick said, “if it’s not, then when we need to go back to the drawing board and jump-start lung cancer screening.”

“When I spent a year in 2014-2015 trying to talk to radio stations, news stations, media, nobody really cared about lung cancer screening,” he said. “But as soon as I had this shiny object, which is the bus, which we labeled as the easiest and most valuable doctor visit, people had an interest.”

The pilot study was supported by local nonprofit foundations through the CHI Memorial Foundation.

This article first appeared on Medscape.com.

Proposed changes in the eligibility criteria for lung cancer screening with low-dose CT could result in a near doubling of eligibility, and could especially benefit Black persons and women, say lung cancer experts.

The new proposals include lowering the age at which screening starts from 55 to 50 years, and to reduce the smoking history from 30 to 20 pack-years.

The draft recommendation from the United States Preventive Service Task Force (USPSTF) is available for public comment until August 3.

The task force recommends that adults age 50 to 80 who have a 20 pack-year or greater smoking history and currently smoke or have quit within the last 15 years undergo annual screening for lung cancer with low-dose CT,

“In my opinion, the proposed criteria by USPSTF represent a huge step in the right direction,” Lecia Sequist, MD, director of innovation at the Mass General Cancer Center in Boston, told Medscape Medical News.

“If these are adopted and implemented, we could see the benefit of screening (measured as reduction in lung cancer mortality) go from 9.8% with current parameters up to 13% with the broader parameters,” she said. “In addition, the new criteria should reduce racial disparities in screening eligibility.”

The recommendation also earned high marks from the American Lung Association.

The USPSTF has continued its ‘B’ recommendation – allowing for coverage of the screening with no cost for many under the Affordable Care Act – and is now proposing to expand the eligibility criteria “so that even more Americans at higher risk for lung cancer can be screened,” the ALA commented.

Start screening at 50  

Lowering the minimum age of screening to 50 would likely mean that more Black individuals and women would be eligible for screening, the recommendation authors contend. The current screening age of 55 is currently recommended under guidelines issued by the American Association for Thoracic Surgery, American Cancer Society, American College of Chest Physicians, and National Comprehensive Cancer Network.

“African Americans have a higher risk of lung cancer, compared with whites, and this risk difference is more apparent at lower levels of smoking intensity,” they write.

As previously reported by Medscape Medical News, lung cancer screening in an urban, largely black cohort yielded roughly double the rates of positive screens and detected lung cancers compared with results from the National Lung Screening Trial, which enrolled mostly White individuals.

In addition, although lung cancer risk is greater for men than women who smoke, and women generally accumulate fewer pack-years than men, there is evidence to suggest that women who smoke may develop lung cancer earlier and with lower levels of exposure.

Therefore, “a strategy of screening persons ages 50 to 80 years who have at least a 20 pack-year smoking history and currently smoke or have quit within the past 15 years (A-50-80-20-15) would lead to a relative increase in the percentage of persons eligible for screening by 81% in men and by 96% in women,” the proposed recommendation states.

What’s the harm?

One of the major concerns about low-dose CT screening for lung cancer is the relatively high rate of false-positive results reported in two large scale clinical trials, the recommendation authors acknowledged.

For example, in the NLST, which was the basis for an earlier USPSTF recommendation (for annual screening of adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit in the previous 15 years), the false-positive rates were 26.3% at baseline, 27.2% at year 1, and 15.9% at year 2.

Similarly, in the NELSON trial, results of which were published earlier this year, false-positive rates for men were 19.8% at baseline, 7.1% at year 1, 9% at year 3, and 3.9% at year 5.5 of screening, they noted.

“Yes, false-positive results are one of the things we need to think carefully about when embarking on lung screening,” Dr. Sequist told Medscape Medical News. “The potential harm of a false-positive (unnecessary scans, biopsies or even surgery) can be minimized by having a multidisciplinary team with experience working up lung nodules see patients who have a positive screening test. In fact, the American College of Radiology recommends that all lung screening programs be paired with such a team.”

Mass General has a pulmonary nodule clinic to evaluate screen-detected lung nodules, with the goal of minimizing unnecessary procedures, she noted.

Asked about the potential harm from radiation exposure, Sequist said that exposure from low-dose CT screening is fairly minimal, comparable to that from solar radiation at sea level over a 6-month period, or about the level from three cross-country airplane trips.

“While it is not zero radiation, there is very little concern that this low level of radiation would cause a cancer or damage one’s lungs,” she said.

Albert Rizzo, MD, chief medical officer of the ALA, said that the potential harms of unnecessary interventions are outweighed by the benefits of detecting lung cancer at an early stage.

“I think what has been learned over the last 5 years is that the original recommendations that were put out really allowed the overall rate of positivity well within what’s seen with mammography, for example, and the number of patients who have needlessly gone on to procedures remains very low, and the morbidity of those procedures remains low as well,” Dr. Rizzo told Medscape Medical News.

Not enough takers

Despite the clear benefits of low-dose CT screening, however, US screening rates for high-risk individuals are still very low, ranging from 12.3% in Massachusetts to a low of 0.5% in Nevada, according to a 2019 research report on the state of lung cancer from the ALA.

“For screening to be most effective, more of the high-risk population should be screened. Currently, screening rates are very low among those at high risk. This may be because of a lack of access or low awareness and knowledge among patients and providers. As rates vary tremendously between states, it is clear that more can be done to increase screening rates,” the report stated.

“I think that there are some mixed messages sent out into the population as to whether or not an individual patient should be screened,” Dr. Rizzo said.

He noted that some physicians may be reluctant to take on the nuanced risk–benefit discussion required, or may not have the time during a brief patient visit.

“It really boils down to that discussion between the physician and the patient who falls under these risk categories, to say, ‘Look, this is what these studies have found, and you fall under a category where if we find a cancer early, it’s very likely you’re going to be saved,’ as compared for waiting for it to present by itself,” he said.

Dr. Sequist and Dr. Rizzo have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Proposed changes in the eligibility criteria for lung cancer screening with low-dose CT could result in a near doubling of eligibility, and could especially benefit Black persons and women, say lung cancer experts.

The new proposals include lowering the age at which screening starts from 55 to 50 years, and to reduce the smoking history from 30 to 20 pack-years.

The draft recommendation from the United States Preventive Service Task Force (USPSTF) is available for public comment until August 3.

The task force recommends that adults age 50 to 80 who have a 20 pack-year or greater smoking history and currently smoke or have quit within the last 15 years undergo annual screening for lung cancer with low-dose CT,

“In my opinion, the proposed criteria by USPSTF represent a huge step in the right direction,” Lecia Sequist, MD, director of innovation at the Mass General Cancer Center in Boston, told Medscape Medical News.

“If these are adopted and implemented, we could see the benefit of screening (measured as reduction in lung cancer mortality) go from 9.8% with current parameters up to 13% with the broader parameters,” she said. “In addition, the new criteria should reduce racial disparities in screening eligibility.”

The recommendation also earned high marks from the American Lung Association.

The USPSTF has continued its ‘B’ recommendation – allowing for coverage of the screening with no cost for many under the Affordable Care Act – and is now proposing to expand the eligibility criteria “so that even more Americans at higher risk for lung cancer can be screened,” the ALA commented.

Start screening at 50  

Lowering the minimum age of screening to 50 would likely mean that more Black individuals and women would be eligible for screening, the recommendation authors contend. The current screening age of 55 is currently recommended under guidelines issued by the American Association for Thoracic Surgery, American Cancer Society, American College of Chest Physicians, and National Comprehensive Cancer Network.

“African Americans have a higher risk of lung cancer, compared with whites, and this risk difference is more apparent at lower levels of smoking intensity,” they write.

As previously reported by Medscape Medical News, lung cancer screening in an urban, largely black cohort yielded roughly double the rates of positive screens and detected lung cancers compared with results from the National Lung Screening Trial, which enrolled mostly White individuals.

In addition, although lung cancer risk is greater for men than women who smoke, and women generally accumulate fewer pack-years than men, there is evidence to suggest that women who smoke may develop lung cancer earlier and with lower levels of exposure.

Therefore, “a strategy of screening persons ages 50 to 80 years who have at least a 20 pack-year smoking history and currently smoke or have quit within the past 15 years (A-50-80-20-15) would lead to a relative increase in the percentage of persons eligible for screening by 81% in men and by 96% in women,” the proposed recommendation states.

What’s the harm?

One of the major concerns about low-dose CT screening for lung cancer is the relatively high rate of false-positive results reported in two large scale clinical trials, the recommendation authors acknowledged.

For example, in the NLST, which was the basis for an earlier USPSTF recommendation (for annual screening of adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit in the previous 15 years), the false-positive rates were 26.3% at baseline, 27.2% at year 1, and 15.9% at year 2.

Similarly, in the NELSON trial, results of which were published earlier this year, false-positive rates for men were 19.8% at baseline, 7.1% at year 1, 9% at year 3, and 3.9% at year 5.5 of screening, they noted.

“Yes, false-positive results are one of the things we need to think carefully about when embarking on lung screening,” Dr. Sequist told Medscape Medical News. “The potential harm of a false-positive (unnecessary scans, biopsies or even surgery) can be minimized by having a multidisciplinary team with experience working up lung nodules see patients who have a positive screening test. In fact, the American College of Radiology recommends that all lung screening programs be paired with such a team.”

Mass General has a pulmonary nodule clinic to evaluate screen-detected lung nodules, with the goal of minimizing unnecessary procedures, she noted.

Asked about the potential harm from radiation exposure, Sequist said that exposure from low-dose CT screening is fairly minimal, comparable to that from solar radiation at sea level over a 6-month period, or about the level from three cross-country airplane trips.

“While it is not zero radiation, there is very little concern that this low level of radiation would cause a cancer or damage one’s lungs,” she said.

Albert Rizzo, MD, chief medical officer of the ALA, said that the potential harms of unnecessary interventions are outweighed by the benefits of detecting lung cancer at an early stage.

“I think what has been learned over the last 5 years is that the original recommendations that were put out really allowed the overall rate of positivity well within what’s seen with mammography, for example, and the number of patients who have needlessly gone on to procedures remains very low, and the morbidity of those procedures remains low as well,” Dr. Rizzo told Medscape Medical News.

Not enough takers

Despite the clear benefits of low-dose CT screening, however, US screening rates for high-risk individuals are still very low, ranging from 12.3% in Massachusetts to a low of 0.5% in Nevada, according to a 2019 research report on the state of lung cancer from the ALA.

“For screening to be most effective, more of the high-risk population should be screened. Currently, screening rates are very low among those at high risk. This may be because of a lack of access or low awareness and knowledge among patients and providers. As rates vary tremendously between states, it is clear that more can be done to increase screening rates,” the report stated.

“I think that there are some mixed messages sent out into the population as to whether or not an individual patient should be screened,” Dr. Rizzo said.

He noted that some physicians may be reluctant to take on the nuanced risk–benefit discussion required, or may not have the time during a brief patient visit.

“It really boils down to that discussion between the physician and the patient who falls under these risk categories, to say, ‘Look, this is what these studies have found, and you fall under a category where if we find a cancer early, it’s very likely you’re going to be saved,’ as compared for waiting for it to present by itself,” he said.

Dr. Sequist and Dr. Rizzo have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Proposed changes in the eligibility criteria for lung cancer screening with low-dose CT could result in a near doubling of eligibility, and could especially benefit Black persons and women, say lung cancer experts.

The new proposals include lowering the age at which screening starts from 55 to 50 years, and to reduce the smoking history from 30 to 20 pack-years.

The draft recommendation from the United States Preventive Service Task Force (USPSTF) is available for public comment until August 3.

The task force recommends that adults age 50 to 80 who have a 20 pack-year or greater smoking history and currently smoke or have quit within the last 15 years undergo annual screening for lung cancer with low-dose CT,

“In my opinion, the proposed criteria by USPSTF represent a huge step in the right direction,” Lecia Sequist, MD, director of innovation at the Mass General Cancer Center in Boston, told Medscape Medical News.

“If these are adopted and implemented, we could see the benefit of screening (measured as reduction in lung cancer mortality) go from 9.8% with current parameters up to 13% with the broader parameters,” she said. “In addition, the new criteria should reduce racial disparities in screening eligibility.”

The recommendation also earned high marks from the American Lung Association.

The USPSTF has continued its ‘B’ recommendation – allowing for coverage of the screening with no cost for many under the Affordable Care Act – and is now proposing to expand the eligibility criteria “so that even more Americans at higher risk for lung cancer can be screened,” the ALA commented.

Start screening at 50  

Lowering the minimum age of screening to 50 would likely mean that more Black individuals and women would be eligible for screening, the recommendation authors contend. The current screening age of 55 is currently recommended under guidelines issued by the American Association for Thoracic Surgery, American Cancer Society, American College of Chest Physicians, and National Comprehensive Cancer Network.

“African Americans have a higher risk of lung cancer, compared with whites, and this risk difference is more apparent at lower levels of smoking intensity,” they write.

As previously reported by Medscape Medical News, lung cancer screening in an urban, largely black cohort yielded roughly double the rates of positive screens and detected lung cancers compared with results from the National Lung Screening Trial, which enrolled mostly White individuals.

In addition, although lung cancer risk is greater for men than women who smoke, and women generally accumulate fewer pack-years than men, there is evidence to suggest that women who smoke may develop lung cancer earlier and with lower levels of exposure.

Therefore, “a strategy of screening persons ages 50 to 80 years who have at least a 20 pack-year smoking history and currently smoke or have quit within the past 15 years (A-50-80-20-15) would lead to a relative increase in the percentage of persons eligible for screening by 81% in men and by 96% in women,” the proposed recommendation states.

What’s the harm?

One of the major concerns about low-dose CT screening for lung cancer is the relatively high rate of false-positive results reported in two large scale clinical trials, the recommendation authors acknowledged.

For example, in the NLST, which was the basis for an earlier USPSTF recommendation (for annual screening of adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit in the previous 15 years), the false-positive rates were 26.3% at baseline, 27.2% at year 1, and 15.9% at year 2.

Similarly, in the NELSON trial, results of which were published earlier this year, false-positive rates for men were 19.8% at baseline, 7.1% at year 1, 9% at year 3, and 3.9% at year 5.5 of screening, they noted.

“Yes, false-positive results are one of the things we need to think carefully about when embarking on lung screening,” Dr. Sequist told Medscape Medical News. “The potential harm of a false-positive (unnecessary scans, biopsies or even surgery) can be minimized by having a multidisciplinary team with experience working up lung nodules see patients who have a positive screening test. In fact, the American College of Radiology recommends that all lung screening programs be paired with such a team.”

Mass General has a pulmonary nodule clinic to evaluate screen-detected lung nodules, with the goal of minimizing unnecessary procedures, she noted.

Asked about the potential harm from radiation exposure, Sequist said that exposure from low-dose CT screening is fairly minimal, comparable to that from solar radiation at sea level over a 6-month period, or about the level from three cross-country airplane trips.

“While it is not zero radiation, there is very little concern that this low level of radiation would cause a cancer or damage one’s lungs,” she said.

Albert Rizzo, MD, chief medical officer of the ALA, said that the potential harms of unnecessary interventions are outweighed by the benefits of detecting lung cancer at an early stage.

“I think what has been learned over the last 5 years is that the original recommendations that were put out really allowed the overall rate of positivity well within what’s seen with mammography, for example, and the number of patients who have needlessly gone on to procedures remains very low, and the morbidity of those procedures remains low as well,” Dr. Rizzo told Medscape Medical News.

Not enough takers

Despite the clear benefits of low-dose CT screening, however, US screening rates for high-risk individuals are still very low, ranging from 12.3% in Massachusetts to a low of 0.5% in Nevada, according to a 2019 research report on the state of lung cancer from the ALA.

“For screening to be most effective, more of the high-risk population should be screened. Currently, screening rates are very low among those at high risk. This may be because of a lack of access or low awareness and knowledge among patients and providers. As rates vary tremendously between states, it is clear that more can be done to increase screening rates,” the report stated.

“I think that there are some mixed messages sent out into the population as to whether or not an individual patient should be screened,” Dr. Rizzo said.

He noted that some physicians may be reluctant to take on the nuanced risk–benefit discussion required, or may not have the time during a brief patient visit.

“It really boils down to that discussion between the physician and the patient who falls under these risk categories, to say, ‘Look, this is what these studies have found, and you fall under a category where if we find a cancer early, it’s very likely you’re going to be saved,’ as compared for waiting for it to present by itself,” he said.

Dr. Sequist and Dr. Rizzo have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Brensocatib, an experimental small-molecule inhibitor targeted to inflammation-regulating neutrophil serine proteases, may be a novel, nonantibiotic option for reducing exacerbations in patients with bronchiectasis, investigators in the phase 2 WILLOW study said.

Among 256 adults with a recent history of bronchiectasis exacerbations, oral brensocatib at doses of both 10 mg and 25 mg daily for 24 weeks was associated with significantly longer time to first exacerbation than placebo, and the 10-mg dose was associated with a significant reduction in the annualized rate of exacerbations, reported James Chalmers, MB, ChB, PhD of Ninewells Hospital and Medical School in Dundee (England).

“We also observed a dose-dependent reduction in neutrophil elastase levels in sputum, which supports the mechanism of action of this drug, and importantly showed a link between reducing neutrophil serine protease activity and clinical benefits in people with bronchiectasis,” he said in at the American Thoracic Society’s virtual clinical trial session.

“This is a very important trial, a landmark trial for people with bronchiectasis, because this is a drug that for the first time appears to be able to target directly neutrophilic inflammation, resulting in clinical benefit,” he said.

Pulmonologist Jennifer L. Taylor-Cousar, MD, MSCS, of National Jewish Health in Denver, who was facilitator for the online presentation but was not involved in the study, said that it offered welcome news.

“For those of us who treat bronchiectasis, a safe and effective anti-inflammatory has really been the Holy Grail, so this is really exciting,” she said.
 

Novel mechanism of action

Frequent exacerbations in bronchiectasis are related to uncontrolled neutrophilic inflammation, and proinflammatory neutrophil serine proteases (NSPs), including neutrophil elastase, are seen at increased levels in sputum of patients with bronchiectasis. In addition, the presence in sputum of elevated NSPs are associated with exacerbations and poor quality of life, Dr. Chalmers said.

Brensocatib is an inhibitor of dipeptidyl peptidase 1 (DPP1), a lysosomal cysteine protease that is responsible for NSP activation in bone marrow during the neutrophil maturation cycle.

In phase 1 trials, brensocatib was associated with a dose-dependent reduction in neutrophil elastase in healthy volunteers.
 

Three WILLOW branches

In the phase 2 WILLOW trial, patients with bronchiectasis not related to cystic fibrosis were screened and stratified by Pseudomonas aeruginosa on sputum culture and use of macrolide antibiotics and then randomized in equal proportions to receive either brensocatib at daily oral doses of 25 mg or 10 mg, or placebo for 24 weeks, followed by a 4-week off-treatment period.

Both doses of brensocatib met the primary endpoint of time to first exacerbation, compared with placebo. The hazard ratio (HR) for the 10-mg brensocatib dose, compared with placebo was 0.58 (P = .029), and the HR for the 25-mg dose was 0.62 (P = .046).

The exacerbation rate over 24 weeks among patients on placebo was 48.3%, compared with 31.7% of patients on 10 mg brensocatib (P = .033) and 33.3% of patients on the 25 mg dose (P = .038).

The annualized exacerbation rate was 1.37 for patients on placebo, compared with 0.88 with 10 mg brensocatib (P = .041) and 1.03 with 25 mg brensocatib (nonsignificant).

In both brensocatib groups there were significant reductions from baseline neutrophil elastase concentrations in sputum, compared with placebo (P = .034 for 10 mg and .021 for 25 mg). During the 4-week period following treatment neutrophil elastase levels in both active drug arms rose rapidly and returned to baseline.

The importance of these reductions was reflected in pooled data from the two brensocatib cohorts, which showed that patients who achieved neutrophil elastase levels below the limit of quantification had a significantly lower incidence of bronchiectasis exacerbations (HR 0.28, P < .0001).

Although the study was not powered to compare changes in postbronchodilator forced expiratory volume in 1 second (FEV₁) levels, placebo-treated patients had a numerically larger decline in lung function from baseline, compared with brensocatib-treated patients.
 

Safety

Expected adverse events with brensocatib included those associated with Papillon-Lefèvre syndrome, a rare congenital condition caused by the absence of the gene coding for DPP1, resulting in keratinization leading to redness, thickening of soles and palms, and severe, destructive periodontal disease, as well as reduced immune response to bacterial infection.

Treatment-emergent adverse events (TEAEs) resulting in study discontinuation occurred in only three patients on placebo and 10 mg brensocatib, and four on the 25-mg dose. TEAEs resulting in treatment discontinuation were more common in the placebo arm, occurring in nine patients compared with six each in the brensocatib arms.

Serious TEAEs occurring in more than 3% of patients in any group included infective exacerbations in three patients on placebo, none on the 10-mg dose, and four on the 25-mg dose of brensocatib. Respective numbers of patients with treatment-emergent pneumonia were three, zero, and four.

Other TEAEs included cough, headache, sputum increase, dyspnea, and diarrhea.

Adverse events of special interest included skin events in 10 patients on placebo, 12 on the 10-mg dose, and 21 on the 25-mg brensocatib dose. Dental changes occurred in 3, 13, and 9 patients, and infections in 9, 12, and 14 patients, respectively.

A phase 3 study to confirm efficacy and establish the optimal dose of brensocatib is planned for the end of 2020, “COVID willing,” Dr. Chalmers said.

Dr. Chalmers disclosed consultancy with and research funding from Insmed, which funded the study. Dr. Taylor-Cousar has disclosed grants and/or personal fees from various companies.

Brensocatib, an experimental small-molecule inhibitor targeted to inflammation-regulating neutrophil serine proteases, may be a novel, nonantibiotic option for reducing exacerbations in patients with bronchiectasis, investigators in the phase 2 WILLOW study said.

Among 256 adults with a recent history of bronchiectasis exacerbations, oral brensocatib at doses of both 10 mg and 25 mg daily for 24 weeks was associated with significantly longer time to first exacerbation than placebo, and the 10-mg dose was associated with a significant reduction in the annualized rate of exacerbations, reported James Chalmers, MB, ChB, PhD of Ninewells Hospital and Medical School in Dundee (England).

“We also observed a dose-dependent reduction in neutrophil elastase levels in sputum, which supports the mechanism of action of this drug, and importantly showed a link between reducing neutrophil serine protease activity and clinical benefits in people with bronchiectasis,” he said in at the American Thoracic Society’s virtual clinical trial session.

“This is a very important trial, a landmark trial for people with bronchiectasis, because this is a drug that for the first time appears to be able to target directly neutrophilic inflammation, resulting in clinical benefit,” he said.

Pulmonologist Jennifer L. Taylor-Cousar, MD, MSCS, of National Jewish Health in Denver, who was facilitator for the online presentation but was not involved in the study, said that it offered welcome news.

“For those of us who treat bronchiectasis, a safe and effective anti-inflammatory has really been the Holy Grail, so this is really exciting,” she said.
 

Novel mechanism of action

Frequent exacerbations in bronchiectasis are related to uncontrolled neutrophilic inflammation, and proinflammatory neutrophil serine proteases (NSPs), including neutrophil elastase, are seen at increased levels in sputum of patients with bronchiectasis. In addition, the presence in sputum of elevated NSPs are associated with exacerbations and poor quality of life, Dr. Chalmers said.

Brensocatib is an inhibitor of dipeptidyl peptidase 1 (DPP1), a lysosomal cysteine protease that is responsible for NSP activation in bone marrow during the neutrophil maturation cycle.

In phase 1 trials, brensocatib was associated with a dose-dependent reduction in neutrophil elastase in healthy volunteers.
 

Three WILLOW branches

In the phase 2 WILLOW trial, patients with bronchiectasis not related to cystic fibrosis were screened and stratified by Pseudomonas aeruginosa on sputum culture and use of macrolide antibiotics and then randomized in equal proportions to receive either brensocatib at daily oral doses of 25 mg or 10 mg, or placebo for 24 weeks, followed by a 4-week off-treatment period.

Both doses of brensocatib met the primary endpoint of time to first exacerbation, compared with placebo. The hazard ratio (HR) for the 10-mg brensocatib dose, compared with placebo was 0.58 (P = .029), and the HR for the 25-mg dose was 0.62 (P = .046).

The exacerbation rate over 24 weeks among patients on placebo was 48.3%, compared with 31.7% of patients on 10 mg brensocatib (P = .033) and 33.3% of patients on the 25 mg dose (P = .038).

The annualized exacerbation rate was 1.37 for patients on placebo, compared with 0.88 with 10 mg brensocatib (P = .041) and 1.03 with 25 mg brensocatib (nonsignificant).

In both brensocatib groups there were significant reductions from baseline neutrophil elastase concentrations in sputum, compared with placebo (P = .034 for 10 mg and .021 for 25 mg). During the 4-week period following treatment neutrophil elastase levels in both active drug arms rose rapidly and returned to baseline.

The importance of these reductions was reflected in pooled data from the two brensocatib cohorts, which showed that patients who achieved neutrophil elastase levels below the limit of quantification had a significantly lower incidence of bronchiectasis exacerbations (HR 0.28, P < .0001).

Although the study was not powered to compare changes in postbronchodilator forced expiratory volume in 1 second (FEV₁) levels, placebo-treated patients had a numerically larger decline in lung function from baseline, compared with brensocatib-treated patients.
 

Safety

Expected adverse events with brensocatib included those associated with Papillon-Lefèvre syndrome, a rare congenital condition caused by the absence of the gene coding for DPP1, resulting in keratinization leading to redness, thickening of soles and palms, and severe, destructive periodontal disease, as well as reduced immune response to bacterial infection.

Treatment-emergent adverse events (TEAEs) resulting in study discontinuation occurred in only three patients on placebo and 10 mg brensocatib, and four on the 25-mg dose. TEAEs resulting in treatment discontinuation were more common in the placebo arm, occurring in nine patients compared with six each in the brensocatib arms.

Serious TEAEs occurring in more than 3% of patients in any group included infective exacerbations in three patients on placebo, none on the 10-mg dose, and four on the 25-mg dose of brensocatib. Respective numbers of patients with treatment-emergent pneumonia were three, zero, and four.

Other TEAEs included cough, headache, sputum increase, dyspnea, and diarrhea.

Adverse events of special interest included skin events in 10 patients on placebo, 12 on the 10-mg dose, and 21 on the 25-mg brensocatib dose. Dental changes occurred in 3, 13, and 9 patients, and infections in 9, 12, and 14 patients, respectively.

A phase 3 study to confirm efficacy and establish the optimal dose of brensocatib is planned for the end of 2020, “COVID willing,” Dr. Chalmers said.

Dr. Chalmers disclosed consultancy with and research funding from Insmed, which funded the study. Dr. Taylor-Cousar has disclosed grants and/or personal fees from various companies.

Brensocatib, an experimental small-molecule inhibitor targeted to inflammation-regulating neutrophil serine proteases, may be a novel, nonantibiotic option for reducing exacerbations in patients with bronchiectasis, investigators in the phase 2 WILLOW study said.

Among 256 adults with a recent history of bronchiectasis exacerbations, oral brensocatib at doses of both 10 mg and 25 mg daily for 24 weeks was associated with significantly longer time to first exacerbation than placebo, and the 10-mg dose was associated with a significant reduction in the annualized rate of exacerbations, reported James Chalmers, MB, ChB, PhD of Ninewells Hospital and Medical School in Dundee (England).

“We also observed a dose-dependent reduction in neutrophil elastase levels in sputum, which supports the mechanism of action of this drug, and importantly showed a link between reducing neutrophil serine protease activity and clinical benefits in people with bronchiectasis,” he said in at the American Thoracic Society’s virtual clinical trial session.

“This is a very important trial, a landmark trial for people with bronchiectasis, because this is a drug that for the first time appears to be able to target directly neutrophilic inflammation, resulting in clinical benefit,” he said.

Pulmonologist Jennifer L. Taylor-Cousar, MD, MSCS, of National Jewish Health in Denver, who was facilitator for the online presentation but was not involved in the study, said that it offered welcome news.

“For those of us who treat bronchiectasis, a safe and effective anti-inflammatory has really been the Holy Grail, so this is really exciting,” she said.
 

Novel mechanism of action

Frequent exacerbations in bronchiectasis are related to uncontrolled neutrophilic inflammation, and proinflammatory neutrophil serine proteases (NSPs), including neutrophil elastase, are seen at increased levels in sputum of patients with bronchiectasis. In addition, the presence in sputum of elevated NSPs are associated with exacerbations and poor quality of life, Dr. Chalmers said.

Brensocatib is an inhibitor of dipeptidyl peptidase 1 (DPP1), a lysosomal cysteine protease that is responsible for NSP activation in bone marrow during the neutrophil maturation cycle.

In phase 1 trials, brensocatib was associated with a dose-dependent reduction in neutrophil elastase in healthy volunteers.
 

Three WILLOW branches

In the phase 2 WILLOW trial, patients with bronchiectasis not related to cystic fibrosis were screened and stratified by Pseudomonas aeruginosa on sputum culture and use of macrolide antibiotics and then randomized in equal proportions to receive either brensocatib at daily oral doses of 25 mg or 10 mg, or placebo for 24 weeks, followed by a 4-week off-treatment period.

Both doses of brensocatib met the primary endpoint of time to first exacerbation, compared with placebo. The hazard ratio (HR) for the 10-mg brensocatib dose, compared with placebo was 0.58 (P = .029), and the HR for the 25-mg dose was 0.62 (P = .046).

The exacerbation rate over 24 weeks among patients on placebo was 48.3%, compared with 31.7% of patients on 10 mg brensocatib (P = .033) and 33.3% of patients on the 25 mg dose (P = .038).

The annualized exacerbation rate was 1.37 for patients on placebo, compared with 0.88 with 10 mg brensocatib (P = .041) and 1.03 with 25 mg brensocatib (nonsignificant).

In both brensocatib groups there were significant reductions from baseline neutrophil elastase concentrations in sputum, compared with placebo (P = .034 for 10 mg and .021 for 25 mg). During the 4-week period following treatment neutrophil elastase levels in both active drug arms rose rapidly and returned to baseline.

The importance of these reductions was reflected in pooled data from the two brensocatib cohorts, which showed that patients who achieved neutrophil elastase levels below the limit of quantification had a significantly lower incidence of bronchiectasis exacerbations (HR 0.28, P < .0001).

Although the study was not powered to compare changes in postbronchodilator forced expiratory volume in 1 second (FEV₁) levels, placebo-treated patients had a numerically larger decline in lung function from baseline, compared with brensocatib-treated patients.
 

Safety

Expected adverse events with brensocatib included those associated with Papillon-Lefèvre syndrome, a rare congenital condition caused by the absence of the gene coding for DPP1, resulting in keratinization leading to redness, thickening of soles and palms, and severe, destructive periodontal disease, as well as reduced immune response to bacterial infection.

Treatment-emergent adverse events (TEAEs) resulting in study discontinuation occurred in only three patients on placebo and 10 mg brensocatib, and four on the 25-mg dose. TEAEs resulting in treatment discontinuation were more common in the placebo arm, occurring in nine patients compared with six each in the brensocatib arms.

Serious TEAEs occurring in more than 3% of patients in any group included infective exacerbations in three patients on placebo, none on the 10-mg dose, and four on the 25-mg dose of brensocatib. Respective numbers of patients with treatment-emergent pneumonia were three, zero, and four.

Other TEAEs included cough, headache, sputum increase, dyspnea, and diarrhea.

Adverse events of special interest included skin events in 10 patients on placebo, 12 on the 10-mg dose, and 21 on the 25-mg brensocatib dose. Dental changes occurred in 3, 13, and 9 patients, and infections in 9, 12, and 14 patients, respectively.

A phase 3 study to confirm efficacy and establish the optimal dose of brensocatib is planned for the end of 2020, “COVID willing,” Dr. Chalmers said.

Dr. Chalmers disclosed consultancy with and research funding from Insmed, which funded the study. Dr. Taylor-Cousar has disclosed grants and/or personal fees from various companies.

Patients with interstitial lung disease–associated pulmonary hypertension who were treated with inhaled treprostinil (Tyvaso) had significantly greater improvement in exercise capacity over 16 weeks, compared with patients who used a placebo inhaler, results of a phase 3 trial showed.

Among 326 patients with pulmonary hypertension (PH) associated with interstitial lung disease (ILD), those who were randomly assigned to treatment with treprostinil had a placebo-corrected median difference from baseline in 6-minute walk distance of 21 m (P = .004), reported Steven D. Nathan, MD, from Inova Fairfax Hospital in Falls Church, Va., on behalf of coinvestigators in the INCREASE study (NCT02630316).

“These results support an additional treatment avenue, and might herald a shift in the clinical management of patients with interstitial lung disease,” he said in the American Thoracic Society’s virtual clinical trial session.

“This was an outstanding presentation and outstanding results. I personally am very excited, because this is a field where I work,” commented Martin Kolb, MD, PhD, from McMaster University, Hamilton, Ont., the facilitator for the online presentation.

The INCREASE trial compared inhaled treprostinil dose four times daily with placebo in patients with a CT scan–confirmed diagnosis of World Health Organization group 3 PH within 6 months before randomization who had evidence of diffuse parenchymal lung disease. Eligible patients could have any form of ILD or combined pulmonary fibrosis and emphysema.

Key inclusion criteria included right-heart catheterization within the previous year with documented pulmonary vascular resistance greater than 3 Wood units, pulmonary capillary wedge pressure 15 mm Hg or less, and mean pulmonary arterial pressure 25 mm Hg or higher.

Patients also had to have a 6-minute walk distance of at least 100 m and have stable disease while on an optimized dose of medications for underlying lung disease. Patients with group 3 connective tissue disease had to have baseline forced vital capacity of less than 70%.

The final study cohorts included patients with idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, connective tissue disease, combined pulmonary fibrosis and emphysema, and occupational lung disease.

The patients were randomized to receive either inhaled treprostinil at a starting dose of 6 mcg/breath four times daily or to placebo (163 patients in each arm). All patients started the study drug at a dose of three breaths four times daily during waking hours. Dose escalations – adding 1 additional breath four times daily – were allowed every 3 days, up to a target dose of 9 breaths (54 mcg) four times daily, and a maximum of 12 breaths (72 mcg) four times daily as clinically tolerated.

A total of 130 patients assigned to treprostinil and 128 assigned to placebo completed 16 weeks of therapy and assessment.

As noted before, patients assigned to treprostinil had a placebo-corrected median difference from baseline in peak 6-minute walk distance, as measured by Hodges-Lehmann estimation, of 21 m (P = .004). An analysis of the same parameter using mixed model repeated measurement showed a placebo-corrected difference from baseline in peak 6-minute walk distance of 31.12 m (P < .001).

Secondary endpoints that were significantly better with treprostinil, compared with placebo, included improvements in N-terminal of the prohormone brain natriuretic peptide, a longer time to clinical worsening, and improvements in peak 6-minute walk distance week 12, and trough 6-minute walk distance at week 15.

Treprostinil was associated with a 39% reduction in risk of clinical worsening (P = .04). In all, 37 patients on treprostinil (22.7%) and 54 on placebo (33.1%) experienced clinical worsening.

For the exploratory endpoints of change in patient reported quality of life as measured by the St. George’s Respiratory Questionnaire, or in peak distance saturation product, however, there were no significant differences between the groups.

In addition, treprostinil was associated with a 34% reduction the risk of exacerbation of underlying lung disease, compared with placebo (P = .03).

The safety profile of treprostinil was similar to that seen in other studies of the drug, and most treatment-related adverse events were mild or moderate in severity. Adverse events led to discontinuation in 10% of patients on treprostinil and 8% on placebo.

Serious adverse events were seen in 23.3% and 25.8%, respectively. The most frequently occurring adverse events of any grade included cough, headache, dyspnea, dizziness, nausea, fatigue, diarrhea, throat irritation, and oropharyngeal pain.

There was no evidence of worsened oxygenation or lung function “allaying V/Q mismatch concerns,” Dr. Nathan said, and there was evidence for an improvement in forced vital capacity with treprostinil.

In the question-and-answer portion of the presentation, Dr. Kolb commented that many clinicians, particularly those who treated patients with ILD, question whether a 21-m difference in walk distance makes much of a difference in patient lives. He relayed a question from a viewer asking how Dr. Nathan and associates reconciled their primary endpoint with the finding that there was no difference in patient-reported quality of life.

“I think that the difference in the 6-minute walk test was both statistically significant and clinically meaningful,” Dr. Nathan replied.

He noted that the primary endpoint used a stringent measure, and that less conservative methods of analysis showed a larger difference in benefit favoring treprostinil. He also pointed out that the original study of inhaled treprostinil added to oral therapy for pulmonary arterial hypertension showed a 20-m improvement in walk distance, and that these results were sufficient to get the inhaled formulation approved in the United States (J Am Coll Cardiol. 2010 May. doi: 10.1016/j.jacc.2010.01.027).

Regarding the failure to detect a difference in quality of life, he said that the study was only 16 weeks in length, and that the St. George’s Respiratory Questionnaire was developed for evaluation of patients with chronic obstructive pulmonary disease, “perhaps not the best instrument to use in an ILD PH study.”

The study was funded by United Therapeutics. Dr. Nathan disclosed advisory committee activity/consulting, research support, and speaker fees from the company. Dr. Kolb has previously disclosed financial relationships with various companies, not including United Therapeutics.

Patients with interstitial lung disease–associated pulmonary hypertension who were treated with inhaled treprostinil (Tyvaso) had significantly greater improvement in exercise capacity over 16 weeks, compared with patients who used a placebo inhaler, results of a phase 3 trial showed.

Among 326 patients with pulmonary hypertension (PH) associated with interstitial lung disease (ILD), those who were randomly assigned to treatment with treprostinil had a placebo-corrected median difference from baseline in 6-minute walk distance of 21 m (P = .004), reported Steven D. Nathan, MD, from Inova Fairfax Hospital in Falls Church, Va., on behalf of coinvestigators in the INCREASE study (NCT02630316).

“These results support an additional treatment avenue, and might herald a shift in the clinical management of patients with interstitial lung disease,” he said in the American Thoracic Society’s virtual clinical trial session.

“This was an outstanding presentation and outstanding results. I personally am very excited, because this is a field where I work,” commented Martin Kolb, MD, PhD, from McMaster University, Hamilton, Ont., the facilitator for the online presentation.

The INCREASE trial compared inhaled treprostinil dose four times daily with placebo in patients with a CT scan–confirmed diagnosis of World Health Organization group 3 PH within 6 months before randomization who had evidence of diffuse parenchymal lung disease. Eligible patients could have any form of ILD or combined pulmonary fibrosis and emphysema.

Key inclusion criteria included right-heart catheterization within the previous year with documented pulmonary vascular resistance greater than 3 Wood units, pulmonary capillary wedge pressure 15 mm Hg or less, and mean pulmonary arterial pressure 25 mm Hg or higher.

Patients also had to have a 6-minute walk distance of at least 100 m and have stable disease while on an optimized dose of medications for underlying lung disease. Patients with group 3 connective tissue disease had to have baseline forced vital capacity of less than 70%.

The final study cohorts included patients with idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, connective tissue disease, combined pulmonary fibrosis and emphysema, and occupational lung disease.

The patients were randomized to receive either inhaled treprostinil at a starting dose of 6 mcg/breath four times daily or to placebo (163 patients in each arm). All patients started the study drug at a dose of three breaths four times daily during waking hours. Dose escalations – adding 1 additional breath four times daily – were allowed every 3 days, up to a target dose of 9 breaths (54 mcg) four times daily, and a maximum of 12 breaths (72 mcg) four times daily as clinically tolerated.

A total of 130 patients assigned to treprostinil and 128 assigned to placebo completed 16 weeks of therapy and assessment.

As noted before, patients assigned to treprostinil had a placebo-corrected median difference from baseline in peak 6-minute walk distance, as measured by Hodges-Lehmann estimation, of 21 m (P = .004). An analysis of the same parameter using mixed model repeated measurement showed a placebo-corrected difference from baseline in peak 6-minute walk distance of 31.12 m (P < .001).

Secondary endpoints that were significantly better with treprostinil, compared with placebo, included improvements in N-terminal of the prohormone brain natriuretic peptide, a longer time to clinical worsening, and improvements in peak 6-minute walk distance week 12, and trough 6-minute walk distance at week 15.

Treprostinil was associated with a 39% reduction in risk of clinical worsening (P = .04). In all, 37 patients on treprostinil (22.7%) and 54 on placebo (33.1%) experienced clinical worsening.

For the exploratory endpoints of change in patient reported quality of life as measured by the St. George’s Respiratory Questionnaire, or in peak distance saturation product, however, there were no significant differences between the groups.

In addition, treprostinil was associated with a 34% reduction the risk of exacerbation of underlying lung disease, compared with placebo (P = .03).

The safety profile of treprostinil was similar to that seen in other studies of the drug, and most treatment-related adverse events were mild or moderate in severity. Adverse events led to discontinuation in 10% of patients on treprostinil and 8% on placebo.

Serious adverse events were seen in 23.3% and 25.8%, respectively. The most frequently occurring adverse events of any grade included cough, headache, dyspnea, dizziness, nausea, fatigue, diarrhea, throat irritation, and oropharyngeal pain.

There was no evidence of worsened oxygenation or lung function “allaying V/Q mismatch concerns,” Dr. Nathan said, and there was evidence for an improvement in forced vital capacity with treprostinil.

In the question-and-answer portion of the presentation, Dr. Kolb commented that many clinicians, particularly those who treated patients with ILD, question whether a 21-m difference in walk distance makes much of a difference in patient lives. He relayed a question from a viewer asking how Dr. Nathan and associates reconciled their primary endpoint with the finding that there was no difference in patient-reported quality of life.

“I think that the difference in the 6-minute walk test was both statistically significant and clinically meaningful,” Dr. Nathan replied.

He noted that the primary endpoint used a stringent measure, and that less conservative methods of analysis showed a larger difference in benefit favoring treprostinil. He also pointed out that the original study of inhaled treprostinil added to oral therapy for pulmonary arterial hypertension showed a 20-m improvement in walk distance, and that these results were sufficient to get the inhaled formulation approved in the United States (J Am Coll Cardiol. 2010 May. doi: 10.1016/j.jacc.2010.01.027).

Regarding the failure to detect a difference in quality of life, he said that the study was only 16 weeks in length, and that the St. George’s Respiratory Questionnaire was developed for evaluation of patients with chronic obstructive pulmonary disease, “perhaps not the best instrument to use in an ILD PH study.”

The study was funded by United Therapeutics. Dr. Nathan disclosed advisory committee activity/consulting, research support, and speaker fees from the company. Dr. Kolb has previously disclosed financial relationships with various companies, not including United Therapeutics.

Patients with interstitial lung disease–associated pulmonary hypertension who were treated with inhaled treprostinil (Tyvaso) had significantly greater improvement in exercise capacity over 16 weeks, compared with patients who used a placebo inhaler, results of a phase 3 trial showed.

Among 326 patients with pulmonary hypertension (PH) associated with interstitial lung disease (ILD), those who were randomly assigned to treatment with treprostinil had a placebo-corrected median difference from baseline in 6-minute walk distance of 21 m (P = .004), reported Steven D. Nathan, MD, from Inova Fairfax Hospital in Falls Church, Va., on behalf of coinvestigators in the INCREASE study (NCT02630316).

“These results support an additional treatment avenue, and might herald a shift in the clinical management of patients with interstitial lung disease,” he said in the American Thoracic Society’s virtual clinical trial session.

“This was an outstanding presentation and outstanding results. I personally am very excited, because this is a field where I work,” commented Martin Kolb, MD, PhD, from McMaster University, Hamilton, Ont., the facilitator for the online presentation.

The INCREASE trial compared inhaled treprostinil dose four times daily with placebo in patients with a CT scan–confirmed diagnosis of World Health Organization group 3 PH within 6 months before randomization who had evidence of diffuse parenchymal lung disease. Eligible patients could have any form of ILD or combined pulmonary fibrosis and emphysema.

Key inclusion criteria included right-heart catheterization within the previous year with documented pulmonary vascular resistance greater than 3 Wood units, pulmonary capillary wedge pressure 15 mm Hg or less, and mean pulmonary arterial pressure 25 mm Hg or higher.

Patients also had to have a 6-minute walk distance of at least 100 m and have stable disease while on an optimized dose of medications for underlying lung disease. Patients with group 3 connective tissue disease had to have baseline forced vital capacity of less than 70%.

The final study cohorts included patients with idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, connective tissue disease, combined pulmonary fibrosis and emphysema, and occupational lung disease.

The patients were randomized to receive either inhaled treprostinil at a starting dose of 6 mcg/breath four times daily or to placebo (163 patients in each arm). All patients started the study drug at a dose of three breaths four times daily during waking hours. Dose escalations – adding 1 additional breath four times daily – were allowed every 3 days, up to a target dose of 9 breaths (54 mcg) four times daily, and a maximum of 12 breaths (72 mcg) four times daily as clinically tolerated.

A total of 130 patients assigned to treprostinil and 128 assigned to placebo completed 16 weeks of therapy and assessment.

As noted before, patients assigned to treprostinil had a placebo-corrected median difference from baseline in peak 6-minute walk distance, as measured by Hodges-Lehmann estimation, of 21 m (P = .004). An analysis of the same parameter using mixed model repeated measurement showed a placebo-corrected difference from baseline in peak 6-minute walk distance of 31.12 m (P < .001).

Secondary endpoints that were significantly better with treprostinil, compared with placebo, included improvements in N-terminal of the prohormone brain natriuretic peptide, a longer time to clinical worsening, and improvements in peak 6-minute walk distance week 12, and trough 6-minute walk distance at week 15.

Treprostinil was associated with a 39% reduction in risk of clinical worsening (P = .04). In all, 37 patients on treprostinil (22.7%) and 54 on placebo (33.1%) experienced clinical worsening.

For the exploratory endpoints of change in patient reported quality of life as measured by the St. George’s Respiratory Questionnaire, or in peak distance saturation product, however, there were no significant differences between the groups.

In addition, treprostinil was associated with a 34% reduction the risk of exacerbation of underlying lung disease, compared with placebo (P = .03).

The safety profile of treprostinil was similar to that seen in other studies of the drug, and most treatment-related adverse events were mild or moderate in severity. Adverse events led to discontinuation in 10% of patients on treprostinil and 8% on placebo.

Serious adverse events were seen in 23.3% and 25.8%, respectively. The most frequently occurring adverse events of any grade included cough, headache, dyspnea, dizziness, nausea, fatigue, diarrhea, throat irritation, and oropharyngeal pain.

There was no evidence of worsened oxygenation or lung function “allaying V/Q mismatch concerns,” Dr. Nathan said, and there was evidence for an improvement in forced vital capacity with treprostinil.

In the question-and-answer portion of the presentation, Dr. Kolb commented that many clinicians, particularly those who treated patients with ILD, question whether a 21-m difference in walk distance makes much of a difference in patient lives. He relayed a question from a viewer asking how Dr. Nathan and associates reconciled their primary endpoint with the finding that there was no difference in patient-reported quality of life.

“I think that the difference in the 6-minute walk test was both statistically significant and clinically meaningful,” Dr. Nathan replied.

He noted that the primary endpoint used a stringent measure, and that less conservative methods of analysis showed a larger difference in benefit favoring treprostinil. He also pointed out that the original study of inhaled treprostinil added to oral therapy for pulmonary arterial hypertension showed a 20-m improvement in walk distance, and that these results were sufficient to get the inhaled formulation approved in the United States (J Am Coll Cardiol. 2010 May. doi: 10.1016/j.jacc.2010.01.027).

Regarding the failure to detect a difference in quality of life, he said that the study was only 16 weeks in length, and that the St. George’s Respiratory Questionnaire was developed for evaluation of patients with chronic obstructive pulmonary disease, “perhaps not the best instrument to use in an ILD PH study.”

The study was funded by United Therapeutics. Dr. Nathan disclosed advisory committee activity/consulting, research support, and speaker fees from the company. Dr. Kolb has previously disclosed financial relationships with various companies, not including United Therapeutics.

Sotatercept, a first-in-class fusion protein designed to reduce vascular remodeling, significantly decreased pulmonary vascular resistance for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.

The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.

“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.

The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.

In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
 

Two dose levels

The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.

A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.

The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).

The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm² in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm² in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm² decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).

Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).

Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.

There was no significant difference between the study arms in change in cardiac output, however.

Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.

Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.

One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.

TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.

One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.

“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”

One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.

TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
 

Why no cardiac improvement?

In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.

“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.

“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”

He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”

As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.

A phase 3 trial is in the works.

The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.

Sotatercept, a first-in-class fusion protein designed to reduce vascular remodeling, significantly decreased pulmonary vascular resistance for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.

The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.

“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.

The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.

In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
 

Two dose levels

The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.

A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.

The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).

The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm² in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm² in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm² decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).

Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).

Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.

There was no significant difference between the study arms in change in cardiac output, however.

Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.

Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.

One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.

TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.

One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.

“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”

One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.

TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
 

Why no cardiac improvement?

In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.

“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.

“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”

He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”

As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.

A phase 3 trial is in the works.

The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.

Sotatercept, a first-in-class fusion protein designed to reduce vascular remodeling, significantly decreased pulmonary vascular resistance for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.

The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.

“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.

The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.

In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
 

Two dose levels

The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.

A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.

The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).

The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm² in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm² in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm² decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).

Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).

Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.

There was no significant difference between the study arms in change in cardiac output, however.

Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.

Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.

One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.

TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.

One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.

“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”

One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.

TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
 

Why no cardiac improvement?

In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.

“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.

“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”

He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”

As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.

A phase 3 trial is in the works.

The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.

Phase 3 trial findings compared outcomes for COPD patients who had triple fixed-dose inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta₂ agonist with patients who received one of two dual-therapy combinations. The results were presented at the American Thoracic Society’s virtual clinical trial session.

A total of 8,509 patients were randomized on a 1:1:1:1 basis to receive twice daily:

• Single-inhaler combinations of the inhaled corticosteroid (ICS) budesonide at one of two doses, the long-acting muscarinic antagonist (LAMA) glycopyrrolate, and the long-acting beta2 agonist (LABA) formoterol.
• Dual-therapy combination glycopyrrolate and formoterol.
• Dual-therapy combination budesonide and formoterol.

The annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 for the triple combinations with 320 mcg and 180 mcg doses of budesonide, respectively, compared with 1.42 for glycopyrrolate-formoterol, and 1.24 for budesonide-formoterol.

Both triple combinations were significantly superior to the dual therapies for controlling exacerbations, reported Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf and Christian-Albrechts University Kiel (Germany), and colleagues in the ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial (NCT02465567).

“Our findings show the benefits of triple therapy with a budesonide-glycopyrrolate-formoterol combination over dual therapy with a LAMA-LABA or an inhaled glucocorticoid-LABA combination with respect to the annual rate of moderate or severe COPD exacerbations, symptoms, and health-related quality of life in patients with moderate to very-severe COPD who are at risk of exacerbations,” they wrote in a study published online in the New England Journal of Medicine..

The trial showed for the first time that “triple therapy that has half the dose of steroid compared to a standard ICS/LABA combination has had greater efficacy for the exacerbation endpoint,” Dr. Rabe said during his presentation.

Triple-therapy combinations with an ICS, LAMA, and LABA are recommended for patients with COPD who remain symptomatic or experience further exacerbations on dual–ICS/LABA or –LAMA/LABA combinations. The triple combinations have been shown in several studies to lower risk of exacerbations and are associated with both better lung function and health-related quality of life, compared with dual therapies, the investigators noted.

However, concerns about adverse events associated with long-term ICS use – including pneumonia, cataracts, and increased fracture risk, possibly related to treatment duration, dose level, or type of corticosteroid used – spurred the ETHOS investigators to compare triple and dual fixed-dose combinations for efficacy and safety over 1 year.
 

Large study

They enrolled 8,509 adults aged 40-80 years with symptomatic COPD (defined as score of 10 or higher on the 40-point COPD Assessment Test). All patients were receiving at least two inhaled maintenance therapies at the time of screening, and had a postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, with a postbronchodilator FEV₁ of 25%-65% of the predicted normal value. The patients all had a smoking history of at least 10 pack-years and a documented history of at least one moderate or severe COPD exacerbation in the year before screening.

The patients were randomized in equal proportions to receive triple therapy with budesonide at 320- or 160-mcg doses plus glycopyrrolate 18 mcg, and formoterol 9.6 mcg twice daily, or to dual therapy with either glycopyrrolate plus formoterol at the same doses, or 320 mcg budesonide plus 9.6 mcg formoterol.

As noted, for the primary endpoint of the estimated annual rate of moderate or severe exacerbations, the triple combinations were associated with significantly lower rates, with a 24% lower rate (rate ratio, 0.76) with 320 mcg budesonide triple therapy, compared with glycopyrrolate-formoterol, and a 13% lower rate (RR, 0.87), compared with budesonide formoterol (P < .001 and P = .003, respectively).

The triple combination with the 160-mcg budesonide dose was associated with a 25% lower annual rate of exacerbations (RR, 0.75) vs. glycopyrrolate-formoterol, and a 14% lower rate (RR, 0.86) vs. budesonide-formoterol (P < .001 and P = .002, respectively).

Secondary efficacy endpoints also favored the triple combination, including a 20% lower rate ratio of severe exacerbations over 52 weeks for the 320-mcg budesonide group, compared with the budesonide-formoterol group (P = .02).

The 320-mcg dose combination was also associated with a 46% lower risk for all-cause mortality, compared with glycopyrrolate-formoterol (hazard ratio, 0.54; P = .0111).

Confirmed pneumonia was seen in 4.2% of patients on the 320-mcg budesonide dose, 3.5% of those in the 160-mcg group, and 4.5% of patients treated with budesonide-formoterol. The incidence of any adverse effect was similar across the treatment groups, ranging from 61.7% to 64.5%.
 

Balance exacerbation, pneumonia risk

In the question-and-answer session following his online presentation, Dr. Rabe was asked how the investigators reconciled their data showing increased incidence of pneumonia in budenoside-containing formulations with claims by the maker of the budesonide-formoterol (Symbicort, AstraZeneca) that budesonide is not associated with increased risk of pneumonia.

“We have to say that there are individuals that we have to balance the benefit of [less] exacerbation against the risk of pneumonia,” he replied, but noted that the size of the effect, observed both in ETHOS and in the KRONOS trial, was relatively small.

“This definitely adds some information for us to think about when we’re trying to do risk-benefit analysis,” commented MeiLan K. Han, MD, MS, from the University of Michigan, who moderated the session but was not involved in the study.

The ETHOS trial was funded by AstraZeneca. Dr. Rabe disclosed consulting/advisory board activity with that company and others. Dr. Han has previously disclosed consulting/advising and research funding relationships with other companies.

SOURCE: Rabe KF et al. N Engl J Med. 2020 Jun 24. doi: 10.1056/NEJMoa1916046.

Phase 3 trial findings compared outcomes for COPD patients who had triple fixed-dose inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta₂ agonist with patients who received one of two dual-therapy combinations. The results were presented at the American Thoracic Society’s virtual clinical trial session.

A total of 8,509 patients were randomized on a 1:1:1:1 basis to receive twice daily:

• Single-inhaler combinations of the inhaled corticosteroid (ICS) budesonide at one of two doses, the long-acting muscarinic antagonist (LAMA) glycopyrrolate, and the long-acting beta2 agonist (LABA) formoterol.
• Dual-therapy combination glycopyrrolate and formoterol.
• Dual-therapy combination budesonide and formoterol.

The annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 for the triple combinations with 320 mcg and 180 mcg doses of budesonide, respectively, compared with 1.42 for glycopyrrolate-formoterol, and 1.24 for budesonide-formoterol.

Both triple combinations were significantly superior to the dual therapies for controlling exacerbations, reported Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf and Christian-Albrechts University Kiel (Germany), and colleagues in the ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial (NCT02465567).

“Our findings show the benefits of triple therapy with a budesonide-glycopyrrolate-formoterol combination over dual therapy with a LAMA-LABA or an inhaled glucocorticoid-LABA combination with respect to the annual rate of moderate or severe COPD exacerbations, symptoms, and health-related quality of life in patients with moderate to very-severe COPD who are at risk of exacerbations,” they wrote in a study published online in the New England Journal of Medicine..

The trial showed for the first time that “triple therapy that has half the dose of steroid compared to a standard ICS/LABA combination has had greater efficacy for the exacerbation endpoint,” Dr. Rabe said during his presentation.

Triple-therapy combinations with an ICS, LAMA, and LABA are recommended for patients with COPD who remain symptomatic or experience further exacerbations on dual–ICS/LABA or –LAMA/LABA combinations. The triple combinations have been shown in several studies to lower risk of exacerbations and are associated with both better lung function and health-related quality of life, compared with dual therapies, the investigators noted.

However, concerns about adverse events associated with long-term ICS use – including pneumonia, cataracts, and increased fracture risk, possibly related to treatment duration, dose level, or type of corticosteroid used – spurred the ETHOS investigators to compare triple and dual fixed-dose combinations for efficacy and safety over 1 year.
 

Large study

They enrolled 8,509 adults aged 40-80 years with symptomatic COPD (defined as score of 10 or higher on the 40-point COPD Assessment Test). All patients were receiving at least two inhaled maintenance therapies at the time of screening, and had a postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, with a postbronchodilator FEV₁ of 25%-65% of the predicted normal value. The patients all had a smoking history of at least 10 pack-years and a documented history of at least one moderate or severe COPD exacerbation in the year before screening.

The patients were randomized in equal proportions to receive triple therapy with budesonide at 320- or 160-mcg doses plus glycopyrrolate 18 mcg, and formoterol 9.6 mcg twice daily, or to dual therapy with either glycopyrrolate plus formoterol at the same doses, or 320 mcg budesonide plus 9.6 mcg formoterol.

As noted, for the primary endpoint of the estimated annual rate of moderate or severe exacerbations, the triple combinations were associated with significantly lower rates, with a 24% lower rate (rate ratio, 0.76) with 320 mcg budesonide triple therapy, compared with glycopyrrolate-formoterol, and a 13% lower rate (RR, 0.87), compared with budesonide formoterol (P < .001 and P = .003, respectively).

The triple combination with the 160-mcg budesonide dose was associated with a 25% lower annual rate of exacerbations (RR, 0.75) vs. glycopyrrolate-formoterol, and a 14% lower rate (RR, 0.86) vs. budesonide-formoterol (P < .001 and P = .002, respectively).

Secondary efficacy endpoints also favored the triple combination, including a 20% lower rate ratio of severe exacerbations over 52 weeks for the 320-mcg budesonide group, compared with the budesonide-formoterol group (P = .02).

The 320-mcg dose combination was also associated with a 46% lower risk for all-cause mortality, compared with glycopyrrolate-formoterol (hazard ratio, 0.54; P = .0111).

Confirmed pneumonia was seen in 4.2% of patients on the 320-mcg budesonide dose, 3.5% of those in the 160-mcg group, and 4.5% of patients treated with budesonide-formoterol. The incidence of any adverse effect was similar across the treatment groups, ranging from 61.7% to 64.5%.
 

Balance exacerbation, pneumonia risk

In the question-and-answer session following his online presentation, Dr. Rabe was asked how the investigators reconciled their data showing increased incidence of pneumonia in budenoside-containing formulations with claims by the maker of the budesonide-formoterol (Symbicort, AstraZeneca) that budesonide is not associated with increased risk of pneumonia.

“We have to say that there are individuals that we have to balance the benefit of [less] exacerbation against the risk of pneumonia,” he replied, but noted that the size of the effect, observed both in ETHOS and in the KRONOS trial, was relatively small.

“This definitely adds some information for us to think about when we’re trying to do risk-benefit analysis,” commented MeiLan K. Han, MD, MS, from the University of Michigan, who moderated the session but was not involved in the study.

The ETHOS trial was funded by AstraZeneca. Dr. Rabe disclosed consulting/advisory board activity with that company and others. Dr. Han has previously disclosed consulting/advising and research funding relationships with other companies.

SOURCE: Rabe KF et al. N Engl J Med. 2020 Jun 24. doi: 10.1056/NEJMoa1916046.

Phase 3 trial findings compared outcomes for COPD patients who had triple fixed-dose inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta₂ agonist with patients who received one of two dual-therapy combinations. The results were presented at the American Thoracic Society’s virtual clinical trial session.

A total of 8,509 patients were randomized on a 1:1:1:1 basis to receive twice daily:

• Single-inhaler combinations of the inhaled corticosteroid (ICS) budesonide at one of two doses, the long-acting muscarinic antagonist (LAMA) glycopyrrolate, and the long-acting beta2 agonist (LABA) formoterol.
• Dual-therapy combination glycopyrrolate and formoterol.
• Dual-therapy combination budesonide and formoterol.

The annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 for the triple combinations with 320 mcg and 180 mcg doses of budesonide, respectively, compared with 1.42 for glycopyrrolate-formoterol, and 1.24 for budesonide-formoterol.

Both triple combinations were significantly superior to the dual therapies for controlling exacerbations, reported Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf and Christian-Albrechts University Kiel (Germany), and colleagues in the ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial (NCT02465567).

“Our findings show the benefits of triple therapy with a budesonide-glycopyrrolate-formoterol combination over dual therapy with a LAMA-LABA or an inhaled glucocorticoid-LABA combination with respect to the annual rate of moderate or severe COPD exacerbations, symptoms, and health-related quality of life in patients with moderate to very-severe COPD who are at risk of exacerbations,” they wrote in a study published online in the New England Journal of Medicine..

The trial showed for the first time that “triple therapy that has half the dose of steroid compared to a standard ICS/LABA combination has had greater efficacy for the exacerbation endpoint,” Dr. Rabe said during his presentation.

Triple-therapy combinations with an ICS, LAMA, and LABA are recommended for patients with COPD who remain symptomatic or experience further exacerbations on dual–ICS/LABA or –LAMA/LABA combinations. The triple combinations have been shown in several studies to lower risk of exacerbations and are associated with both better lung function and health-related quality of life, compared with dual therapies, the investigators noted.

However, concerns about adverse events associated with long-term ICS use – including pneumonia, cataracts, and increased fracture risk, possibly related to treatment duration, dose level, or type of corticosteroid used – spurred the ETHOS investigators to compare triple and dual fixed-dose combinations for efficacy and safety over 1 year.
 

Large study

They enrolled 8,509 adults aged 40-80 years with symptomatic COPD (defined as score of 10 or higher on the 40-point COPD Assessment Test). All patients were receiving at least two inhaled maintenance therapies at the time of screening, and had a postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, with a postbronchodilator FEV₁ of 25%-65% of the predicted normal value. The patients all had a smoking history of at least 10 pack-years and a documented history of at least one moderate or severe COPD exacerbation in the year before screening.

The patients were randomized in equal proportions to receive triple therapy with budesonide at 320- or 160-mcg doses plus glycopyrrolate 18 mcg, and formoterol 9.6 mcg twice daily, or to dual therapy with either glycopyrrolate plus formoterol at the same doses, or 320 mcg budesonide plus 9.6 mcg formoterol.

As noted, for the primary endpoint of the estimated annual rate of moderate or severe exacerbations, the triple combinations were associated with significantly lower rates, with a 24% lower rate (rate ratio, 0.76) with 320 mcg budesonide triple therapy, compared with glycopyrrolate-formoterol, and a 13% lower rate (RR, 0.87), compared with budesonide formoterol (P < .001 and P = .003, respectively).

The triple combination with the 160-mcg budesonide dose was associated with a 25% lower annual rate of exacerbations (RR, 0.75) vs. glycopyrrolate-formoterol, and a 14% lower rate (RR, 0.86) vs. budesonide-formoterol (P < .001 and P = .002, respectively).

Secondary efficacy endpoints also favored the triple combination, including a 20% lower rate ratio of severe exacerbations over 52 weeks for the 320-mcg budesonide group, compared with the budesonide-formoterol group (P = .02).

The 320-mcg dose combination was also associated with a 46% lower risk for all-cause mortality, compared with glycopyrrolate-formoterol (hazard ratio, 0.54; P = .0111).

Confirmed pneumonia was seen in 4.2% of patients on the 320-mcg budesonide dose, 3.5% of those in the 160-mcg group, and 4.5% of patients treated with budesonide-formoterol. The incidence of any adverse effect was similar across the treatment groups, ranging from 61.7% to 64.5%.
 

Balance exacerbation, pneumonia risk

In the question-and-answer session following his online presentation, Dr. Rabe was asked how the investigators reconciled their data showing increased incidence of pneumonia in budenoside-containing formulations with claims by the maker of the budesonide-formoterol (Symbicort, AstraZeneca) that budesonide is not associated with increased risk of pneumonia.

“We have to say that there are individuals that we have to balance the benefit of [less] exacerbation against the risk of pneumonia,” he replied, but noted that the size of the effect, observed both in ETHOS and in the KRONOS trial, was relatively small.

“This definitely adds some information for us to think about when we’re trying to do risk-benefit analysis,” commented MeiLan K. Han, MD, MS, from the University of Michigan, who moderated the session but was not involved in the study.

The ETHOS trial was funded by AstraZeneca. Dr. Rabe disclosed consulting/advisory board activity with that company and others. Dr. Han has previously disclosed consulting/advising and research funding relationships with other companies.

SOURCE: Rabe KF et al. N Engl J Med. 2020 Jun 24. doi: 10.1056/NEJMoa1916046.

Patients with Philadelphia chromosome–positive acute lymphoblastic or chronic myeloid leukemias in lymphoid blast phase may have longer event-free and overall survival with a combination of inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif) than with standard chemotherapy combined with a targeted agent, investigators in a phase 1/2 study reported.

Among patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia (Ph+ CML) in lymphoid blast phase treated with inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif), the median overall survival was 15.4 months. In contrast, median overall survival for similar patients treated with chemotherapy and a tyrosine kinase inhibitor (TKI) was less than 6 months, reported Nitin Jain, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.

The study was presented in a scientific poster session as part of the virtual annual congress of the European Hematology Association.

“Patients with relapsed/refractory Philadelphia chromosome–positive ALL/CML in lymphoid blast crisis are also best managed with a TKI targeting the constitutively active ABL kinase with the TKI selected based on presence of ABL kinase mutations and prior TKI history,” commented Marlise R. Luskin, MD, a leukemia specialist at the Dana-Farber Cancer Institute in Boston.

“A critical question for this patient population is whether these two approaches [TKI and inotuzumab ozogamicin] can be administered safely in combination. I congratulate MD Anderson for completion of this Phase I trial which demonstrates that inotuzumab and bosutinib can be safely combined with identification of a maximum tolerated dose of bosutinib 400 mg daily when administered in combination. I look forward to further studies that explore the efficacy of combination versus the approved single-agent regimen,” she said in an interview.
 

Study details

To see whether they could improve the dismal outcomes for patients with Ph+ ALL or Ph+ CML in lymphoid blast phase, they studied the combination of inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, and bosutinib, an inhibitor of the ABL kinase. Inotuzumab is approved in the United States for treatment of adults with relapsed or refractory B-cell precursor ALL, bosutinib is approved for the treatment of patients with newly-diagnosed chronic phase Ph+ CML and for adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The investigators enrolled 16 patients with Ph+ ALL and 2 with Ph+ CML with bone marrow blasts greater than 5%, CD22 expressed on at least 20% of blasts, and good to fair performance status. The patients also had adequate organ function as measured by liver enzyme, total bilirubin, and serum creatinine levels. Patients with the T315I mutation, prior anti-CD22 therapy, active graft-versus-host disease, or liver disease were excluded.

The patients received inotuzumab 0.8 mg/m² intravenously on day 1, they received 0.5 mg/m² on days 8 and 15 of cycle 1, and they received 0.5 mg/m² on days 1, 8, and 15 of cycles 2 through 6. Each cycle was 4 weeks. Patients who had a complete remission (CR), had complete cytogenetic remission (CCyR), or became negative for minimal residual disease (MRD) continued on 1 mg/m² every 4 weeks. Bosutinib was dosed continuously day starting on the first day of cycle 1 and continued until disease progression or toxicity.

After a median follow-up of 36.7 months, 11 of the 18 patients had CRs, and 4 had CRs with incomplete recovery of hematologic counts. In addition, 13 of 16 patients with without diploid cytogenetics at the start of the study had CCyr; 14 patients had major molecular remission; 10 had complete molecular remission, and 11 were negative by flow cytometry.

As noted before, the median overall survival was 15.4 months. Event-free survival – time to lack of response, relapse, MRD relapse requiring therapy, or death – was 8 months. The event-free survival data were not censored for allogeneic stem cell transplant. Six patients underwent transplant while in remission.

The primary objective of the phase 1 trial was to evaluate safety of the combination and determine the maximum tolerated dose of bosutinib, which was determined to be 400 mg daily. At this dose level, one patient had a dose-limiting toxicity in the form of a grade 3 skin rash.

The most frequent adverse events were diarrhea and rash, in 50% of patients each, and nausea in 39% of patients. Grade 3 adverse events included were rash in three patients and reversible alanine aminotransferase and hyponatremia in one patient each. No patients developed veno-occlusive disease, and there no deaths within 30 days of the start of therapy.

Dr. Jain disclosed consultancy, honoraria, advisory board/committee activity, and research funding from Pfizer, maker of inotuzumab ozogamicin and bosutinib. Dr. Luskin reported no relevant disclosures.

SOURCE: Jain N et al. EHA25, Abstract EP396.

Patients with Philadelphia chromosome–positive acute lymphoblastic or chronic myeloid leukemias in lymphoid blast phase may have longer event-free and overall survival with a combination of inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif) than with standard chemotherapy combined with a targeted agent, investigators in a phase 1/2 study reported.

Among patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia (Ph+ CML) in lymphoid blast phase treated with inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif), the median overall survival was 15.4 months. In contrast, median overall survival for similar patients treated with chemotherapy and a tyrosine kinase inhibitor (TKI) was less than 6 months, reported Nitin Jain, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.

The study was presented in a scientific poster session as part of the virtual annual congress of the European Hematology Association.

“Patients with relapsed/refractory Philadelphia chromosome–positive ALL/CML in lymphoid blast crisis are also best managed with a TKI targeting the constitutively active ABL kinase with the TKI selected based on presence of ABL kinase mutations and prior TKI history,” commented Marlise R. Luskin, MD, a leukemia specialist at the Dana-Farber Cancer Institute in Boston.

“A critical question for this patient population is whether these two approaches [TKI and inotuzumab ozogamicin] can be administered safely in combination. I congratulate MD Anderson for completion of this Phase I trial which demonstrates that inotuzumab and bosutinib can be safely combined with identification of a maximum tolerated dose of bosutinib 400 mg daily when administered in combination. I look forward to further studies that explore the efficacy of combination versus the approved single-agent regimen,” she said in an interview.
 

Study details

To see whether they could improve the dismal outcomes for patients with Ph+ ALL or Ph+ CML in lymphoid blast phase, they studied the combination of inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, and bosutinib, an inhibitor of the ABL kinase. Inotuzumab is approved in the United States for treatment of adults with relapsed or refractory B-cell precursor ALL, bosutinib is approved for the treatment of patients with newly-diagnosed chronic phase Ph+ CML and for adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The investigators enrolled 16 patients with Ph+ ALL and 2 with Ph+ CML with bone marrow blasts greater than 5%, CD22 expressed on at least 20% of blasts, and good to fair performance status. The patients also had adequate organ function as measured by liver enzyme, total bilirubin, and serum creatinine levels. Patients with the T315I mutation, prior anti-CD22 therapy, active graft-versus-host disease, or liver disease were excluded.

The patients received inotuzumab 0.8 mg/m² intravenously on day 1, they received 0.5 mg/m² on days 8 and 15 of cycle 1, and they received 0.5 mg/m² on days 1, 8, and 15 of cycles 2 through 6. Each cycle was 4 weeks. Patients who had a complete remission (CR), had complete cytogenetic remission (CCyR), or became negative for minimal residual disease (MRD) continued on 1 mg/m² every 4 weeks. Bosutinib was dosed continuously day starting on the first day of cycle 1 and continued until disease progression or toxicity.

After a median follow-up of 36.7 months, 11 of the 18 patients had CRs, and 4 had CRs with incomplete recovery of hematologic counts. In addition, 13 of 16 patients with without diploid cytogenetics at the start of the study had CCyr; 14 patients had major molecular remission; 10 had complete molecular remission, and 11 were negative by flow cytometry.

As noted before, the median overall survival was 15.4 months. Event-free survival – time to lack of response, relapse, MRD relapse requiring therapy, or death – was 8 months. The event-free survival data were not censored for allogeneic stem cell transplant. Six patients underwent transplant while in remission.

The primary objective of the phase 1 trial was to evaluate safety of the combination and determine the maximum tolerated dose of bosutinib, which was determined to be 400 mg daily. At this dose level, one patient had a dose-limiting toxicity in the form of a grade 3 skin rash.

The most frequent adverse events were diarrhea and rash, in 50% of patients each, and nausea in 39% of patients. Grade 3 adverse events included were rash in three patients and reversible alanine aminotransferase and hyponatremia in one patient each. No patients developed veno-occlusive disease, and there no deaths within 30 days of the start of therapy.

Dr. Jain disclosed consultancy, honoraria, advisory board/committee activity, and research funding from Pfizer, maker of inotuzumab ozogamicin and bosutinib. Dr. Luskin reported no relevant disclosures.

SOURCE: Jain N et al. EHA25, Abstract EP396.

Patients with Philadelphia chromosome–positive acute lymphoblastic or chronic myeloid leukemias in lymphoid blast phase may have longer event-free and overall survival with a combination of inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif) than with standard chemotherapy combined with a targeted agent, investigators in a phase 1/2 study reported.

Among patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia (Ph+ CML) in lymphoid blast phase treated with inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif), the median overall survival was 15.4 months. In contrast, median overall survival for similar patients treated with chemotherapy and a tyrosine kinase inhibitor (TKI) was less than 6 months, reported Nitin Jain, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.

The study was presented in a scientific poster session as part of the virtual annual congress of the European Hematology Association.

“Patients with relapsed/refractory Philadelphia chromosome–positive ALL/CML in lymphoid blast crisis are also best managed with a TKI targeting the constitutively active ABL kinase with the TKI selected based on presence of ABL kinase mutations and prior TKI history,” commented Marlise R. Luskin, MD, a leukemia specialist at the Dana-Farber Cancer Institute in Boston.

“A critical question for this patient population is whether these two approaches [TKI and inotuzumab ozogamicin] can be administered safely in combination. I congratulate MD Anderson for completion of this Phase I trial which demonstrates that inotuzumab and bosutinib can be safely combined with identification of a maximum tolerated dose of bosutinib 400 mg daily when administered in combination. I look forward to further studies that explore the efficacy of combination versus the approved single-agent regimen,” she said in an interview.
 

Study details

To see whether they could improve the dismal outcomes for patients with Ph+ ALL or Ph+ CML in lymphoid blast phase, they studied the combination of inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, and bosutinib, an inhibitor of the ABL kinase. Inotuzumab is approved in the United States for treatment of adults with relapsed or refractory B-cell precursor ALL, bosutinib is approved for the treatment of patients with newly-diagnosed chronic phase Ph+ CML and for adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The investigators enrolled 16 patients with Ph+ ALL and 2 with Ph+ CML with bone marrow blasts greater than 5%, CD22 expressed on at least 20% of blasts, and good to fair performance status. The patients also had adequate organ function as measured by liver enzyme, total bilirubin, and serum creatinine levels. Patients with the T315I mutation, prior anti-CD22 therapy, active graft-versus-host disease, or liver disease were excluded.

The patients received inotuzumab 0.8 mg/m² intravenously on day 1, they received 0.5 mg/m² on days 8 and 15 of cycle 1, and they received 0.5 mg/m² on days 1, 8, and 15 of cycles 2 through 6. Each cycle was 4 weeks. Patients who had a complete remission (CR), had complete cytogenetic remission (CCyR), or became negative for minimal residual disease (MRD) continued on 1 mg/m² every 4 weeks. Bosutinib was dosed continuously day starting on the first day of cycle 1 and continued until disease progression or toxicity.

After a median follow-up of 36.7 months, 11 of the 18 patients had CRs, and 4 had CRs with incomplete recovery of hematologic counts. In addition, 13 of 16 patients with without diploid cytogenetics at the start of the study had CCyr; 14 patients had major molecular remission; 10 had complete molecular remission, and 11 were negative by flow cytometry.

As noted before, the median overall survival was 15.4 months. Event-free survival – time to lack of response, relapse, MRD relapse requiring therapy, or death – was 8 months. The event-free survival data were not censored for allogeneic stem cell transplant. Six patients underwent transplant while in remission.

The primary objective of the phase 1 trial was to evaluate safety of the combination and determine the maximum tolerated dose of bosutinib, which was determined to be 400 mg daily. At this dose level, one patient had a dose-limiting toxicity in the form of a grade 3 skin rash.

The most frequent adverse events were diarrhea and rash, in 50% of patients each, and nausea in 39% of patients. Grade 3 adverse events included were rash in three patients and reversible alanine aminotransferase and hyponatremia in one patient each. No patients developed veno-occlusive disease, and there no deaths within 30 days of the start of therapy.

Dr. Jain disclosed consultancy, honoraria, advisory board/committee activity, and research funding from Pfizer, maker of inotuzumab ozogamicin and bosutinib. Dr. Luskin reported no relevant disclosures.

SOURCE: Jain N et al. EHA25, Abstract EP396.

Therapy-related acute lymphoblastic leukemia (tALL) is less common and less well known than therapy-related acute myeloid leukemia, but tALL also appears to be associated with poor-prognosis features, compared with de novo ALL, investigators said.

“Currently, this condition is not fully recognized by the [World Health Organization] classification, but it has emerged as a relevant and increasingly common form of ALL. There is no standardized therapy for tALL at this time due to the rarity of the condition. Therefore, more information regarding characteristics, prognosis, and treatment is needed,” wrote Brayan Merchán, MD, and colleagues at Princess Margaret Hospital in Toronto.

At their center, the median overall survival (OS) among 58 patients with tALL who received front line induction therapy was 13 months, although patients who were able to undergo hematopoietic stem cell transplant had a 400% longer OS than patients who did not receive HSCT, they reported in an electronic poster presented as part of the virtual annual congress of the European Hematology Association.

A hematologist-oncologist who has studied tALL agreed that it appears to be a distinct clinical entity from de novo ALL.

“It is distinct from the other ALL because the age [at diagnosis] is different, the cytogenetic and molecular profiles are different, and while responses are the same, it seems that survival is lower in cases who don’t go through bone marrow transplant as consolidation,” said Ibrahim Aldoss, MD, from City of Hope Medical Center in Duarte, Calif.

Dr. Aldoss, who was not involved in the study, was the lead author of a study published in 2018 which found that, “[a]lthough survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities” (Haematologica. 2018 Oct; 103[10]:1662-8).

He noted that induction regimen options for patients with tALL may be limited because some patients may had previous exposures to cytotoxic chemotherapy agents – such as anthracyclines used in standard regimens for breast cancer – that have cumulative toxicities and lifetime dose limits.

In addition, “these patients tend to be older, because they went through another cancer and then developed therapy-related ALL, and usually they’re not eligible for pediatric-inspired regimens that we use more frequently in younger patients,” he said.
 

Retrospective study

Dr. Merchán and colleagues conducted a retrospective study of all consecutive adults with ALL treated at their center from 1999 to 2019 and followed until January 2020. Of this group, they identified 59 patients who had been exposed to chemotherapy or radiation for other diseases prior to their ALL diagnosis.

The mean age of the 59 patients (31 women and 28 men) was 54.7 years. In all, 34 had solid cancers and 25 had hematologic malignancies before their ALL diagnosis. The most common diagnosis was breast cancer in 15 patients, followed by multiple myeloma in 11, lymphoma in 7, and AML in 5. Other prior diagnoses were not specified.

Prior therapies included chemotherapy alone in 18 patients, radiotherapy alone in 19, and 20 had both treatment modalities (information about 2 remaining patients was not presented).

For the overall population the median time to tALL diagnosis was 5 years, but for 9 patients with the poor-prognosis MLL gene rearrangement the median time to tALL was just 21 months. The disease latency period was 21 months for patients who received chemotherapy, compared with 117 months for patients treated with radiotherapy.

The majority of patients (53) had B-phenotype ALL. Of the 49 for whom cytogenetic data were available, 41 had cytogenetic abnormalities, including the MLL rearrangement in 9, and complex karyotype in 7. Of all 59 patients, 12 had translocation t(9;22).

One patient did not undergo induction therapy for ALL because of poor performance status. All of the other patients received induction therapy, either a Dana-Farber Cancer Institute protocol in 44 patients, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in 5, or blinatumomab in 3.

A complete response was seen in 41 patients (70%); 7 patients died during induction from causes attributed to therapy.

The mean follow-up for all patients was 27 months, and median overall survival was 13 months.

Median overall survival was 98 months for patients who underwent allogeneic HSCT versus a median of 19 months for patients who did not undergo transplant. This difference was not statistically significant, however, likely because of the small sample size.

Causes of death in 11 patients after transplant included relapse in 4 and graft-versus-host disease in 2 (other causes were not specified). Among the 34 patients who did not undergo HSCT following induction, 15 died from disease progression.

“From our results, tALL patients who were able to receive HSCT had better OS. Our data also supports the notion that tALL may be distinct entity with poor prognosis features compared to de novo ALL,” the investigators concluded.

The authors did not disclose a funding source. Dr. Merchán and Dr. Aldoss reported no relevant disclosures.

SOURCE: Merchán B et al. EHA25, Abstract EP391.

Therapy-related acute lymphoblastic leukemia (tALL) is less common and less well known than therapy-related acute myeloid leukemia, but tALL also appears to be associated with poor-prognosis features, compared with de novo ALL, investigators said.

“Currently, this condition is not fully recognized by the [World Health Organization] classification, but it has emerged as a relevant and increasingly common form of ALL. There is no standardized therapy for tALL at this time due to the rarity of the condition. Therefore, more information regarding characteristics, prognosis, and treatment is needed,” wrote Brayan Merchán, MD, and colleagues at Princess Margaret Hospital in Toronto.

At their center, the median overall survival (OS) among 58 patients with tALL who received front line induction therapy was 13 months, although patients who were able to undergo hematopoietic stem cell transplant had a 400% longer OS than patients who did not receive HSCT, they reported in an electronic poster presented as part of the virtual annual congress of the European Hematology Association.

A hematologist-oncologist who has studied tALL agreed that it appears to be a distinct clinical entity from de novo ALL.

“It is distinct from the other ALL because the age [at diagnosis] is different, the cytogenetic and molecular profiles are different, and while responses are the same, it seems that survival is lower in cases who don’t go through bone marrow transplant as consolidation,” said Ibrahim Aldoss, MD, from City of Hope Medical Center in Duarte, Calif.

Dr. Aldoss, who was not involved in the study, was the lead author of a study published in 2018 which found that, “[a]lthough survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities” (Haematologica. 2018 Oct; 103[10]:1662-8).

He noted that induction regimen options for patients with tALL may be limited because some patients may had previous exposures to cytotoxic chemotherapy agents – such as anthracyclines used in standard regimens for breast cancer – that have cumulative toxicities and lifetime dose limits.

In addition, “these patients tend to be older, because they went through another cancer and then developed therapy-related ALL, and usually they’re not eligible for pediatric-inspired regimens that we use more frequently in younger patients,” he said.
 

Retrospective study

Dr. Merchán and colleagues conducted a retrospective study of all consecutive adults with ALL treated at their center from 1999 to 2019 and followed until January 2020. Of this group, they identified 59 patients who had been exposed to chemotherapy or radiation for other diseases prior to their ALL diagnosis.

The mean age of the 59 patients (31 women and 28 men) was 54.7 years. In all, 34 had solid cancers and 25 had hematologic malignancies before their ALL diagnosis. The most common diagnosis was breast cancer in 15 patients, followed by multiple myeloma in 11, lymphoma in 7, and AML in 5. Other prior diagnoses were not specified.

Prior therapies included chemotherapy alone in 18 patients, radiotherapy alone in 19, and 20 had both treatment modalities (information about 2 remaining patients was not presented).

For the overall population the median time to tALL diagnosis was 5 years, but for 9 patients with the poor-prognosis MLL gene rearrangement the median time to tALL was just 21 months. The disease latency period was 21 months for patients who received chemotherapy, compared with 117 months for patients treated with radiotherapy.

The majority of patients (53) had B-phenotype ALL. Of the 49 for whom cytogenetic data were available, 41 had cytogenetic abnormalities, including the MLL rearrangement in 9, and complex karyotype in 7. Of all 59 patients, 12 had translocation t(9;22).

One patient did not undergo induction therapy for ALL because of poor performance status. All of the other patients received induction therapy, either a Dana-Farber Cancer Institute protocol in 44 patients, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in 5, or blinatumomab in 3.

A complete response was seen in 41 patients (70%); 7 patients died during induction from causes attributed to therapy.

The mean follow-up for all patients was 27 months, and median overall survival was 13 months.

Median overall survival was 98 months for patients who underwent allogeneic HSCT versus a median of 19 months for patients who did not undergo transplant. This difference was not statistically significant, however, likely because of the small sample size.

Causes of death in 11 patients after transplant included relapse in 4 and graft-versus-host disease in 2 (other causes were not specified). Among the 34 patients who did not undergo HSCT following induction, 15 died from disease progression.

“From our results, tALL patients who were able to receive HSCT had better OS. Our data also supports the notion that tALL may be distinct entity with poor prognosis features compared to de novo ALL,” the investigators concluded.

The authors did not disclose a funding source. Dr. Merchán and Dr. Aldoss reported no relevant disclosures.

SOURCE: Merchán B et al. EHA25, Abstract EP391.

Therapy-related acute lymphoblastic leukemia (tALL) is less common and less well known than therapy-related acute myeloid leukemia, but tALL also appears to be associated with poor-prognosis features, compared with de novo ALL, investigators said.

“Currently, this condition is not fully recognized by the [World Health Organization] classification, but it has emerged as a relevant and increasingly common form of ALL. There is no standardized therapy for tALL at this time due to the rarity of the condition. Therefore, more information regarding characteristics, prognosis, and treatment is needed,” wrote Brayan Merchán, MD, and colleagues at Princess Margaret Hospital in Toronto.

At their center, the median overall survival (OS) among 58 patients with tALL who received front line induction therapy was 13 months, although patients who were able to undergo hematopoietic stem cell transplant had a 400% longer OS than patients who did not receive HSCT, they reported in an electronic poster presented as part of the virtual annual congress of the European Hematology Association.

A hematologist-oncologist who has studied tALL agreed that it appears to be a distinct clinical entity from de novo ALL.

“It is distinct from the other ALL because the age [at diagnosis] is different, the cytogenetic and molecular profiles are different, and while responses are the same, it seems that survival is lower in cases who don’t go through bone marrow transplant as consolidation,” said Ibrahim Aldoss, MD, from City of Hope Medical Center in Duarte, Calif.

Dr. Aldoss, who was not involved in the study, was the lead author of a study published in 2018 which found that, “[a]lthough survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities” (Haematologica. 2018 Oct; 103[10]:1662-8).

He noted that induction regimen options for patients with tALL may be limited because some patients may had previous exposures to cytotoxic chemotherapy agents – such as anthracyclines used in standard regimens for breast cancer – that have cumulative toxicities and lifetime dose limits.

In addition, “these patients tend to be older, because they went through another cancer and then developed therapy-related ALL, and usually they’re not eligible for pediatric-inspired regimens that we use more frequently in younger patients,” he said.
 

Retrospective study

Dr. Merchán and colleagues conducted a retrospective study of all consecutive adults with ALL treated at their center from 1999 to 2019 and followed until January 2020. Of this group, they identified 59 patients who had been exposed to chemotherapy or radiation for other diseases prior to their ALL diagnosis.

The mean age of the 59 patients (31 women and 28 men) was 54.7 years. In all, 34 had solid cancers and 25 had hematologic malignancies before their ALL diagnosis. The most common diagnosis was breast cancer in 15 patients, followed by multiple myeloma in 11, lymphoma in 7, and AML in 5. Other prior diagnoses were not specified.

Prior therapies included chemotherapy alone in 18 patients, radiotherapy alone in 19, and 20 had both treatment modalities (information about 2 remaining patients was not presented).

For the overall population the median time to tALL diagnosis was 5 years, but for 9 patients with the poor-prognosis MLL gene rearrangement the median time to tALL was just 21 months. The disease latency period was 21 months for patients who received chemotherapy, compared with 117 months for patients treated with radiotherapy.

The majority of patients (53) had B-phenotype ALL. Of the 49 for whom cytogenetic data were available, 41 had cytogenetic abnormalities, including the MLL rearrangement in 9, and complex karyotype in 7. Of all 59 patients, 12 had translocation t(9;22).

One patient did not undergo induction therapy for ALL because of poor performance status. All of the other patients received induction therapy, either a Dana-Farber Cancer Institute protocol in 44 patients, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in 5, or blinatumomab in 3.

A complete response was seen in 41 patients (70%); 7 patients died during induction from causes attributed to therapy.

The mean follow-up for all patients was 27 months, and median overall survival was 13 months.

Median overall survival was 98 months for patients who underwent allogeneic HSCT versus a median of 19 months for patients who did not undergo transplant. This difference was not statistically significant, however, likely because of the small sample size.

Causes of death in 11 patients after transplant included relapse in 4 and graft-versus-host disease in 2 (other causes were not specified). Among the 34 patients who did not undergo HSCT following induction, 15 died from disease progression.

“From our results, tALL patients who were able to receive HSCT had better OS. Our data also supports the notion that tALL may be distinct entity with poor prognosis features compared to de novo ALL,” the investigators concluded.

The authors did not disclose a funding source. Dr. Merchán and Dr. Aldoss reported no relevant disclosures.

SOURCE: Merchán B et al. EHA25, Abstract EP391.

The risk of progression or death for patients with relapsed or refractory multiple myeloma was nearly halved with the addition of isatuximab to carfilzomib and dexamethasone, according to an interim analysis of the phase 3 IKEMA trial (NCT03275285).

After a median follow-up of 20.7 months, the median progression-free survival had not been reached for 179 patients treated with isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (together, known as Isa-Kd), compared with 19.5 months for 123 patients treated with carfilzomib and dexamethasone alone (Kd). The hazard ratio for progression free survival with the triple combination was 0.531 (P = .0007), reported coprincipal investigator Phillipe Moreau, MD, from the University Hospital Hôtel-Dieu in Nantes, France.

“The benefit of the triplet combination was observed across subgroups, including patients difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” he said in a late-breaking abstract presentation during the virtual annual congress of the European Hematology Association.

Isatuximab is an immunoglobulin G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein on multiple myeloma cells, with a mechanism of action similar to that of another anti-CD38 antibody, daratumumab (Darzalex). Isatuximab is approved in the United States and Europe in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma after at least two prior lines of therapy.
 

A ‘me too’ agent?

It’s unclear, however, whether isatuximab offers any additional benefit over daratumumab, an agent approved for use both in front line therapy combinations and for patients with relapsed/refractory disease, said Brea C. Lipe, MD, a multiple myeloma specialist at the University of Rochester (N.Y.) Wilmot Cancer Institute, who was not involved in the study.

“Every time we get a new drug it’s nice to have another option, but it doesn’t really add anything different from daratumumab at this point,” she said in an interview.

Dr. Lipe noted the IKEMA results are similar to those seen in the phase 3 CANDOR trial, comparing carfilzomib, dexamethasone, and daratumumab to carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. In addition, it’s unknown whether patients with disease that is refractory to daratumumab could benefit from isatuximab, she said.

Although isatuximab has been touted as offering more rapid and more convenient dosing than daratumumab, the introduction of rapid infusion and subcutaneous administration of daratumumab has negated any theoretical advantage of the newcomer, Dr. Lipe added.
 

Study details

In the IKEMA trial, 302 patients with relapsed/refractory multiple myeloma who’d received one to three prior lines of therapy were stratified by the number of prior lines and by revised Multiple Myeloma International Staging System (R-ISS) and were then randomized on a 3:2 basis to treatment with carfilzomib 20 mg/m² on days 1, 2, 8, 9, 15, and 16 of cycle 1 and 56 mg/m² on the corresponding days of each subsequent cycle plus dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle, with or without isatuximab. The antibody was dosed 10 mg/kg on days 1, 8, 15, and 22 in cycle 1 then every 2 weeks thereafter.

Treatments were continued until disease progression, unacceptable toxicity, or patient choice intervened.

At a prespecified interim analysis, the trial met its primary endpoint of a minimum 41% risk reduction in the hazard rate for progression free survival (PFS), with an actual risk reduction of 47%.

An analysis of PFS by subgroup showed significant benefits with the triple combination for patients aged 65 years and older, those with baseline estimated glomerular filtration rates below 60 mL/min per 1.73 m², those with more than one prior line of therapy, those who had not previously received a proteasome inhibitor (e.g., bortezomib) or immunomodulatory agent (e.g., lenalidomide), those with high-risk cytogenetic status, and those with R-ISS stage II at study entry.

Overall response rates were similar between the study arms, at 86.6% with Isa-Kd and 82.9% with Kd, but the rate of very good partial responses or better was significantly higher with the triplet, at 72.6% versus 56.1% (P = .0011). The rate of minimal residual disease negativity was also significantly lower with Isa-Kd in the intent-to-treat population, at 29.6% versus 13%, respectively (P = .0004).

Overall survival data were not mature at the time of data cutoff and will be reported later, Dr. Moreau said.

Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 76.8% of patients on the triplet and 67.2% of those on Kd. The incidences of death, serious TEAEs, or adverse events leading to discontinuation of therapy did not differ markedly between the treatment arms, however. Grade 3 or greater cardiac failure occurred in seven patients treated with the triplet (4%) and five treated with Kd (4.1%); respective rates of grade 3 or greater hematologic abnormalities included anemia in 22% and 19.7%, neutropenia in 19.2% and 7.4%, and thrombocytopenia in 29.9% and 23.8%.

The primary completion date for the trial is estimated to occur in November 2020, with final results in November 2023.

The study was sponsored by Sanofi. Dr. Moreau disclosed honoraria and a consulting or advisory role with several companies, not including Sanofi. Dr. Lipe disclosed impending advisory board activity for Janssen.

SOURCE: Moreau P et al. EHA Congress, Abstract LB2603.

The risk of progression or death for patients with relapsed or refractory multiple myeloma was nearly halved with the addition of isatuximab to carfilzomib and dexamethasone, according to an interim analysis of the phase 3 IKEMA trial (NCT03275285).

After a median follow-up of 20.7 months, the median progression-free survival had not been reached for 179 patients treated with isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (together, known as Isa-Kd), compared with 19.5 months for 123 patients treated with carfilzomib and dexamethasone alone (Kd). The hazard ratio for progression free survival with the triple combination was 0.531 (P = .0007), reported coprincipal investigator Phillipe Moreau, MD, from the University Hospital Hôtel-Dieu in Nantes, France.

“The benefit of the triplet combination was observed across subgroups, including patients difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” he said in a late-breaking abstract presentation during the virtual annual congress of the European Hematology Association.

Isatuximab is an immunoglobulin G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein on multiple myeloma cells, with a mechanism of action similar to that of another anti-CD38 antibody, daratumumab (Darzalex). Isatuximab is approved in the United States and Europe in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma after at least two prior lines of therapy.
 

A ‘me too’ agent?

It’s unclear, however, whether isatuximab offers any additional benefit over daratumumab, an agent approved for use both in front line therapy combinations and for patients with relapsed/refractory disease, said Brea C. Lipe, MD, a multiple myeloma specialist at the University of Rochester (N.Y.) Wilmot Cancer Institute, who was not involved in the study.

“Every time we get a new drug it’s nice to have another option, but it doesn’t really add anything different from daratumumab at this point,” she said in an interview.

Dr. Lipe noted the IKEMA results are similar to those seen in the phase 3 CANDOR trial, comparing carfilzomib, dexamethasone, and daratumumab to carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. In addition, it’s unknown whether patients with disease that is refractory to daratumumab could benefit from isatuximab, she said.

Although isatuximab has been touted as offering more rapid and more convenient dosing than daratumumab, the introduction of rapid infusion and subcutaneous administration of daratumumab has negated any theoretical advantage of the newcomer, Dr. Lipe added.
 

Study details

In the IKEMA trial, 302 patients with relapsed/refractory multiple myeloma who’d received one to three prior lines of therapy were stratified by the number of prior lines and by revised Multiple Myeloma International Staging System (R-ISS) and were then randomized on a 3:2 basis to treatment with carfilzomib 20 mg/m² on days 1, 2, 8, 9, 15, and 16 of cycle 1 and 56 mg/m² on the corresponding days of each subsequent cycle plus dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle, with or without isatuximab. The antibody was dosed 10 mg/kg on days 1, 8, 15, and 22 in cycle 1 then every 2 weeks thereafter.

Treatments were continued until disease progression, unacceptable toxicity, or patient choice intervened.

At a prespecified interim analysis, the trial met its primary endpoint of a minimum 41% risk reduction in the hazard rate for progression free survival (PFS), with an actual risk reduction of 47%.

An analysis of PFS by subgroup showed significant benefits with the triple combination for patients aged 65 years and older, those with baseline estimated glomerular filtration rates below 60 mL/min per 1.73 m², those with more than one prior line of therapy, those who had not previously received a proteasome inhibitor (e.g., bortezomib) or immunomodulatory agent (e.g., lenalidomide), those with high-risk cytogenetic status, and those with R-ISS stage II at study entry.

Overall response rates were similar between the study arms, at 86.6% with Isa-Kd and 82.9% with Kd, but the rate of very good partial responses or better was significantly higher with the triplet, at 72.6% versus 56.1% (P = .0011). The rate of minimal residual disease negativity was also significantly lower with Isa-Kd in the intent-to-treat population, at 29.6% versus 13%, respectively (P = .0004).

Overall survival data were not mature at the time of data cutoff and will be reported later, Dr. Moreau said.

Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 76.8% of patients on the triplet and 67.2% of those on Kd. The incidences of death, serious TEAEs, or adverse events leading to discontinuation of therapy did not differ markedly between the treatment arms, however. Grade 3 or greater cardiac failure occurred in seven patients treated with the triplet (4%) and five treated with Kd (4.1%); respective rates of grade 3 or greater hematologic abnormalities included anemia in 22% and 19.7%, neutropenia in 19.2% and 7.4%, and thrombocytopenia in 29.9% and 23.8%.

The primary completion date for the trial is estimated to occur in November 2020, with final results in November 2023.

The study was sponsored by Sanofi. Dr. Moreau disclosed honoraria and a consulting or advisory role with several companies, not including Sanofi. Dr. Lipe disclosed impending advisory board activity for Janssen.

SOURCE: Moreau P et al. EHA Congress, Abstract LB2603.

The risk of progression or death for patients with relapsed or refractory multiple myeloma was nearly halved with the addition of isatuximab to carfilzomib and dexamethasone, according to an interim analysis of the phase 3 IKEMA trial (NCT03275285).

After a median follow-up of 20.7 months, the median progression-free survival had not been reached for 179 patients treated with isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (together, known as Isa-Kd), compared with 19.5 months for 123 patients treated with carfilzomib and dexamethasone alone (Kd). The hazard ratio for progression free survival with the triple combination was 0.531 (P = .0007), reported coprincipal investigator Phillipe Moreau, MD, from the University Hospital Hôtel-Dieu in Nantes, France.

“The benefit of the triplet combination was observed across subgroups, including patients difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” he said in a late-breaking abstract presentation during the virtual annual congress of the European Hematology Association.

Isatuximab is an immunoglobulin G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein on multiple myeloma cells, with a mechanism of action similar to that of another anti-CD38 antibody, daratumumab (Darzalex). Isatuximab is approved in the United States and Europe in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma after at least two prior lines of therapy.
 

A ‘me too’ agent?

It’s unclear, however, whether isatuximab offers any additional benefit over daratumumab, an agent approved for use both in front line therapy combinations and for patients with relapsed/refractory disease, said Brea C. Lipe, MD, a multiple myeloma specialist at the University of Rochester (N.Y.) Wilmot Cancer Institute, who was not involved in the study.

“Every time we get a new drug it’s nice to have another option, but it doesn’t really add anything different from daratumumab at this point,” she said in an interview.

Dr. Lipe noted the IKEMA results are similar to those seen in the phase 3 CANDOR trial, comparing carfilzomib, dexamethasone, and daratumumab to carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. In addition, it’s unknown whether patients with disease that is refractory to daratumumab could benefit from isatuximab, she said.

Although isatuximab has been touted as offering more rapid and more convenient dosing than daratumumab, the introduction of rapid infusion and subcutaneous administration of daratumumab has negated any theoretical advantage of the newcomer, Dr. Lipe added.
 

Study details

In the IKEMA trial, 302 patients with relapsed/refractory multiple myeloma who’d received one to three prior lines of therapy were stratified by the number of prior lines and by revised Multiple Myeloma International Staging System (R-ISS) and were then randomized on a 3:2 basis to treatment with carfilzomib 20 mg/m² on days 1, 2, 8, 9, 15, and 16 of cycle 1 and 56 mg/m² on the corresponding days of each subsequent cycle plus dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle, with or without isatuximab. The antibody was dosed 10 mg/kg on days 1, 8, 15, and 22 in cycle 1 then every 2 weeks thereafter.

Treatments were continued until disease progression, unacceptable toxicity, or patient choice intervened.

At a prespecified interim analysis, the trial met its primary endpoint of a minimum 41% risk reduction in the hazard rate for progression free survival (PFS), with an actual risk reduction of 47%.

An analysis of PFS by subgroup showed significant benefits with the triple combination for patients aged 65 years and older, those with baseline estimated glomerular filtration rates below 60 mL/min per 1.73 m², those with more than one prior line of therapy, those who had not previously received a proteasome inhibitor (e.g., bortezomib) or immunomodulatory agent (e.g., lenalidomide), those with high-risk cytogenetic status, and those with R-ISS stage II at study entry.

Overall response rates were similar between the study arms, at 86.6% with Isa-Kd and 82.9% with Kd, but the rate of very good partial responses or better was significantly higher with the triplet, at 72.6% versus 56.1% (P = .0011). The rate of minimal residual disease negativity was also significantly lower with Isa-Kd in the intent-to-treat population, at 29.6% versus 13%, respectively (P = .0004).

Overall survival data were not mature at the time of data cutoff and will be reported later, Dr. Moreau said.

Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 76.8% of patients on the triplet and 67.2% of those on Kd. The incidences of death, serious TEAEs, or adverse events leading to discontinuation of therapy did not differ markedly between the treatment arms, however. Grade 3 or greater cardiac failure occurred in seven patients treated with the triplet (4%) and five treated with Kd (4.1%); respective rates of grade 3 or greater hematologic abnormalities included anemia in 22% and 19.7%, neutropenia in 19.2% and 7.4%, and thrombocytopenia in 29.9% and 23.8%.

The primary completion date for the trial is estimated to occur in November 2020, with final results in November 2023.

The study was sponsored by Sanofi. Dr. Moreau disclosed honoraria and a consulting or advisory role with several companies, not including Sanofi. Dr. Lipe disclosed impending advisory board activity for Janssen.

SOURCE: Moreau P et al. EHA Congress, Abstract LB2603.