The SVS Foundation has just published its 2019 Annual Report. This year, the report focuses on how past award recipients have used their grants to impact and improve patient care. More than $13 million in grants over the past three decades have given recipients the support they need to impact the lives of patients and those who provide care. Read about the stories, see the numbers and consider giving to the SVS Foundation in their 2019 Annual Report.

The SVS Foundation has just published its 2019 Annual Report. This year, the report focuses on how past award recipients have used their grants to impact and improve patient care. More than $13 million in grants over the past three decades have given recipients the support they need to impact the lives of patients and those who provide care. Read about the stories, see the numbers and consider giving to the SVS Foundation in their 2019 Annual Report.

The SVS Foundation has just published its 2019 Annual Report. This year, the report focuses on how past award recipients have used their grants to impact and improve patient care. More than $13 million in grants over the past three decades have given recipients the support they need to impact the lives of patients and those who provide care. Read about the stories, see the numbers and consider giving to the SVS Foundation in their 2019 Annual Report.

The SVS, in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), has launched a new leadership development program. Its aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. The program is open to academic and community practice vascular surgeons from the US or Canada who are 5-10 years out from training. Learn more here.

The SVS, in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), has launched a new leadership development program. Its aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. The program is open to academic and community practice vascular surgeons from the US or Canada who are 5-10 years out from training. Learn more here.

The SVS, in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), has launched a new leadership development program. Its aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. The program is open to academic and community practice vascular surgeons from the US or Canada who are 5-10 years out from training. Learn more here.

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Click here to access November 2019 Quality Improvement in Cardiovascular and Diabetes Care

Table of Contents

• Research News
• Open Clinical Trials for American Indians With Diabetes Mellitus
• Program Process Change to Improve Completion of Foot Exams and Amputation Risk Assessments for Veterans with Diabetes
• An Intervention to Address Obesity in Patients with Diabetes
• Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans
• A National Survey of Veterans Affairs Medical Centers’ Cardiology Services

Click here to access November 2019 Quality Improvement in Cardiovascular and Diabetes Care

Table of Contents

• Research News
• Open Clinical Trials for American Indians With Diabetes Mellitus
• Program Process Change to Improve Completion of Foot Exams and Amputation Risk Assessments for Veterans with Diabetes
• An Intervention to Address Obesity in Patients with Diabetes
• Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans
• A National Survey of Veterans Affairs Medical Centers’ Cardiology Services

Click here to access November 2019 Quality Improvement in Cardiovascular and Diabetes Care

Table of Contents

• Research News
• Open Clinical Trials for American Indians With Diabetes Mellitus
• Program Process Change to Improve Completion of Foot Exams and Amputation Risk Assessments for Veterans with Diabetes
• An Intervention to Address Obesity in Patients with Diabetes
• Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans
• A National Survey of Veterans Affairs Medical Centers’ Cardiology Services

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

[email protected]

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

[email protected]

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

[email protected]

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

[email protected]

Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.

Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.

Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.

Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.

Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.

Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.

Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.

Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.

Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.

Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.

Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.

Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.

Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.

Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.

Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.