Sharon Worcester

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

[email protected]

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

[email protected]

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

[email protected]

A cell-free DNA (cfDNA) test, or “liquid biopsy,” identifies more biomarkers and does so more quickly than tissue-based genotyping for guiding treatment in newly diagnosed advanced non–small cell lung cancer (NSCLC), according to a finding from a prospective study.

In 282 patients with newly diagnosed advanced NSCLC who were enrolled in the multicenter Noninvasive versus Invasive Lung Evaluation (NILE) study between July 2016 and April 2018, the “well-validated, comprehensive, and highly sensitive test” – Guardant360 – detected at least one guideline-recommended biomarker mutation in significantly more cases than did tissue-based tests alone (77 vs. 60 patients), Vassiliki A. Papadimitrakopoulou, MD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

“Additionally, the cfDNA results were delivered significantly faster than the standard-of-care tissue results [median, 9 vs. 15 days],” said Dr. Papadimitrakopoulou, chief of the section of thoracic medical oncology and the Jay and Lori Eisenberg Distinguished Professor in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston.


Guardant360 assesses for all guideline-recommended genomic biomarkers, Dr. Papadimitrakopoulou said, noting that nine such biomarkers have been identified. All biomarkers identified using the liquid biopsy were also detected in tissue every time.

“Plasma cfDNA testing therefore had 100% positive predictive value,” she said.

This is important, because “we know that about 30% of patients with newly diagnosed advanced non–small lung cancer have therapeutically targetable genomic alterations that make them eligible for targeted therapies,” she said.

“Identifying these patients is important, as the response rate to the properly identified targeted therapy is higher than response rates to first-line chemotherapy or immune checkpoint inhibitor therapy,” she added, explaining that tissue-based assessment has long been the standard of care option for identifying genomic biomarkers, but is limited by the risks associated with the biopsy procedure, the inability to test for all relevant mutations, and the time it takes – up to 30 days – to obtain results.

“[The NILE] results have very exciting implications for clinical practice, especially in light of the expanding list of genomic biomarkers to be assessed,” she said, concluding that the findings from NILE – the largest study of newly diagnosed advanced NSCLC – demonstrate that the clinical utility of this well-validated, comprehensive, sensitive cfDNA test “is cardinal in identification of patients with guideline-recommended biomarker-positive tumors, and it is an alternative to SOC [standard of care] tissue testing in the first-line testing.”

Clinical follow-up of patients is ongoing, she noted.

This study was funded by Guardant Health. Dr. Papadimitrakopoulou serves on the advisory boards of several pharmaceutical companies. She reported receiving CME speaker fees from F. Hoffmann–La Roche, and has received research support from Eli Lilly, Novartis, Merck, AstraZeneca, F. Hoffmann–La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte and Guardant Health.

SOURCE: Papadimitrakopoulou VA et al. AACR 2019, Abstract 4460..

A cell-free DNA (cfDNA) test, or “liquid biopsy,” identifies more biomarkers and does so more quickly than tissue-based genotyping for guiding treatment in newly diagnosed advanced non–small cell lung cancer (NSCLC), according to a finding from a prospective study.

In 282 patients with newly diagnosed advanced NSCLC who were enrolled in the multicenter Noninvasive versus Invasive Lung Evaluation (NILE) study between July 2016 and April 2018, the “well-validated, comprehensive, and highly sensitive test” – Guardant360 – detected at least one guideline-recommended biomarker mutation in significantly more cases than did tissue-based tests alone (77 vs. 60 patients), Vassiliki A. Papadimitrakopoulou, MD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

“Additionally, the cfDNA results were delivered significantly faster than the standard-of-care tissue results [median, 9 vs. 15 days],” said Dr. Papadimitrakopoulou, chief of the section of thoracic medical oncology and the Jay and Lori Eisenberg Distinguished Professor in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston.


Guardant360 assesses for all guideline-recommended genomic biomarkers, Dr. Papadimitrakopoulou said, noting that nine such biomarkers have been identified. All biomarkers identified using the liquid biopsy were also detected in tissue every time.

“Plasma cfDNA testing therefore had 100% positive predictive value,” she said.

This is important, because “we know that about 30% of patients with newly diagnosed advanced non–small lung cancer have therapeutically targetable genomic alterations that make them eligible for targeted therapies,” she said.

“Identifying these patients is important, as the response rate to the properly identified targeted therapy is higher than response rates to first-line chemotherapy or immune checkpoint inhibitor therapy,” she added, explaining that tissue-based assessment has long been the standard of care option for identifying genomic biomarkers, but is limited by the risks associated with the biopsy procedure, the inability to test for all relevant mutations, and the time it takes – up to 30 days – to obtain results.

“[The NILE] results have very exciting implications for clinical practice, especially in light of the expanding list of genomic biomarkers to be assessed,” she said, concluding that the findings from NILE – the largest study of newly diagnosed advanced NSCLC – demonstrate that the clinical utility of this well-validated, comprehensive, sensitive cfDNA test “is cardinal in identification of patients with guideline-recommended biomarker-positive tumors, and it is an alternative to SOC [standard of care] tissue testing in the first-line testing.”

Clinical follow-up of patients is ongoing, she noted.

This study was funded by Guardant Health. Dr. Papadimitrakopoulou serves on the advisory boards of several pharmaceutical companies. She reported receiving CME speaker fees from F. Hoffmann–La Roche, and has received research support from Eli Lilly, Novartis, Merck, AstraZeneca, F. Hoffmann–La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte and Guardant Health.

SOURCE: Papadimitrakopoulou VA et al. AACR 2019, Abstract 4460..

A cell-free DNA (cfDNA) test, or “liquid biopsy,” identifies more biomarkers and does so more quickly than tissue-based genotyping for guiding treatment in newly diagnosed advanced non–small cell lung cancer (NSCLC), according to a finding from a prospective study.

In 282 patients with newly diagnosed advanced NSCLC who were enrolled in the multicenter Noninvasive versus Invasive Lung Evaluation (NILE) study between July 2016 and April 2018, the “well-validated, comprehensive, and highly sensitive test” – Guardant360 – detected at least one guideline-recommended biomarker mutation in significantly more cases than did tissue-based tests alone (77 vs. 60 patients), Vassiliki A. Papadimitrakopoulou, MD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

“Additionally, the cfDNA results were delivered significantly faster than the standard-of-care tissue results [median, 9 vs. 15 days],” said Dr. Papadimitrakopoulou, chief of the section of thoracic medical oncology and the Jay and Lori Eisenberg Distinguished Professor in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston.


Guardant360 assesses for all guideline-recommended genomic biomarkers, Dr. Papadimitrakopoulou said, noting that nine such biomarkers have been identified. All biomarkers identified using the liquid biopsy were also detected in tissue every time.

“Plasma cfDNA testing therefore had 100% positive predictive value,” she said.

This is important, because “we know that about 30% of patients with newly diagnosed advanced non–small lung cancer have therapeutically targetable genomic alterations that make them eligible for targeted therapies,” she said.

“Identifying these patients is important, as the response rate to the properly identified targeted therapy is higher than response rates to first-line chemotherapy or immune checkpoint inhibitor therapy,” she added, explaining that tissue-based assessment has long been the standard of care option for identifying genomic biomarkers, but is limited by the risks associated with the biopsy procedure, the inability to test for all relevant mutations, and the time it takes – up to 30 days – to obtain results.

“[The NILE] results have very exciting implications for clinical practice, especially in light of the expanding list of genomic biomarkers to be assessed,” she said, concluding that the findings from NILE – the largest study of newly diagnosed advanced NSCLC – demonstrate that the clinical utility of this well-validated, comprehensive, sensitive cfDNA test “is cardinal in identification of patients with guideline-recommended biomarker-positive tumors, and it is an alternative to SOC [standard of care] tissue testing in the first-line testing.”

Clinical follow-up of patients is ongoing, she noted.

This study was funded by Guardant Health. Dr. Papadimitrakopoulou serves on the advisory boards of several pharmaceutical companies. She reported receiving CME speaker fees from F. Hoffmann–La Roche, and has received research support from Eli Lilly, Novartis, Merck, AstraZeneca, F. Hoffmann–La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte and Guardant Health.

SOURCE: Papadimitrakopoulou VA et al. AACR 2019, Abstract 4460..

A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
 

Hints of inflammation’s effects in non-RA patients

The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.

A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).

The trial was remarkable in that it was stopped early for efficacy, he noted.

“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”

The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).

Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.

Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
 

Effect of RA treatments on CVD risk

The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.

“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.

One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).

All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.

With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.

“I think we’ll know more about this in the near future,” he said.

As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.

The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.

Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
 

The TARGET trial

In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.

“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.

However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.

The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.

“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.

A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”

“The answer is partially yes and partially no,” he said.

The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.

RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).

“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.

“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.

The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.

“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
 

Hints of inflammation’s effects in non-RA patients

The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.

A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).

The trial was remarkable in that it was stopped early for efficacy, he noted.

“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”

The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).

Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.

Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
 

Effect of RA treatments on CVD risk

The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.

“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.

One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).

All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.

With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.

“I think we’ll know more about this in the near future,” he said.

As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.

The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.

Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
 

The TARGET trial

In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.

“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.

However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.

The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.

“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.

A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”

“The answer is partially yes and partially no,” he said.

The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.

RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).

“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.

“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.

The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.

“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
 

Hints of inflammation’s effects in non-RA patients

The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.

A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).

The trial was remarkable in that it was stopped early for efficacy, he noted.

“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”

The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).

Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.

Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
 

Effect of RA treatments on CVD risk

The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.

“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.

One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).

All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.

With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.

“I think we’ll know more about this in the near future,” he said.

As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.

The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.

Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
 

The TARGET trial

In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.

“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.

However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.

The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.

“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.

A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”

“The answer is partially yes and partially no,” he said.

The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.

RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).

“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.

“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.

The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.

“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – Allogeneic blood and marrow transplantation (alloBMT) with posttransplant cyclophosphamide (PTCy) is relatively safe and feasible in septuagenarians with hematologic malignancies and should be considered in this population, findings from a review of 108 cases suggest.

Sharon Worcester/MDedge News

The main difference in outcomes in older versus younger patients is a higher – but still low – rate of nonrelapse mortality (NRM) that appears to be due in part to age-related causes, Philip Hollingsworth Imus, MD, of Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, reported at the Transplantation & Cellular Therapy Meetings.

Overall survival (OS) among the 108 consecutive patients over age 70 years who underwent alloBMT at Johns Hopkins from Jan. 1, 2009, through March 31, 2018, was 64% at 1 year and 43% at 3 years, and progression-free survival (PFS) was 50% at 1 year and 32% at 3 years, Dr. Imus said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

NRM, especially later NRM, however, seemed to be increased, he said, noting that 6-month NRM was acceptable at 14%, but at 1 and 3 years it was 20% and 29%, respectively.

“In contrast to younger patients, [hematopoietic cell transplantation–specific comorbidity index] did not seem to predict NRM in our cohort,” he said.

Early causes of NRM were “in keeping with what we typically see,” and included pneumonia, sepsis, and a few cases of cytokine release syndrome, but later causes of NRM included some that are commonly seen in older patients without hematologic malignancies, such as secondary malignancies, dementia, falls, and cerebrovascular accidents, he said.

[email protected]

SOURCE: Imus P et al. TCT 2019, Abstract 42.

HOUSTON – Allogeneic blood and marrow transplantation (alloBMT) with posttransplant cyclophosphamide (PTCy) is relatively safe and feasible in septuagenarians with hematologic malignancies and should be considered in this population, findings from a review of 108 cases suggest.

Sharon Worcester/MDedge News

The main difference in outcomes in older versus younger patients is a higher – but still low – rate of nonrelapse mortality (NRM) that appears to be due in part to age-related causes, Philip Hollingsworth Imus, MD, of Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, reported at the Transplantation & Cellular Therapy Meetings.

Overall survival (OS) among the 108 consecutive patients over age 70 years who underwent alloBMT at Johns Hopkins from Jan. 1, 2009, through March 31, 2018, was 64% at 1 year and 43% at 3 years, and progression-free survival (PFS) was 50% at 1 year and 32% at 3 years, Dr. Imus said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

NRM, especially later NRM, however, seemed to be increased, he said, noting that 6-month NRM was acceptable at 14%, but at 1 and 3 years it was 20% and 29%, respectively.

“In contrast to younger patients, [hematopoietic cell transplantation–specific comorbidity index] did not seem to predict NRM in our cohort,” he said.

Early causes of NRM were “in keeping with what we typically see,” and included pneumonia, sepsis, and a few cases of cytokine release syndrome, but later causes of NRM included some that are commonly seen in older patients without hematologic malignancies, such as secondary malignancies, dementia, falls, and cerebrovascular accidents, he said.

[email protected]

SOURCE: Imus P et al. TCT 2019, Abstract 42.

HOUSTON – Allogeneic blood and marrow transplantation (alloBMT) with posttransplant cyclophosphamide (PTCy) is relatively safe and feasible in septuagenarians with hematologic malignancies and should be considered in this population, findings from a review of 108 cases suggest.

Sharon Worcester/MDedge News

The main difference in outcomes in older versus younger patients is a higher – but still low – rate of nonrelapse mortality (NRM) that appears to be due in part to age-related causes, Philip Hollingsworth Imus, MD, of Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, reported at the Transplantation & Cellular Therapy Meetings.

Overall survival (OS) among the 108 consecutive patients over age 70 years who underwent alloBMT at Johns Hopkins from Jan. 1, 2009, through March 31, 2018, was 64% at 1 year and 43% at 3 years, and progression-free survival (PFS) was 50% at 1 year and 32% at 3 years, Dr. Imus said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

NRM, especially later NRM, however, seemed to be increased, he said, noting that 6-month NRM was acceptable at 14%, but at 1 and 3 years it was 20% and 29%, respectively.

“In contrast to younger patients, [hematopoietic cell transplantation–specific comorbidity index] did not seem to predict NRM in our cohort,” he said.

Early causes of NRM were “in keeping with what we typically see,” and included pneumonia, sepsis, and a few cases of cytokine release syndrome, but later causes of NRM included some that are commonly seen in older patients without hematologic malignancies, such as secondary malignancies, dementia, falls, and cerebrovascular accidents, he said.

[email protected]

SOURCE: Imus P et al. TCT 2019, Abstract 42.

True polymyositis is rare, so it’s important to carefully consider other likely diagnoses, according to Lisa Christopher-Stine, MD.

“When someone refers you [a patient with suspected] polymyositis, I want you to do a checklist in your head and say, ‘Have I thought about these five things?’ ” Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

The five most common diagnoses in patients labeled as having polymyositis are immune-mediated necrotizing myopathy (IMNM), overlap with other rheumatologic conditions, antisynthetase syndrome, inclusion body myositis (IBM), and muscular dystrophy, she explained.

“You may say, ‘look, it’s all what you call it,’ but I think we need to be a little bit more careful in what we call it,” she said.

IMNM

Patients with IMNM present with clinical symptoms similar to those seen in polymyositis and dermatomyositis – mainly proximal muscle weakness.

However, there are some important differences, both clinically and histologically, Dr. Christopher-Stine said.

“Look for higher [creatine kinase (CK)] levels,” she said. “In the thousands, usually multiple thousands ... like 5,000, 10,000, 2,000 ... that’s when you’re thinking about a necrotizing phenotype before you even look at the biopsy.”

CK levels will usually be under 30,000 U/L in IMNM, she noted, adding that data increasingly suggest that the extensive muscle necrosis in IMNM explains the elevated CK levels versus those seen in other myopathies.

Myalgias also tend to be more prominent in IMNM than in polymyositis.

“These folks hurt,” she said, noting that IMNM patients tend to have more extensive muscle atrophy and functional disability. “Many will be wheelchair bound within 9 months of diagnosis; it’s not subtle.”

The most important tool for making an IMNM diagnosis is muscle biopsy; look for prominent myocyte necrosis and a relative paucity of lymphocytes, she advised.

Overlap

Sometimes patients with polymyositis also have other rheumatologic conditions that shouldn’t be overlooked, therefore “overlap is its own category,” she said.

“In our experience, the most common overlap is scleroderma,” she noted, adding that the scleroderma is often, but not always, subtle, and that there may be overlapping autoantibodies.

Overt sclerodactyly is rarely seen, although a small amount may be present, but significant Raynaud’s phenomenon is common in these patients, and tiny telangiectasias across the neck are a tell-tale sign.

“Why does that matter? It’s not an esoteric argument; those are the folks that go on to have pulmonary hypertension,” she said. “They can have the same [interstitial lung disease] and all of the other internal scleroderma manifestations.”

Think about overlap and “look close phenotypically and with antibodies,” she advised.

There is also “the typical RA seropositive overlap,” she said, but lupus only rarely overlaps with myositis.

“However, the next diagnosis on the list – antisynthetase syndrome – can be a forme fruste where you first see a seronegative RA-like picture, and it’s important to think about that as well,” she said.

Antisynthetase syndrome

In patients referred for polymyositis, it’s also important to evaluate for antisynthetase syndrome, Dr. Christopher-Stine said.

The arthritis seen in the extramuscular phenotype of the syndrome is rarely deforming, but despite what many physicians were taught, “it absolutely can be erosive,” she said.

In fact, 40% of people with this syndrome present with an isolated forme fruste seronegative rheumatoid arthritis, she said.

Roughening and desquamation of the skin on the radial surface of fingers or palms – a sign known as mechanic’s hands – that doesn’t have another identifiable cause suggests this diagnosis in patients with this type of arthritis, as does interstitial lung disease and Raynaud’s phenomenon.

The Raynaud’s can be “fairly significant in the sense that it is bothersome,” but it usually doesn’t lead to ulceration or digital necrosis.

This is different from what is seen with the scleroderma phenotype, she said, adding that “if you’re starting to see gangrene and digital loss, think of something else.”

IBM

IBM is “probably the No. 1 most-missed diagnosis” among patients referred for what is initially believed to be polymyositis, Dr. Christopher-Stine said.

“I used to think that this was missed at entry, that everybody [with IBM] had all of these criteria and that rheumatologists really didn’t understand this phenotype ... but some people morph into this,” she said, explaining that they often start out looking like they have polymyositis with proximal muscle weakness.

“They may even initially respond to steroids. And then they get this phenotype,” she said.

Older men are more likely to present with the phenotype from the beginning; women, in her experience, tend to present with what appears to be polymyositis, and then develop the phenotype over time, she noted.

An IBM diagnosis requires age over 30 years, but most patients are over 50, she said.

“This is the only one of the myopathies that is preferential to men,” she added, noting that it affects men twice as often as it does women.

The syndrome is characterized by proximal strength loss and muscle atrophy. Also, a finding that a patient’s knee extensors are weaker than their hip flexors is “a fantastic bedside sign” differentiating IBM from polymyositis, she said.

That’s not to say IBM patients don’t have hip flexor weakness, but their knee extensors usually are “considerably weaker by a grade strength or more” versus their hip flexors, she explained.

“It’s a very easy bedside test. In typical other myopathies we have this, but the knee extensors aren’t that weak in general, or they’re not as weak as the hip flexors,” she added.

Another sign is distal strength loss, particularly in the forearm and finger flexors.

“I was taught to have them make a fist; don’t have them make a fist,” she said, explaining that this recruits intrinsic muscles which basically allows cheating that may mask weakness.

Instead, ask them to flex just their distal interphalangeal joints by making a claw and using the fingers to pull against your fingers, she suggested.

Mixed myopathic and neuropathic features on electromyography also indicate IBM, she said.

Muscle biopsy may be helpful, but inclusions are seen in less than one-third of IBM patients.

“At times, we have had to biopsy three times to see them at all, and some people never show them, so you have to rely on your clinical acumen if you don’t see them,” she said.

Also, keep in mind that these patients are often labeled as having treatment-resistant polymyositis.

“Please, when somebody refers to you somebody that’s treatment resistant, that may be the case, but I want you to think maybe they’re treatment resistant because they don’t have that disease.”
 

Muscular dystrophy

Some cases of myositis mimic certain types of muscular dystrophy, Dr. Christopher-Stine said, providing a checklist of muscular dystrophies that can look “clinically completely indistinguishable from a typical inflammatory myopathy,” and should therefore be considered in these patients.

The checklist includes Duchenne’s manifesting carrier, limb girdle muscular dystrophy type 2b, myotonic dystrophy (usually type 2), and facioscapulohumeral muscular dystrophy.

Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.

[email protected]

True polymyositis is rare, so it’s important to carefully consider other likely diagnoses, according to Lisa Christopher-Stine, MD.

“When someone refers you [a patient with suspected] polymyositis, I want you to do a checklist in your head and say, ‘Have I thought about these five things?’ ” Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

The five most common diagnoses in patients labeled as having polymyositis are immune-mediated necrotizing myopathy (IMNM), overlap with other rheumatologic conditions, antisynthetase syndrome, inclusion body myositis (IBM), and muscular dystrophy, she explained.

“You may say, ‘look, it’s all what you call it,’ but I think we need to be a little bit more careful in what we call it,” she said.

IMNM

Patients with IMNM present with clinical symptoms similar to those seen in polymyositis and dermatomyositis – mainly proximal muscle weakness.

However, there are some important differences, both clinically and histologically, Dr. Christopher-Stine said.

“Look for higher [creatine kinase (CK)] levels,” she said. “In the thousands, usually multiple thousands ... like 5,000, 10,000, 2,000 ... that’s when you’re thinking about a necrotizing phenotype before you even look at the biopsy.”

CK levels will usually be under 30,000 U/L in IMNM, she noted, adding that data increasingly suggest that the extensive muscle necrosis in IMNM explains the elevated CK levels versus those seen in other myopathies.

Myalgias also tend to be more prominent in IMNM than in polymyositis.

“These folks hurt,” she said, noting that IMNM patients tend to have more extensive muscle atrophy and functional disability. “Many will be wheelchair bound within 9 months of diagnosis; it’s not subtle.”

The most important tool for making an IMNM diagnosis is muscle biopsy; look for prominent myocyte necrosis and a relative paucity of lymphocytes, she advised.

Overlap

Sometimes patients with polymyositis also have other rheumatologic conditions that shouldn’t be overlooked, therefore “overlap is its own category,” she said.

“In our experience, the most common overlap is scleroderma,” she noted, adding that the scleroderma is often, but not always, subtle, and that there may be overlapping autoantibodies.

Overt sclerodactyly is rarely seen, although a small amount may be present, but significant Raynaud’s phenomenon is common in these patients, and tiny telangiectasias across the neck are a tell-tale sign.

“Why does that matter? It’s not an esoteric argument; those are the folks that go on to have pulmonary hypertension,” she said. “They can have the same [interstitial lung disease] and all of the other internal scleroderma manifestations.”

Think about overlap and “look close phenotypically and with antibodies,” she advised.

There is also “the typical RA seropositive overlap,” she said, but lupus only rarely overlaps with myositis.

“However, the next diagnosis on the list – antisynthetase syndrome – can be a forme fruste where you first see a seronegative RA-like picture, and it’s important to think about that as well,” she said.

Antisynthetase syndrome

In patients referred for polymyositis, it’s also important to evaluate for antisynthetase syndrome, Dr. Christopher-Stine said.

The arthritis seen in the extramuscular phenotype of the syndrome is rarely deforming, but despite what many physicians were taught, “it absolutely can be erosive,” she said.

In fact, 40% of people with this syndrome present with an isolated forme fruste seronegative rheumatoid arthritis, she said.

Roughening and desquamation of the skin on the radial surface of fingers or palms – a sign known as mechanic’s hands – that doesn’t have another identifiable cause suggests this diagnosis in patients with this type of arthritis, as does interstitial lung disease and Raynaud’s phenomenon.

The Raynaud’s can be “fairly significant in the sense that it is bothersome,” but it usually doesn’t lead to ulceration or digital necrosis.

This is different from what is seen with the scleroderma phenotype, she said, adding that “if you’re starting to see gangrene and digital loss, think of something else.”

IBM

IBM is “probably the No. 1 most-missed diagnosis” among patients referred for what is initially believed to be polymyositis, Dr. Christopher-Stine said.

“I used to think that this was missed at entry, that everybody [with IBM] had all of these criteria and that rheumatologists really didn’t understand this phenotype ... but some people morph into this,” she said, explaining that they often start out looking like they have polymyositis with proximal muscle weakness.

“They may even initially respond to steroids. And then they get this phenotype,” she said.

Older men are more likely to present with the phenotype from the beginning; women, in her experience, tend to present with what appears to be polymyositis, and then develop the phenotype over time, she noted.

An IBM diagnosis requires age over 30 years, but most patients are over 50, she said.

“This is the only one of the myopathies that is preferential to men,” she added, noting that it affects men twice as often as it does women.

The syndrome is characterized by proximal strength loss and muscle atrophy. Also, a finding that a patient’s knee extensors are weaker than their hip flexors is “a fantastic bedside sign” differentiating IBM from polymyositis, she said.

That’s not to say IBM patients don’t have hip flexor weakness, but their knee extensors usually are “considerably weaker by a grade strength or more” versus their hip flexors, she explained.

“It’s a very easy bedside test. In typical other myopathies we have this, but the knee extensors aren’t that weak in general, or they’re not as weak as the hip flexors,” she added.

Another sign is distal strength loss, particularly in the forearm and finger flexors.

“I was taught to have them make a fist; don’t have them make a fist,” she said, explaining that this recruits intrinsic muscles which basically allows cheating that may mask weakness.

Instead, ask them to flex just their distal interphalangeal joints by making a claw and using the fingers to pull against your fingers, she suggested.

Mixed myopathic and neuropathic features on electromyography also indicate IBM, she said.

Muscle biopsy may be helpful, but inclusions are seen in less than one-third of IBM patients.

“At times, we have had to biopsy three times to see them at all, and some people never show them, so you have to rely on your clinical acumen if you don’t see them,” she said.

Also, keep in mind that these patients are often labeled as having treatment-resistant polymyositis.

“Please, when somebody refers to you somebody that’s treatment resistant, that may be the case, but I want you to think maybe they’re treatment resistant because they don’t have that disease.”
 

Muscular dystrophy

Some cases of myositis mimic certain types of muscular dystrophy, Dr. Christopher-Stine said, providing a checklist of muscular dystrophies that can look “clinically completely indistinguishable from a typical inflammatory myopathy,” and should therefore be considered in these patients.

The checklist includes Duchenne’s manifesting carrier, limb girdle muscular dystrophy type 2b, myotonic dystrophy (usually type 2), and facioscapulohumeral muscular dystrophy.

Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.

[email protected]

True polymyositis is rare, so it’s important to carefully consider other likely diagnoses, according to Lisa Christopher-Stine, MD.

“When someone refers you [a patient with suspected] polymyositis, I want you to do a checklist in your head and say, ‘Have I thought about these five things?’ ” Dr. Christopher-Stine, director of the Johns Hopkins Myositis Center, Baltimore, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

The five most common diagnoses in patients labeled as having polymyositis are immune-mediated necrotizing myopathy (IMNM), overlap with other rheumatologic conditions, antisynthetase syndrome, inclusion body myositis (IBM), and muscular dystrophy, she explained.

“You may say, ‘look, it’s all what you call it,’ but I think we need to be a little bit more careful in what we call it,” she said.

IMNM

Patients with IMNM present with clinical symptoms similar to those seen in polymyositis and dermatomyositis – mainly proximal muscle weakness.

However, there are some important differences, both clinically and histologically, Dr. Christopher-Stine said.

“Look for higher [creatine kinase (CK)] levels,” she said. “In the thousands, usually multiple thousands ... like 5,000, 10,000, 2,000 ... that’s when you’re thinking about a necrotizing phenotype before you even look at the biopsy.”

CK levels will usually be under 30,000 U/L in IMNM, she noted, adding that data increasingly suggest that the extensive muscle necrosis in IMNM explains the elevated CK levels versus those seen in other myopathies.

Myalgias also tend to be more prominent in IMNM than in polymyositis.

“These folks hurt,” she said, noting that IMNM patients tend to have more extensive muscle atrophy and functional disability. “Many will be wheelchair bound within 9 months of diagnosis; it’s not subtle.”

The most important tool for making an IMNM diagnosis is muscle biopsy; look for prominent myocyte necrosis and a relative paucity of lymphocytes, she advised.

Overlap

Sometimes patients with polymyositis also have other rheumatologic conditions that shouldn’t be overlooked, therefore “overlap is its own category,” she said.

“In our experience, the most common overlap is scleroderma,” she noted, adding that the scleroderma is often, but not always, subtle, and that there may be overlapping autoantibodies.

Overt sclerodactyly is rarely seen, although a small amount may be present, but significant Raynaud’s phenomenon is common in these patients, and tiny telangiectasias across the neck are a tell-tale sign.

“Why does that matter? It’s not an esoteric argument; those are the folks that go on to have pulmonary hypertension,” she said. “They can have the same [interstitial lung disease] and all of the other internal scleroderma manifestations.”

Think about overlap and “look close phenotypically and with antibodies,” she advised.

There is also “the typical RA seropositive overlap,” she said, but lupus only rarely overlaps with myositis.

“However, the next diagnosis on the list – antisynthetase syndrome – can be a forme fruste where you first see a seronegative RA-like picture, and it’s important to think about that as well,” she said.

Antisynthetase syndrome

In patients referred for polymyositis, it’s also important to evaluate for antisynthetase syndrome, Dr. Christopher-Stine said.

The arthritis seen in the extramuscular phenotype of the syndrome is rarely deforming, but despite what many physicians were taught, “it absolutely can be erosive,” she said.

In fact, 40% of people with this syndrome present with an isolated forme fruste seronegative rheumatoid arthritis, she said.

Roughening and desquamation of the skin on the radial surface of fingers or palms – a sign known as mechanic’s hands – that doesn’t have another identifiable cause suggests this diagnosis in patients with this type of arthritis, as does interstitial lung disease and Raynaud’s phenomenon.

The Raynaud’s can be “fairly significant in the sense that it is bothersome,” but it usually doesn’t lead to ulceration or digital necrosis.

This is different from what is seen with the scleroderma phenotype, she said, adding that “if you’re starting to see gangrene and digital loss, think of something else.”

IBM

IBM is “probably the No. 1 most-missed diagnosis” among patients referred for what is initially believed to be polymyositis, Dr. Christopher-Stine said.

“I used to think that this was missed at entry, that everybody [with IBM] had all of these criteria and that rheumatologists really didn’t understand this phenotype ... but some people morph into this,” she said, explaining that they often start out looking like they have polymyositis with proximal muscle weakness.

“They may even initially respond to steroids. And then they get this phenotype,” she said.

Older men are more likely to present with the phenotype from the beginning; women, in her experience, tend to present with what appears to be polymyositis, and then develop the phenotype over time, she noted.

An IBM diagnosis requires age over 30 years, but most patients are over 50, she said.

“This is the only one of the myopathies that is preferential to men,” she added, noting that it affects men twice as often as it does women.

The syndrome is characterized by proximal strength loss and muscle atrophy. Also, a finding that a patient’s knee extensors are weaker than their hip flexors is “a fantastic bedside sign” differentiating IBM from polymyositis, she said.

That’s not to say IBM patients don’t have hip flexor weakness, but their knee extensors usually are “considerably weaker by a grade strength or more” versus their hip flexors, she explained.

“It’s a very easy bedside test. In typical other myopathies we have this, but the knee extensors aren’t that weak in general, or they’re not as weak as the hip flexors,” she added.

Another sign is distal strength loss, particularly in the forearm and finger flexors.

“I was taught to have them make a fist; don’t have them make a fist,” she said, explaining that this recruits intrinsic muscles which basically allows cheating that may mask weakness.

Instead, ask them to flex just their distal interphalangeal joints by making a claw and using the fingers to pull against your fingers, she suggested.

Mixed myopathic and neuropathic features on electromyography also indicate IBM, she said.

Muscle biopsy may be helpful, but inclusions are seen in less than one-third of IBM patients.

“At times, we have had to biopsy three times to see them at all, and some people never show them, so you have to rely on your clinical acumen if you don’t see them,” she said.

Also, keep in mind that these patients are often labeled as having treatment-resistant polymyositis.

“Please, when somebody refers to you somebody that’s treatment resistant, that may be the case, but I want you to think maybe they’re treatment resistant because they don’t have that disease.”
 

Muscular dystrophy

Some cases of myositis mimic certain types of muscular dystrophy, Dr. Christopher-Stine said, providing a checklist of muscular dystrophies that can look “clinically completely indistinguishable from a typical inflammatory myopathy,” and should therefore be considered in these patients.

The checklist includes Duchenne’s manifesting carrier, limb girdle muscular dystrophy type 2b, myotonic dystrophy (usually type 2), and facioscapulohumeral muscular dystrophy.

Dr. Christopher-Stine reported having intellectual property interest in a novel Inova Diagnostics autoantibody assay detection for anti-HMGCR. She was also the safety officer for the JBT-101 Trial sponsored by Corbus and funded by the National Institutes of Health.

[email protected]

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.

The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.

“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.

It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.


With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.

“But also, RA characteristics played a big role,” he said.

Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).

Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.

To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.

The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.

“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.

As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.

Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.

Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.

Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).

The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:

• CVD screening every 5 years.
• Use of a 1.5 multiplier for risk scores.
• Secondary screening with imaging for select patients.
• Management of traditional risk factors according to local guidelines.
• Minimization of the use of NSAIDs and corticosteroids.
• Emphasis on lifestyle management.

Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.

“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.

That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.

He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.

“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.

A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.

For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.

Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.

Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.

Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.

[email protected]

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

[email protected]

SOURCE: Li AM et al. ASH 2018, Abstract 556.

The Food and Drug Administration has identified 457 unique cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and 9 related deaths since 2010, and received 246 new medical device reports (MDRs) regarding BIA-ALCL between September 2017 and September 2018, according to an update from the agency’s Center for Devices and Radiological Health.

gorodenkoff/iStock/Getty Images Plus

That brings the total number of reports to 660; however, that number reflects duplicative cases, Binita Ashar, MD, a general surgeon and the director of the division of surgical devices at the center, said in a statement.

“These types of increases in the MDRs are to be expected and may include past cases that were not previously reported to the FDA,” Dr. Ashar said, addressing the high number of new reports. “The increased number of MDRs contributes to our evolving understanding of BIA-ALCL and represents a more thorough and comprehensive analysis.”

BIA-ALCL is a type of non-Hodgkin lymphoma and a known risk from breast implants that was first communicated by the FDA in 2011. Regular updates have been provided with respect to related medical device reports, cases, deaths, and known risks.

“We hope that this information prompts providers and patients to have important, informed conversations about breast implants and the risk of BIA-ALCL. At the same time, we remain committed to working in partnership with all stakeholders to continue to study, understand, and provide updates about this important public health issue,” Dr. Ashar said.

To that end, the center also issued a Letter to Health Care Providers to “encourage those who regularly treat patients, including primary care physicians and gynecologists, to learn about BIA-ALCL in patients with breast implants.”

Patients and providers are encouraged to file MDRs with the FDA via MedWatch, the FDA Safety Information and Adverse Event Reporting program, she said.

[email protected]

The Food and Drug Administration has identified 457 unique cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and 9 related deaths since 2010, and received 246 new medical device reports (MDRs) regarding BIA-ALCL between September 2017 and September 2018, according to an update from the agency’s Center for Devices and Radiological Health.

gorodenkoff/iStock/Getty Images Plus

That brings the total number of reports to 660; however, that number reflects duplicative cases, Binita Ashar, MD, a general surgeon and the director of the division of surgical devices at the center, said in a statement.

“These types of increases in the MDRs are to be expected and may include past cases that were not previously reported to the FDA,” Dr. Ashar said, addressing the high number of new reports. “The increased number of MDRs contributes to our evolving understanding of BIA-ALCL and represents a more thorough and comprehensive analysis.”

BIA-ALCL is a type of non-Hodgkin lymphoma and a known risk from breast implants that was first communicated by the FDA in 2011. Regular updates have been provided with respect to related medical device reports, cases, deaths, and known risks.

“We hope that this information prompts providers and patients to have important, informed conversations about breast implants and the risk of BIA-ALCL. At the same time, we remain committed to working in partnership with all stakeholders to continue to study, understand, and provide updates about this important public health issue,” Dr. Ashar said.

To that end, the center also issued a Letter to Health Care Providers to “encourage those who regularly treat patients, including primary care physicians and gynecologists, to learn about BIA-ALCL in patients with breast implants.”

Patients and providers are encouraged to file MDRs with the FDA via MedWatch, the FDA Safety Information and Adverse Event Reporting program, she said.

[email protected]

The Food and Drug Administration has identified 457 unique cases of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) and 9 related deaths since 2010, and received 246 new medical device reports (MDRs) regarding BIA-ALCL between September 2017 and September 2018, according to an update from the agency’s Center for Devices and Radiological Health.

gorodenkoff/iStock/Getty Images Plus

That brings the total number of reports to 660; however, that number reflects duplicative cases, Binita Ashar, MD, a general surgeon and the director of the division of surgical devices at the center, said in a statement.

“These types of increases in the MDRs are to be expected and may include past cases that were not previously reported to the FDA,” Dr. Ashar said, addressing the high number of new reports. “The increased number of MDRs contributes to our evolving understanding of BIA-ALCL and represents a more thorough and comprehensive analysis.”

BIA-ALCL is a type of non-Hodgkin lymphoma and a known risk from breast implants that was first communicated by the FDA in 2011. Regular updates have been provided with respect to related medical device reports, cases, deaths, and known risks.

“We hope that this information prompts providers and patients to have important, informed conversations about breast implants and the risk of BIA-ALCL. At the same time, we remain committed to working in partnership with all stakeholders to continue to study, understand, and provide updates about this important public health issue,” Dr. Ashar said.

To that end, the center also issued a Letter to Health Care Providers to “encourage those who regularly treat patients, including primary care physicians and gynecologists, to learn about BIA-ALCL in patients with breast implants.”

Patients and providers are encouraged to file MDRs with the FDA via MedWatch, the FDA Safety Information and Adverse Event Reporting program, she said.

[email protected]

Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.

“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.

However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.

He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.

For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.

A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.

“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”

The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.

It appears an important problem relates to test kit variability, he said.

“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.

In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).

Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.

Anti–double-stranded DNA assays

Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.

For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.

The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.

Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.

Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”

Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.

[email protected]

Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.

“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.

However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.

He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.

For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.

A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.

“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”

The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.

It appears an important problem relates to test kit variability, he said.

“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.

In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).

Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.

Anti–double-stranded DNA assays

Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.

For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.

The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.

Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.

Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”

Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.

[email protected]

Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.

“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.

However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.

He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.

For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.

A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.

“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”

The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.

It appears an important problem relates to test kit variability, he said.

“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.

In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).

Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.

Anti–double-stranded DNA assays

Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.

For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.

The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.

Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.

Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”

Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.

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