ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

jensmith@mdedge.com

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

jensmith@mdedge.com

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

jensmith@mdedge.com

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

A phase 2 study of temozolomide in gastrointestinal stromal tumors (GIST) received one of the 12 grants awarded in October by the US Food and Drug Administration (FDA) to enhance the development of medical products for patients with rare diseases. Jason Sicklick, MD, and the University of California San Diego in La Jolla will receive $1.5 million over 3 years to conduct the phase 2 study (NCT03556384). The objective of the study is to determine the efficacy at 6 months of temozolomide therapy in patients with the SDH-mutant/deficient subtype. Temozolomide is approved by the FDA to treat newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytomas. It is not approved for the treatment of SDH-mutant/deficient GIST.

The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program. Other orphan diseases receiving grants included glomerulopathy, gliomas, Fanconi anemia, sickle cell respiratory complications, Duchenne muscular dystrophy, HPV associated respiratory papillomatosis, refractory viral infections and T-cell immunodeficiency, oral cancer, retinoblastoma, cerebellar brain tumors, and acute myeloid leukemia.

A phase 2 study of temozolomide in gastrointestinal stromal tumors (GIST) received one of the 12 grants awarded in October by the US Food and Drug Administration (FDA) to enhance the development of medical products for patients with rare diseases. Jason Sicklick, MD, and the University of California San Diego in La Jolla will receive $1.5 million over 3 years to conduct the phase 2 study (NCT03556384). The objective of the study is to determine the efficacy at 6 months of temozolomide therapy in patients with the SDH-mutant/deficient subtype. Temozolomide is approved by the FDA to treat newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytomas. It is not approved for the treatment of SDH-mutant/deficient GIST.

The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program. Other orphan diseases receiving grants included glomerulopathy, gliomas, Fanconi anemia, sickle cell respiratory complications, Duchenne muscular dystrophy, HPV associated respiratory papillomatosis, refractory viral infections and T-cell immunodeficiency, oral cancer, retinoblastoma, cerebellar brain tumors, and acute myeloid leukemia.

A phase 2 study of temozolomide in gastrointestinal stromal tumors (GIST) received one of the 12 grants awarded in October by the US Food and Drug Administration (FDA) to enhance the development of medical products for patients with rare diseases. Jason Sicklick, MD, and the University of California San Diego in La Jolla will receive $1.5 million over 3 years to conduct the phase 2 study (NCT03556384). The objective of the study is to determine the efficacy at 6 months of temozolomide therapy in patients with the SDH-mutant/deficient subtype. Temozolomide is approved by the FDA to treat newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytomas. It is not approved for the treatment of SDH-mutant/deficient GIST.

The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program. Other orphan diseases receiving grants included glomerulopathy, gliomas, Fanconi anemia, sickle cell respiratory complications, Duchenne muscular dystrophy, HPV associated respiratory papillomatosis, refractory viral infections and T-cell immunodeficiency, oral cancer, retinoblastoma, cerebellar brain tumors, and acute myeloid leukemia.

Research clinicians from the US and abroad participated in a scientific research roundtable this past September to establish the most important issues facing leiomyosarcoma (LMS) research and clinical trials. The workshop, expected to be an annual event, is a joint effort of the National Leiomyosarcoma Foundation (NLMSF) and Sarcoma Patients EuroNet (SPAEN).

The roundtable’s mission is to bring together sarcoma experts for a meeting dedicated to LMS, where participants discuss the present state of LMS and the continued challenges of diagnosis and treatment. Its goal is to develop working plans to close the gaps in LMS patient care and improve LMS patient-care protocols. They also advise the NLMSF on worthy and important research projects that deserve the foundation’s future funding efforts.

Plans for roundtable meetings in 2020 and 2021 are already underway. Between the annual meetings, workgroups continue to take steps toward addressing the issues identified by the roundtable. For more information on the roundtable and NLMSF, visit: https://nlmsf.org.

Research clinicians from the US and abroad participated in a scientific research roundtable this past September to establish the most important issues facing leiomyosarcoma (LMS) research and clinical trials. The workshop, expected to be an annual event, is a joint effort of the National Leiomyosarcoma Foundation (NLMSF) and Sarcoma Patients EuroNet (SPAEN).

The roundtable’s mission is to bring together sarcoma experts for a meeting dedicated to LMS, where participants discuss the present state of LMS and the continued challenges of diagnosis and treatment. Its goal is to develop working plans to close the gaps in LMS patient care and improve LMS patient-care protocols. They also advise the NLMSF on worthy and important research projects that deserve the foundation’s future funding efforts.

Plans for roundtable meetings in 2020 and 2021 are already underway. Between the annual meetings, workgroups continue to take steps toward addressing the issues identified by the roundtable. For more information on the roundtable and NLMSF, visit: https://nlmsf.org.

Research clinicians from the US and abroad participated in a scientific research roundtable this past September to establish the most important issues facing leiomyosarcoma (LMS) research and clinical trials. The workshop, expected to be an annual event, is a joint effort of the National Leiomyosarcoma Foundation (NLMSF) and Sarcoma Patients EuroNet (SPAEN).

The roundtable’s mission is to bring together sarcoma experts for a meeting dedicated to LMS, where participants discuss the present state of LMS and the continued challenges of diagnosis and treatment. Its goal is to develop working plans to close the gaps in LMS patient care and improve LMS patient-care protocols. They also advise the NLMSF on worthy and important research projects that deserve the foundation’s future funding efforts.

Plans for roundtable meetings in 2020 and 2021 are already underway. Between the annual meetings, workgroups continue to take steps toward addressing the issues identified by the roundtable. For more information on the roundtable and NLMSF, visit: https://nlmsf.org.

The Hospitalist recently spoke with Brian Schroeder, MHA, FACHE, FHM, assistant vice president, Hospital & Emergency Medicine, at Atrium Health Medical Group in Charlotte, N.C., to discuss his participation in the State of Hospital Medicine Survey, which is distributed every other year, and how he uses the resulting report to guide important operational decisions.
 

Please describe your current role.

At Carolinas Hospitalist Group, we have approximately 250 providers at nearly 20 care locations across North Carolina. Along with my specialty medical director, I am responsible for the strategic growth, program development, and financial performance for our practice.

How did you first become involved with the Society of Hospital Medicine?

When I first entered the hospital medicine world in 2008, I was looking for an organization that supported our specialty. My physician leaders at the time pointed me to SHM. Since the beginning of my time as a member, I have attended the Annual Conference each year, the SHM Leadership Academy, served on an SHM committee, and participate in SHM’s multisite Leaders group. Additionally, I have served as faculty at SHM’s annual conference for 3 years – and will be presenting for the third time at HM20.

Why is it important that people participate in the State of Hospital Medicine Survey?

Participation in the survey is key for establishing benchmarks for our specialty. The more people participate (from various arenas like private groups, health system employees, and vendors), the more accurate the data. Over the past 4 years, SHM has improved the submission process of survey data – especially for practices with multiple locations.

How has the data in the report impacted important business decisions for your group?

We rely heavily on the investment/provider benchmark within the survey data. Over the years, as the investment/provider was decreasing nationally, our own investment/provider was increasing. Based on the survey, we were able to closely evaluate our staffing models at each location and determine the appropriate skill mix-to-volume ratio. Through turnover and growth, we have strategically hired advanced practice providers to align our investment more closely with the benchmark. Over the past 2 years, our investment/provider metric has decreased significantly. We were able to accomplish this while continuing to provide appropriate care to our patients. We also utilize the Report to monitor performance incentive metrics, staffing model trends, and encounter/provider ratios.

What would you tell people who are on the fence about participating in the survey – and ultimately, purchasing the finished product?

Do it! Our practice would never skip a submission year. The data produced from the survey helps us improve our clinical operations and maximize our financial affordability. The data also assists in defending staffing decisions and clinical operations change with senior leadership within the organization.

Don’t miss your chance to submit data that will build the latest snapshot of the hospital medicine specialty. The State of Hospital Medicine Survey is open now and runs through February 16, 2020. Learn more and register to participate at hospitalmedicine.org/survey.

The Hospitalist recently spoke with Brian Schroeder, MHA, FACHE, FHM, assistant vice president, Hospital & Emergency Medicine, at Atrium Health Medical Group in Charlotte, N.C., to discuss his participation in the State of Hospital Medicine Survey, which is distributed every other year, and how he uses the resulting report to guide important operational decisions.
 

Please describe your current role.

At Carolinas Hospitalist Group, we have approximately 250 providers at nearly 20 care locations across North Carolina. Along with my specialty medical director, I am responsible for the strategic growth, program development, and financial performance for our practice.

How did you first become involved with the Society of Hospital Medicine?

When I first entered the hospital medicine world in 2008, I was looking for an organization that supported our specialty. My physician leaders at the time pointed me to SHM. Since the beginning of my time as a member, I have attended the Annual Conference each year, the SHM Leadership Academy, served on an SHM committee, and participate in SHM’s multisite Leaders group. Additionally, I have served as faculty at SHM’s annual conference for 3 years – and will be presenting for the third time at HM20.

Why is it important that people participate in the State of Hospital Medicine Survey?

Participation in the survey is key for establishing benchmarks for our specialty. The more people participate (from various arenas like private groups, health system employees, and vendors), the more accurate the data. Over the past 4 years, SHM has improved the submission process of survey data – especially for practices with multiple locations.

How has the data in the report impacted important business decisions for your group?

We rely heavily on the investment/provider benchmark within the survey data. Over the years, as the investment/provider was decreasing nationally, our own investment/provider was increasing. Based on the survey, we were able to closely evaluate our staffing models at each location and determine the appropriate skill mix-to-volume ratio. Through turnover and growth, we have strategically hired advanced practice providers to align our investment more closely with the benchmark. Over the past 2 years, our investment/provider metric has decreased significantly. We were able to accomplish this while continuing to provide appropriate care to our patients. We also utilize the Report to monitor performance incentive metrics, staffing model trends, and encounter/provider ratios.

What would you tell people who are on the fence about participating in the survey – and ultimately, purchasing the finished product?

Do it! Our practice would never skip a submission year. The data produced from the survey helps us improve our clinical operations and maximize our financial affordability. The data also assists in defending staffing decisions and clinical operations change with senior leadership within the organization.

Don’t miss your chance to submit data that will build the latest snapshot of the hospital medicine specialty. The State of Hospital Medicine Survey is open now and runs through February 16, 2020. Learn more and register to participate at hospitalmedicine.org/survey.

The Hospitalist recently spoke with Brian Schroeder, MHA, FACHE, FHM, assistant vice president, Hospital & Emergency Medicine, at Atrium Health Medical Group in Charlotte, N.C., to discuss his participation in the State of Hospital Medicine Survey, which is distributed every other year, and how he uses the resulting report to guide important operational decisions.
 

Please describe your current role.

At Carolinas Hospitalist Group, we have approximately 250 providers at nearly 20 care locations across North Carolina. Along with my specialty medical director, I am responsible for the strategic growth, program development, and financial performance for our practice.

How did you first become involved with the Society of Hospital Medicine?

When I first entered the hospital medicine world in 2008, I was looking for an organization that supported our specialty. My physician leaders at the time pointed me to SHM. Since the beginning of my time as a member, I have attended the Annual Conference each year, the SHM Leadership Academy, served on an SHM committee, and participate in SHM’s multisite Leaders group. Additionally, I have served as faculty at SHM’s annual conference for 3 years – and will be presenting for the third time at HM20.

Why is it important that people participate in the State of Hospital Medicine Survey?

Participation in the survey is key for establishing benchmarks for our specialty. The more people participate (from various arenas like private groups, health system employees, and vendors), the more accurate the data. Over the past 4 years, SHM has improved the submission process of survey data – especially for practices with multiple locations.

How has the data in the report impacted important business decisions for your group?

We rely heavily on the investment/provider benchmark within the survey data. Over the years, as the investment/provider was decreasing nationally, our own investment/provider was increasing. Based on the survey, we were able to closely evaluate our staffing models at each location and determine the appropriate skill mix-to-volume ratio. Through turnover and growth, we have strategically hired advanced practice providers to align our investment more closely with the benchmark. Over the past 2 years, our investment/provider metric has decreased significantly. We were able to accomplish this while continuing to provide appropriate care to our patients. We also utilize the Report to monitor performance incentive metrics, staffing model trends, and encounter/provider ratios.

What would you tell people who are on the fence about participating in the survey – and ultimately, purchasing the finished product?

Do it! Our practice would never skip a submission year. The data produced from the survey helps us improve our clinical operations and maximize our financial affordability. The data also assists in defending staffing decisions and clinical operations change with senior leadership within the organization.

Don’t miss your chance to submit data that will build the latest snapshot of the hospital medicine specialty. The State of Hospital Medicine Survey is open now and runs through February 16, 2020. Learn more and register to participate at hospitalmedicine.org/survey.

MADRID – Renowned dermatologic clinical trialist Kim A. Papp, MD, PhD, is known to pick his words carefully, and the word he uses to describe the quality of life improvement documented in psoriasis patients treated with the novel investigational humanized monoclonal antibody bimekizumab is “phenomenal.”

Bruce Jancin/MDedge News

Dr. Papp was lead investigator in the previously reported phase 2b multicenter BE ABLE 1 trial, in which 250 patients with moderate to severe chronic plaque psoriasis were randomized double-blind to various doses of bimekizumab or placebo every 4 weeks for 12 weeks (J Am Acad Dermatol. 2018 Aug;79[2]:277-86.e10. doi: 10.1016/j.jaad.2018.03.037). He was also lead investigator in the 48-week phase 2b BE ABLE 2 extension study. He presented the 60-week quality-of-life BE ABLE 2 results for the first time at the annual congress of the European Academy of Dermatology and Venereology.

“Small numbers, but the results are nonetheless very compelling,” said Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.

Bimekizumab is unique in that it selectively neutralizes both interleukin-17A and -17F, two closely related proinflammatory cytokines which, when upregulated, synergize with other proinflammatory cytokines to drive psoriasis and other immune-mediated inflammatory diseases. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit only IL-17A, and brodalumab (Siliq) targets the IL-17 receptor A. The bimekizumab clinical trials program – a work in progress – aims to demonstrate that dual neutralization of IL-17A and -17F provides a more complete therapeutic approach in psoriasis, with greater efficacy and fewer safety concerns than with current biologics, the dermatologist explained.

In BE ABLE 1, the primary endpoint of at least a 90% reduction in Psoriasis Area and Severity Index (PASI90) response was achieved at week 12 in 46%-79% of patients randomized to bimekizumab in dose-dependent fashion. Those PASI90 responses were maintained with additional treatment out to week 60 in BE ABLE 2 in 80%-100% of patients.

Dr. Papp’s focus at EADV 2019 was on the quality-of-life improvement achieved in bimekizumab-treated patients, a benefit not captured by PASI scores. For this purpose, he and coinvestigators turned to the Dermatology Life Quality Index (DLQI), measured in structured fashion every 4 weeks out to week 60.

“We often forget that even though we’re looking at the patient from the outside, what’s really important is how well they respond to our treatments internally. The DLQI is not a perfect tool, but it’s the best tool we have available. It gives us a fairly good survey of the various domains that affect patients’ day-to-day living,” he said.

In BE ABLE 1, the proportion of week-12 PASI90 responders achieving a DLQI of 0 or 1 – indicative of essentially no disease impact on quality of life – increased rapidly up until week 8. At week 12, 70%-100% of the PASI90 responders in the various treatment arms had a DLQI of 0 or 1. This quality-of-life improvement, like the PASI90 response, proved durable: When the week-12 PASI90 responders were assessed at week 60 in BE ABLE 2, 76%-93% of them had a DLQI of 0 or 1.

The improvements in quality of life correlated with clinical response. BE ABLE enrollees had an average PASI score of 19 at baseline. Overall, 79% of those with an absolute PASI score of 0 at week 12 had a DLQI of 0 or 1 at that time, as did 95% of those with a PASI of 0 at week 60. A PASI of 1 was associated with a 77% likelihood of a DLQI of 0 or 1 at week 12 and an 82% rate at week 60. In contrast, patients with an absolute PASI of 2-4 at week 12 had a 46% rate of DLQI 0/1, and those with a PASI 2-4 at week 60 had a 50% chance of having a DLQI of 0/1.

Phase 3 clinical trials of bimekizumab totaling several thousand psoriasis patients are ongoing.

The BE ABLE trials were sponsored by UCB Pharma. Dr. Papp reported serving as a consultant to and/or recipient of research grants from UCB and dozens of other pharmaceutical companies.

bjancin@mdedge.com

SOURCE: Papp KA. EADV 2019 Abstract FC02.02.

MADRID – Renowned dermatologic clinical trialist Kim A. Papp, MD, PhD, is known to pick his words carefully, and the word he uses to describe the quality of life improvement documented in psoriasis patients treated with the novel investigational humanized monoclonal antibody bimekizumab is “phenomenal.”

Bruce Jancin/MDedge News

Dr. Papp was lead investigator in the previously reported phase 2b multicenter BE ABLE 1 trial, in which 250 patients with moderate to severe chronic plaque psoriasis were randomized double-blind to various doses of bimekizumab or placebo every 4 weeks for 12 weeks (J Am Acad Dermatol. 2018 Aug;79[2]:277-86.e10. doi: 10.1016/j.jaad.2018.03.037). He was also lead investigator in the 48-week phase 2b BE ABLE 2 extension study. He presented the 60-week quality-of-life BE ABLE 2 results for the first time at the annual congress of the European Academy of Dermatology and Venereology.

“Small numbers, but the results are nonetheless very compelling,” said Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.

Bimekizumab is unique in that it selectively neutralizes both interleukin-17A and -17F, two closely related proinflammatory cytokines which, when upregulated, synergize with other proinflammatory cytokines to drive psoriasis and other immune-mediated inflammatory diseases. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit only IL-17A, and brodalumab (Siliq) targets the IL-17 receptor A. The bimekizumab clinical trials program – a work in progress – aims to demonstrate that dual neutralization of IL-17A and -17F provides a more complete therapeutic approach in psoriasis, with greater efficacy and fewer safety concerns than with current biologics, the dermatologist explained.

In BE ABLE 1, the primary endpoint of at least a 90% reduction in Psoriasis Area and Severity Index (PASI90) response was achieved at week 12 in 46%-79% of patients randomized to bimekizumab in dose-dependent fashion. Those PASI90 responses were maintained with additional treatment out to week 60 in BE ABLE 2 in 80%-100% of patients.

Dr. Papp’s focus at EADV 2019 was on the quality-of-life improvement achieved in bimekizumab-treated patients, a benefit not captured by PASI scores. For this purpose, he and coinvestigators turned to the Dermatology Life Quality Index (DLQI), measured in structured fashion every 4 weeks out to week 60.

“We often forget that even though we’re looking at the patient from the outside, what’s really important is how well they respond to our treatments internally. The DLQI is not a perfect tool, but it’s the best tool we have available. It gives us a fairly good survey of the various domains that affect patients’ day-to-day living,” he said.

In BE ABLE 1, the proportion of week-12 PASI90 responders achieving a DLQI of 0 or 1 – indicative of essentially no disease impact on quality of life – increased rapidly up until week 8. At week 12, 70%-100% of the PASI90 responders in the various treatment arms had a DLQI of 0 or 1. This quality-of-life improvement, like the PASI90 response, proved durable: When the week-12 PASI90 responders were assessed at week 60 in BE ABLE 2, 76%-93% of them had a DLQI of 0 or 1.

The improvements in quality of life correlated with clinical response. BE ABLE enrollees had an average PASI score of 19 at baseline. Overall, 79% of those with an absolute PASI score of 0 at week 12 had a DLQI of 0 or 1 at that time, as did 95% of those with a PASI of 0 at week 60. A PASI of 1 was associated with a 77% likelihood of a DLQI of 0 or 1 at week 12 and an 82% rate at week 60. In contrast, patients with an absolute PASI of 2-4 at week 12 had a 46% rate of DLQI 0/1, and those with a PASI 2-4 at week 60 had a 50% chance of having a DLQI of 0/1.

Phase 3 clinical trials of bimekizumab totaling several thousand psoriasis patients are ongoing.

The BE ABLE trials were sponsored by UCB Pharma. Dr. Papp reported serving as a consultant to and/or recipient of research grants from UCB and dozens of other pharmaceutical companies.

bjancin@mdedge.com

SOURCE: Papp KA. EADV 2019 Abstract FC02.02.

MADRID – Renowned dermatologic clinical trialist Kim A. Papp, MD, PhD, is known to pick his words carefully, and the word he uses to describe the quality of life improvement documented in psoriasis patients treated with the novel investigational humanized monoclonal antibody bimekizumab is “phenomenal.”

Bruce Jancin/MDedge News

Dr. Papp was lead investigator in the previously reported phase 2b multicenter BE ABLE 1 trial, in which 250 patients with moderate to severe chronic plaque psoriasis were randomized double-blind to various doses of bimekizumab or placebo every 4 weeks for 12 weeks (J Am Acad Dermatol. 2018 Aug;79[2]:277-86.e10. doi: 10.1016/j.jaad.2018.03.037). He was also lead investigator in the 48-week phase 2b BE ABLE 2 extension study. He presented the 60-week quality-of-life BE ABLE 2 results for the first time at the annual congress of the European Academy of Dermatology and Venereology.

“Small numbers, but the results are nonetheless very compelling,” said Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.

Bimekizumab is unique in that it selectively neutralizes both interleukin-17A and -17F, two closely related proinflammatory cytokines which, when upregulated, synergize with other proinflammatory cytokines to drive psoriasis and other immune-mediated inflammatory diseases. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit only IL-17A, and brodalumab (Siliq) targets the IL-17 receptor A. The bimekizumab clinical trials program – a work in progress – aims to demonstrate that dual neutralization of IL-17A and -17F provides a more complete therapeutic approach in psoriasis, with greater efficacy and fewer safety concerns than with current biologics, the dermatologist explained.

In BE ABLE 1, the primary endpoint of at least a 90% reduction in Psoriasis Area and Severity Index (PASI90) response was achieved at week 12 in 46%-79% of patients randomized to bimekizumab in dose-dependent fashion. Those PASI90 responses were maintained with additional treatment out to week 60 in BE ABLE 2 in 80%-100% of patients.

Dr. Papp’s focus at EADV 2019 was on the quality-of-life improvement achieved in bimekizumab-treated patients, a benefit not captured by PASI scores. For this purpose, he and coinvestigators turned to the Dermatology Life Quality Index (DLQI), measured in structured fashion every 4 weeks out to week 60.

“We often forget that even though we’re looking at the patient from the outside, what’s really important is how well they respond to our treatments internally. The DLQI is not a perfect tool, but it’s the best tool we have available. It gives us a fairly good survey of the various domains that affect patients’ day-to-day living,” he said.

In BE ABLE 1, the proportion of week-12 PASI90 responders achieving a DLQI of 0 or 1 – indicative of essentially no disease impact on quality of life – increased rapidly up until week 8. At week 12, 70%-100% of the PASI90 responders in the various treatment arms had a DLQI of 0 or 1. This quality-of-life improvement, like the PASI90 response, proved durable: When the week-12 PASI90 responders were assessed at week 60 in BE ABLE 2, 76%-93% of them had a DLQI of 0 or 1.

The improvements in quality of life correlated with clinical response. BE ABLE enrollees had an average PASI score of 19 at baseline. Overall, 79% of those with an absolute PASI score of 0 at week 12 had a DLQI of 0 or 1 at that time, as did 95% of those with a PASI of 0 at week 60. A PASI of 1 was associated with a 77% likelihood of a DLQI of 0 or 1 at week 12 and an 82% rate at week 60. In contrast, patients with an absolute PASI of 2-4 at week 12 had a 46% rate of DLQI 0/1, and those with a PASI 2-4 at week 60 had a 50% chance of having a DLQI of 0/1.

Phase 3 clinical trials of bimekizumab totaling several thousand psoriasis patients are ongoing.

The BE ABLE trials were sponsored by UCB Pharma. Dr. Papp reported serving as a consultant to and/or recipient of research grants from UCB and dozens of other pharmaceutical companies.

bjancin@mdedge.com

SOURCE: Papp KA. EADV 2019 Abstract FC02.02.

Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.

The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.

“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.

A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”

However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.

The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.

Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.

Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.

Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.

The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.

Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.

Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.

Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.

“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.

The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.

SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.

Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.

The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.

“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.

A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”

However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.

The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.

Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.

Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.

Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.

The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.

Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.

Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.

Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.

“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.

The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.

SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.

Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.

The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.

“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.

A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”

However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.

The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.

Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.

Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.

Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.

The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.

Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.

Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.

Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.

“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.

The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.

SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.

MADRID – European atopic dermatitis experts have issued formal guidance on a seriously neglected topic: treatment of the disease during pregnancy, breastfeeding, and in men planning to father children.

Bruce Jancin/MDedge News

The impetus for the project was clear: “Treatment of atopic dermatitis in pregnancy is often forgotten or even ignored,” Christian Vestergaard, MD, PhD, declared at a meeting of the European Task Force on Atopic Dermatitis held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.

He presented highlights of the task force’s position paper on the topic, for which he served as first author. The group’s recommendations are based on expert opinion, since randomized clinical trial literature in this area is nonexistent because of ethical concerns. But the task force, comprising a who’s who in European dermatology, drew on a wealth of collective clinical experience in this area.

“We have all of Europe involved in doing this position statement. It’s meant as what we think is proper treatment and what we can say about the different drugs,” explained Dr. Vestergaard, a dermatologist at the University of Aarhus (Denmark).

Most nonobstetricians are intimidated by atopic dermatitis (AD) in pregnancy, and are concerned about the potential for treatment-related harm to the fetus. As a consequence, they are reluctant to recommend anything beyond weak class I topical corticosteroids and emollients. That’s clearly insufficient in light of the vast scope of need, he asserted. After all, AD affects 15%-20% of all children and persists or reappears in adulthood in one out of five of them. Half of those adults are women, many of whom will at some point wish to become pregnant. And many men with AD will eventually want to father children.

A key message from the task force is that untreated AD in pregnancy potentially places the mother and fetus at risk of serious complications, including Staphylococcus aureus infection and eczema herpeticum.

“If you take one thing away from our position paper, it’s that you can use class II or III topical corticosteroids in pregnant women as first-line therapy,” Dr. Vestergaard said.

This stance contradicts a longstanding widely held concern that topical steroids in pregnancy might increase the risk of facial cleft in the offspring, a worry that has been convincingly debunked in a Cochrane systematic review of 14 studies including more than 1.6 million pregnancies. The report concluded there was no association between topical corticosteroids of any potency with preterm delivery, birth defects, or low Apgar scores (Cochrane Database Syst Rev. 2015 Oct 26. doi: 10.1002/14651858.CD007346.pub3).

The task force recommends that if class II or III topical corticosteroid use in pregnancy exceeds 200 g/month, it’s worth considering add-on UV therapy, with narrow band UVB-311 nm as the regimen of choice; it can be used liberally. UV therapy with psoralens is not advised because of a theoretical risk of mutagenicity.

Product labeling for the topical calcineurin inhibitors declares that the agents should not be used during pregnancy. However, the European task force position paper takes issue with that and declares that topical tacrolimus (Protopic) can be considered an off-label first-line therapy in pregnant women with an insufficient response to liberal use of emollients. The same holds true for breastfeeding patients with AD. Just as when topical corticosteroids are used in the nipple area, topical tacrolimus should be applied after nursing, and the nipple area should be gently cleaned before nursing.

The rationale behind recommending topical tacrolimus as a first-line treatment is that systemic absorption of the drug is trivial. Plus, observational studies of oral tacrolimus in pregnant women who have received a solid organ transplant have shown no increase in congenital malformations.

The task force recommends against the use of topical pimecrolimus (Elidel) or crisaborole (Eucrisa) in pregnancy or lactation due to lack of clinical experience in these settings, Dr. Vestergaard continued.

The task force position is that chlorhexidine and other topical antiseptics – with the notable exception of triclosan – can be used in pregnancy to prevent recurrent skin infections. Aminoglycosides should be avoided, but topical fusidic acid is a reasonable antibiotic for treatment of small areas of clinically infected atopic dermatitis in pregnancy.
 

Systemic therapies

If disease control is insufficient with topical therapy, it’s appropriate to engage in shared decision-making with the patient regarding systemic treatment. She needs to understand up front that the worldwide overall background stillbirth rate in the general population is about 3%, and that severe congenital malformations are present in up to 6% of all live births.

“You need to inform them that they can have systemic therapy and give birth to a child with congenital defects which have nothing to do with the medication,” noted Dr. Vestergaard.

That said, the task force recommends cyclosporine as the off-label, first-line systemic therapy in pregnancy and lactation when long-term treatment is required. This guidance is based largely upon reassuring evidence in solid organ transplant recipients.

The recommended second-line therapy is systemic corticosteroids, but it’s a qualified recommendation. Dr. Vestergaard and colleagues find that systemic corticosteroid therapy is only rarely needed in pregnant AD patients, and the task force recommendation is to limit the use to less than 2-3 weeks and no more than 0.5 mg/kg per day of prednisone. Dexamethasone is not recommended.

Azathioprine should not be started in pregnancy, according to the task force, but when no other options are available, it may be continued in women already on the drug, albeit at half of the prepregnancy dose.

Dupilumab (Dupixent) is to be avoided in pregnant women with AD until more clinical experience becomes available.

Treatment of prospective fathers with AD

The European task force recommends that topical therapies can be prescribed in prospective fathers without any special concerns. The same is true for systemic corticosteroids. Methotrexate should be halted 3 months before planned pregnancy, as is the case for mycophenolate mofetil (CellCept). Azathioprine is recommended when other options have failed. Cyclosporine is deemed a reasonable option in the treatment of men with severe AD at the time of conception if other treatments have failed; of note, neither the Food and Drug Administration nor the European regulatory agency have issued contraindications for the use of the drug in men who wish to become fathers.

Mycophenolate mofetil carries a theoretical risk of teratogenicity. The European task force recommends that men should use condoms while on the drug and for at least 90 days afterward.
 

Unplanned pregnancy in women on systemic therapy

The recommended course of action is to immediately stop systemic therapy, intensify appropriate topical therapy in anticipation of worsening AD, and refer the patient to an obstetrician and a teratology information center for an individualized risk assessment. Methotrexate and mycophenolate mofetil are known teratogens.

The full 16-page task force position paper was published shortly before EADV 2019 (J Eur Acad Dermatol Venereol. 2019 Sep;33[9]:1644-59).

The report was developed without commercial sponsorship. Dr. Vestergaard indicated he has received research grants from and/or serves as a consultant to eight pharmaceutical companies.

bjancin@mdedge.com

MADRID – European atopic dermatitis experts have issued formal guidance on a seriously neglected topic: treatment of the disease during pregnancy, breastfeeding, and in men planning to father children.

Bruce Jancin/MDedge News

The impetus for the project was clear: “Treatment of atopic dermatitis in pregnancy is often forgotten or even ignored,” Christian Vestergaard, MD, PhD, declared at a meeting of the European Task Force on Atopic Dermatitis held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.

He presented highlights of the task force’s position paper on the topic, for which he served as first author. The group’s recommendations are based on expert opinion, since randomized clinical trial literature in this area is nonexistent because of ethical concerns. But the task force, comprising a who’s who in European dermatology, drew on a wealth of collective clinical experience in this area.

“We have all of Europe involved in doing this position statement. It’s meant as what we think is proper treatment and what we can say about the different drugs,” explained Dr. Vestergaard, a dermatologist at the University of Aarhus (Denmark).

Most nonobstetricians are intimidated by atopic dermatitis (AD) in pregnancy, and are concerned about the potential for treatment-related harm to the fetus. As a consequence, they are reluctant to recommend anything beyond weak class I topical corticosteroids and emollients. That’s clearly insufficient in light of the vast scope of need, he asserted. After all, AD affects 15%-20% of all children and persists or reappears in adulthood in one out of five of them. Half of those adults are women, many of whom will at some point wish to become pregnant. And many men with AD will eventually want to father children.

A key message from the task force is that untreated AD in pregnancy potentially places the mother and fetus at risk of serious complications, including Staphylococcus aureus infection and eczema herpeticum.

“If you take one thing away from our position paper, it’s that you can use class II or III topical corticosteroids in pregnant women as first-line therapy,” Dr. Vestergaard said.

This stance contradicts a longstanding widely held concern that topical steroids in pregnancy might increase the risk of facial cleft in the offspring, a worry that has been convincingly debunked in a Cochrane systematic review of 14 studies including more than 1.6 million pregnancies. The report concluded there was no association between topical corticosteroids of any potency with preterm delivery, birth defects, or low Apgar scores (Cochrane Database Syst Rev. 2015 Oct 26. doi: 10.1002/14651858.CD007346.pub3).

The task force recommends that if class II or III topical corticosteroid use in pregnancy exceeds 200 g/month, it’s worth considering add-on UV therapy, with narrow band UVB-311 nm as the regimen of choice; it can be used liberally. UV therapy with psoralens is not advised because of a theoretical risk of mutagenicity.

Product labeling for the topical calcineurin inhibitors declares that the agents should not be used during pregnancy. However, the European task force position paper takes issue with that and declares that topical tacrolimus (Protopic) can be considered an off-label first-line therapy in pregnant women with an insufficient response to liberal use of emollients. The same holds true for breastfeeding patients with AD. Just as when topical corticosteroids are used in the nipple area, topical tacrolimus should be applied after nursing, and the nipple area should be gently cleaned before nursing.

The rationale behind recommending topical tacrolimus as a first-line treatment is that systemic absorption of the drug is trivial. Plus, observational studies of oral tacrolimus in pregnant women who have received a solid organ transplant have shown no increase in congenital malformations.

The task force recommends against the use of topical pimecrolimus (Elidel) or crisaborole (Eucrisa) in pregnancy or lactation due to lack of clinical experience in these settings, Dr. Vestergaard continued.

The task force position is that chlorhexidine and other topical antiseptics – with the notable exception of triclosan – can be used in pregnancy to prevent recurrent skin infections. Aminoglycosides should be avoided, but topical fusidic acid is a reasonable antibiotic for treatment of small areas of clinically infected atopic dermatitis in pregnancy.
 

Systemic therapies

If disease control is insufficient with topical therapy, it’s appropriate to engage in shared decision-making with the patient regarding systemic treatment. She needs to understand up front that the worldwide overall background stillbirth rate in the general population is about 3%, and that severe congenital malformations are present in up to 6% of all live births.

“You need to inform them that they can have systemic therapy and give birth to a child with congenital defects which have nothing to do with the medication,” noted Dr. Vestergaard.

That said, the task force recommends cyclosporine as the off-label, first-line systemic therapy in pregnancy and lactation when long-term treatment is required. This guidance is based largely upon reassuring evidence in solid organ transplant recipients.

The recommended second-line therapy is systemic corticosteroids, but it’s a qualified recommendation. Dr. Vestergaard and colleagues find that systemic corticosteroid therapy is only rarely needed in pregnant AD patients, and the task force recommendation is to limit the use to less than 2-3 weeks and no more than 0.5 mg/kg per day of prednisone. Dexamethasone is not recommended.

Azathioprine should not be started in pregnancy, according to the task force, but when no other options are available, it may be continued in women already on the drug, albeit at half of the prepregnancy dose.

Dupilumab (Dupixent) is to be avoided in pregnant women with AD until more clinical experience becomes available.

Treatment of prospective fathers with AD

The European task force recommends that topical therapies can be prescribed in prospective fathers without any special concerns. The same is true for systemic corticosteroids. Methotrexate should be halted 3 months before planned pregnancy, as is the case for mycophenolate mofetil (CellCept). Azathioprine is recommended when other options have failed. Cyclosporine is deemed a reasonable option in the treatment of men with severe AD at the time of conception if other treatments have failed; of note, neither the Food and Drug Administration nor the European regulatory agency have issued contraindications for the use of the drug in men who wish to become fathers.

Mycophenolate mofetil carries a theoretical risk of teratogenicity. The European task force recommends that men should use condoms while on the drug and for at least 90 days afterward.
 

Unplanned pregnancy in women on systemic therapy

The recommended course of action is to immediately stop systemic therapy, intensify appropriate topical therapy in anticipation of worsening AD, and refer the patient to an obstetrician and a teratology information center for an individualized risk assessment. Methotrexate and mycophenolate mofetil are known teratogens.

The full 16-page task force position paper was published shortly before EADV 2019 (J Eur Acad Dermatol Venereol. 2019 Sep;33[9]:1644-59).

The report was developed without commercial sponsorship. Dr. Vestergaard indicated he has received research grants from and/or serves as a consultant to eight pharmaceutical companies.

bjancin@mdedge.com

MADRID – European atopic dermatitis experts have issued formal guidance on a seriously neglected topic: treatment of the disease during pregnancy, breastfeeding, and in men planning to father children.

Bruce Jancin/MDedge News

The impetus for the project was clear: “Treatment of atopic dermatitis in pregnancy is often forgotten or even ignored,” Christian Vestergaard, MD, PhD, declared at a meeting of the European Task Force on Atopic Dermatitis held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.

He presented highlights of the task force’s position paper on the topic, for which he served as first author. The group’s recommendations are based on expert opinion, since randomized clinical trial literature in this area is nonexistent because of ethical concerns. But the task force, comprising a who’s who in European dermatology, drew on a wealth of collective clinical experience in this area.

“We have all of Europe involved in doing this position statement. It’s meant as what we think is proper treatment and what we can say about the different drugs,” explained Dr. Vestergaard, a dermatologist at the University of Aarhus (Denmark).

Most nonobstetricians are intimidated by atopic dermatitis (AD) in pregnancy, and are concerned about the potential for treatment-related harm to the fetus. As a consequence, they are reluctant to recommend anything beyond weak class I topical corticosteroids and emollients. That’s clearly insufficient in light of the vast scope of need, he asserted. After all, AD affects 15%-20% of all children and persists or reappears in adulthood in one out of five of them. Half of those adults are women, many of whom will at some point wish to become pregnant. And many men with AD will eventually want to father children.

A key message from the task force is that untreated AD in pregnancy potentially places the mother and fetus at risk of serious complications, including Staphylococcus aureus infection and eczema herpeticum.

“If you take one thing away from our position paper, it’s that you can use class II or III topical corticosteroids in pregnant women as first-line therapy,” Dr. Vestergaard said.

This stance contradicts a longstanding widely held concern that topical steroids in pregnancy might increase the risk of facial cleft in the offspring, a worry that has been convincingly debunked in a Cochrane systematic review of 14 studies including more than 1.6 million pregnancies. The report concluded there was no association between topical corticosteroids of any potency with preterm delivery, birth defects, or low Apgar scores (Cochrane Database Syst Rev. 2015 Oct 26. doi: 10.1002/14651858.CD007346.pub3).

The task force recommends that if class II or III topical corticosteroid use in pregnancy exceeds 200 g/month, it’s worth considering add-on UV therapy, with narrow band UVB-311 nm as the regimen of choice; it can be used liberally. UV therapy with psoralens is not advised because of a theoretical risk of mutagenicity.

Product labeling for the topical calcineurin inhibitors declares that the agents should not be used during pregnancy. However, the European task force position paper takes issue with that and declares that topical tacrolimus (Protopic) can be considered an off-label first-line therapy in pregnant women with an insufficient response to liberal use of emollients. The same holds true for breastfeeding patients with AD. Just as when topical corticosteroids are used in the nipple area, topical tacrolimus should be applied after nursing, and the nipple area should be gently cleaned before nursing.

The rationale behind recommending topical tacrolimus as a first-line treatment is that systemic absorption of the drug is trivial. Plus, observational studies of oral tacrolimus in pregnant women who have received a solid organ transplant have shown no increase in congenital malformations.

The task force recommends against the use of topical pimecrolimus (Elidel) or crisaborole (Eucrisa) in pregnancy or lactation due to lack of clinical experience in these settings, Dr. Vestergaard continued.

The task force position is that chlorhexidine and other topical antiseptics – with the notable exception of triclosan – can be used in pregnancy to prevent recurrent skin infections. Aminoglycosides should be avoided, but topical fusidic acid is a reasonable antibiotic for treatment of small areas of clinically infected atopic dermatitis in pregnancy.
 

Systemic therapies

If disease control is insufficient with topical therapy, it’s appropriate to engage in shared decision-making with the patient regarding systemic treatment. She needs to understand up front that the worldwide overall background stillbirth rate in the general population is about 3%, and that severe congenital malformations are present in up to 6% of all live births.

“You need to inform them that they can have systemic therapy and give birth to a child with congenital defects which have nothing to do with the medication,” noted Dr. Vestergaard.

That said, the task force recommends cyclosporine as the off-label, first-line systemic therapy in pregnancy and lactation when long-term treatment is required. This guidance is based largely upon reassuring evidence in solid organ transplant recipients.

The recommended second-line therapy is systemic corticosteroids, but it’s a qualified recommendation. Dr. Vestergaard and colleagues find that systemic corticosteroid therapy is only rarely needed in pregnant AD patients, and the task force recommendation is to limit the use to less than 2-3 weeks and no more than 0.5 mg/kg per day of prednisone. Dexamethasone is not recommended.

Azathioprine should not be started in pregnancy, according to the task force, but when no other options are available, it may be continued in women already on the drug, albeit at half of the prepregnancy dose.

Dupilumab (Dupixent) is to be avoided in pregnant women with AD until more clinical experience becomes available.

Treatment of prospective fathers with AD

The European task force recommends that topical therapies can be prescribed in prospective fathers without any special concerns. The same is true for systemic corticosteroids. Methotrexate should be halted 3 months before planned pregnancy, as is the case for mycophenolate mofetil (CellCept). Azathioprine is recommended when other options have failed. Cyclosporine is deemed a reasonable option in the treatment of men with severe AD at the time of conception if other treatments have failed; of note, neither the Food and Drug Administration nor the European regulatory agency have issued contraindications for the use of the drug in men who wish to become fathers.

Mycophenolate mofetil carries a theoretical risk of teratogenicity. The European task force recommends that men should use condoms while on the drug and for at least 90 days afterward.
 

Unplanned pregnancy in women on systemic therapy

The recommended course of action is to immediately stop systemic therapy, intensify appropriate topical therapy in anticipation of worsening AD, and refer the patient to an obstetrician and a teratology information center for an individualized risk assessment. Methotrexate and mycophenolate mofetil are known teratogens.

The full 16-page task force position paper was published shortly before EADV 2019 (J Eur Acad Dermatol Venereol. 2019 Sep;33[9]:1644-59).

The report was developed without commercial sponsorship. Dr. Vestergaard indicated he has received research grants from and/or serves as a consultant to eight pharmaceutical companies.

bjancin@mdedge.com

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.

Neil Osterweil/MDedge News

“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.

Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).

The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.

The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.

The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.

Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.

The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.

For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.

In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.

They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.

At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.

“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.

Benjamin Pena/Medscape

In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.

“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.

The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.

SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.

With much of the public now wearing devices on their wrists or elsewhere capable of recording a range of vital signs, including heart rate abnormalities, the Heart Rhythm Society launched a guide for American consumers about wearables and the data they collect during a session on Jan. 9 at CES 2020 in Las Vegas.

Mitchel L. Zoler/MDedge News

While providing a succinct but comprehensive overview of the types of wearables and the health metrics they can record, the main and recurring message of the 10-page e-pamphlet is that, when a layperson has a question or concern about their data, the best course is to consult a clinician.

The “Guidance for Wearable Health Solutions,” produced by the Heart Rhythm Society (HRS) along with the Consumer Technology Association (CTA, which presents the annual CES exhibition), cautions that “most wearables are primarily suited for fitness and wellness,” and stresses that wearables “are not a substitute for medical devices prescribed by a clinician.” And in all cases, the document advises, when questions arise about the data – including an apparently high heart rate; a reading the device identifies as abnormal; and when symptoms appear such as a rapid heart rate, dizziness, or fluttering or flopping of the heart – the response that the guidance advocates is consistent: Talk with your clinician.

“Heart Rhythm Society members are seeing more and more patients with their own data collected by wearables,” said Nassir F. Marrouche, MD, professor of medicine and director of electrophysiology at Tulane University, New Orleans, and a member of the panel that wrote the guidance document for the HRS and CTA. “Every provider is dealing with consumer wearable data. The need is important for consumers to be supported. Consumers and patients are buying over-the-counter devices and using them for diagnosis and management, with little to no guidance, and we want to help them feel supported in managing their data and understand what to do with it,” Dr. Marrouche said in an interview.

“This is a new reality in medicine; the direction of information is changing. Consumers are collecting data themselves and coming to physicians already informed. There is a new shift in how information is collected, shared, and used.” Dr. Marrouche was 1 of 5 cardiac electrophysiologists who served on the 11-member writing group.

The new document for consumers “addresses an unmet need,” and the HRS collaboration with the CTA was “a unique opportunity to develop useful guidance that supports education and empowers consumers,” said Christina Wurster, chief strategy officer for the HRS in Washington and a member of the writing panel. “The questions outlined in the document are questions our members receive daily. The document is a resource they can direct people to.”

The HRS and CTA will “partner with consumer advocacy groups and professional societies to further disseminate the document,” added Ms. Wurster. “We’ll also have a strong push on social media to reach consumer audiences and drive awareness of this new resource,” she said in an interview. In addition, HRS “has strategic partnerships with other societies and will aim to work with them for dissemination, including societies related to internal medicine, emergency medicine, cardiology, and nursing, as well as also working with patient and consumer advocacy groups to reach the public.” The CTA will also actively publicize and disseminate the guidance document through their members.
 

Clinical guidelines play catch-up

Ironically, the HRS has issued this guidance to the public and has told people to take their wearable-collected heart data to clinicians before the HRS or any other medical group has advised clinicians on how they should handle, interpret, and use heart rhythm data collected this way.

Presumably, many if not most of the people with questions about their heart data from wearables are asymptomatic, because symptoms are what usually drive patients with a cardiac arrhythmia to consult a physician – they don’t wait to see what their device tells them. But the best way to manage asymptomatic arrhythmias like atrial fibrillation (AFib) remains a big clinical uncertainty today, with no evidence base as a guide, although several studies exploring this question are in progress.

Mitchel L. Zoler/MDedge News

“There are no clear and definitive data showing that treating subclinical atrial fibrillation improves outcomes. That’s what we need, and until we get these data you won’t see strong recommendations in guidelines” to screen patients for asymptomatic AFib or other arrhythmias, said Sana M. Al-Khatib, MD, a cardiac electrophysiologist and professor of medicine at Duke University, Durham, N.C., during the 2019 American Heart Association scientific sessions in Philadelphia in a talk about wearables and guidelines.

“If you intervene with silent AFib, do you improve outcomes? That evidence is lacking,” she said. Another shortcoming of current evidence is a clear understanding of what AFib burden warrants intervention, added Dr. Al-Khatib. “We see high-rate AFib episodes recorded in patients with implanted cardiac devices [and no symptoms], and we don’t know what to do with that either.”

The closest any existing guideline from a medical society comes to currently endorsing screening for AFib by a wearable is the 2016 European Society of Cardiology’s AFib management guidelines, which give “opportunistic screening” among people aged older than 65 years a IB recommendation, but specifically for screening by taking a patient’s pulse or with a ECG recording, with no mention of the screening role for wearables (Eur Heart J. 2016 Oct 7;37[38]:2893-967), Dr. Al-Khatib noted.

The most extensive data on screening for asymptomatic AFib in an unselected population came in the recently reported results from the Apple Heart Study, which enrolled more than 419,000 people monitored by a smart watch for a median of 117 days. During this screening, 2,161 people (0.52%) received a notification of having an irregular pulse (including 3.1% of those who were aged at least 65 years), which triggered more intensive assessment with an ECG patch for a median of 13 days in 450 of the 2,161 screening positives (21%) who agreed to participate in this follow-up. Among those 450 people, the patch test identified 34% as having actual AFib (N Engl J Med. 2019 Nov 14;381[20]:1909-17). But while this study provided evidence that screening for an irregular heartbeat with a wearable can identify AFib with some level of success, the results did not address whether this approach improved short- or long-term patient outcomes.

In addition, what the Apple Heart Study results showed was that this sort of screening results in a relatively large volume of follow-up testing. Of the 2,161 participants who received an irregular pulse notification, 1,376 (64%) returned a 90-day survey. Of these, 787 (57%) reported contact with a health care provider outside the study, 28% were prescribed a new medication, 33% were recommended to see a specialist (such as a cardiologist), and 36% were recommended to have additional testing.

Mitchel L. Zoler/MDedge News

“The results raise the question that a lot of resources were used,” to assess patients with a positive screening result, noted Paul A. Heidenreich, MD, a cardiologist and professor of medicine at Stanford (Calif.) University who studies quality of care for patients with heart disease. He estimated that, in the Apple Heart Study, each of the more than 2,000 patients who screening positive for an irregular heartbeat and underwent subsequent assessment ran up about $700 worth of follow-up testing. But he added that, in the case of AFib, the primary intervention that many previously undiagnosed AFib patients receive is some sort of anticoagulation for stroke prevention. Moreover, because this intervention is so effective there is a lot of money to play with to make AFib screening cost effective, as judged by typical, contemporary metrics of cost efficacy that value a quality-adjusted life-year (QALY) gain as reasonable for society to pay if the cost of an incremental QALY is $50,000-$150,000.

If the benchmark is a cost that’s within $50,000/QALY, then an average follow-up cost of $116/person to assess screened positives can fall within this cost ceiling. If the benchmark is $150,000/QALY, then follow-up costs can run as high as $491/person screened, said Dr. Heidenreich during the same AHA session where Dr. Al-Khatib spoke last November.

Despite this good news for screening for AFib with a wearable from a cost-effectiveness perspective, “there is so much uncertainty regarding the benefit and the consequences of incidental findings that we need an outcomes study before widespread implementation” of this type of screening, Dr. Heidenreich concluded. “We need an outcomes study to feel comfortable” with screening. “There is a huge potential for extra care that we don’t understand.”

Dr. Marrouche agreed that collecting adequate evidence to drive changes in clinical guidelines on how to use data from wearables has lagged behind the rapid spread of wearables and the information they can produce among the American public. “Outcomes and evidence will support guidelines development, but in the meantime, we’re offering education to clinicians, patients, and consumers. Consumers own their data, and they can share them with whomever they choose.”

The document notes that people who use wearables are, in general, “enthusiastic about tracking their data, not only for their own use, but also to share” with others, often on social media websites.

“We cannot control that, but our goal in the document is focused on the clinical relevance [of the data] and to help people better understand their data and use it in a meaningful and safe way,” Dr. Marrouche said.

Dr. Marrouche has been a consultant to, advisor to, or received research support from Abbott, Biosense Webster, Biotronik, GE Healthcare, Medtronic, Preventice, Sanofi-Aventis, Siemens, and Vytronus. Ms. Wurster is an employee of the Heart Rhythm Society. Dr. Al-Khatib has been a consultant to Milestone Pharmaceuticals and Medtronic, and she has also received other financial benefits from Medtronic. Dr. Heidenreich had no disclosures,

mzoler@mdedge.com

With much of the public now wearing devices on their wrists or elsewhere capable of recording a range of vital signs, including heart rate abnormalities, the Heart Rhythm Society launched a guide for American consumers about wearables and the data they collect during a session on Jan. 9 at CES 2020 in Las Vegas.

Mitchel L. Zoler/MDedge News

While providing a succinct but comprehensive overview of the types of wearables and the health metrics they can record, the main and recurring message of the 10-page e-pamphlet is that, when a layperson has a question or concern about their data, the best course is to consult a clinician.

The “Guidance for Wearable Health Solutions,” produced by the Heart Rhythm Society (HRS) along with the Consumer Technology Association (CTA, which presents the annual CES exhibition), cautions that “most wearables are primarily suited for fitness and wellness,” and stresses that wearables “are not a substitute for medical devices prescribed by a clinician.” And in all cases, the document advises, when questions arise about the data – including an apparently high heart rate; a reading the device identifies as abnormal; and when symptoms appear such as a rapid heart rate, dizziness, or fluttering or flopping of the heart – the response that the guidance advocates is consistent: Talk with your clinician.

“Heart Rhythm Society members are seeing more and more patients with their own data collected by wearables,” said Nassir F. Marrouche, MD, professor of medicine and director of electrophysiology at Tulane University, New Orleans, and a member of the panel that wrote the guidance document for the HRS and CTA. “Every provider is dealing with consumer wearable data. The need is important for consumers to be supported. Consumers and patients are buying over-the-counter devices and using them for diagnosis and management, with little to no guidance, and we want to help them feel supported in managing their data and understand what to do with it,” Dr. Marrouche said in an interview.

“This is a new reality in medicine; the direction of information is changing. Consumers are collecting data themselves and coming to physicians already informed. There is a new shift in how information is collected, shared, and used.” Dr. Marrouche was 1 of 5 cardiac electrophysiologists who served on the 11-member writing group.

The new document for consumers “addresses an unmet need,” and the HRS collaboration with the CTA was “a unique opportunity to develop useful guidance that supports education and empowers consumers,” said Christina Wurster, chief strategy officer for the HRS in Washington and a member of the writing panel. “The questions outlined in the document are questions our members receive daily. The document is a resource they can direct people to.”

The HRS and CTA will “partner with consumer advocacy groups and professional societies to further disseminate the document,” added Ms. Wurster. “We’ll also have a strong push on social media to reach consumer audiences and drive awareness of this new resource,” she said in an interview. In addition, HRS “has strategic partnerships with other societies and will aim to work with them for dissemination, including societies related to internal medicine, emergency medicine, cardiology, and nursing, as well as also working with patient and consumer advocacy groups to reach the public.” The CTA will also actively publicize and disseminate the guidance document through their members.
 

Clinical guidelines play catch-up

Ironically, the HRS has issued this guidance to the public and has told people to take their wearable-collected heart data to clinicians before the HRS or any other medical group has advised clinicians on how they should handle, interpret, and use heart rhythm data collected this way.

Presumably, many if not most of the people with questions about their heart data from wearables are asymptomatic, because symptoms are what usually drive patients with a cardiac arrhythmia to consult a physician – they don’t wait to see what their device tells them. But the best way to manage asymptomatic arrhythmias like atrial fibrillation (AFib) remains a big clinical uncertainty today, with no evidence base as a guide, although several studies exploring this question are in progress.

Mitchel L. Zoler/MDedge News

“There are no clear and definitive data showing that treating subclinical atrial fibrillation improves outcomes. That’s what we need, and until we get these data you won’t see strong recommendations in guidelines” to screen patients for asymptomatic AFib or other arrhythmias, said Sana M. Al-Khatib, MD, a cardiac electrophysiologist and professor of medicine at Duke University, Durham, N.C., during the 2019 American Heart Association scientific sessions in Philadelphia in a talk about wearables and guidelines.

“If you intervene with silent AFib, do you improve outcomes? That evidence is lacking,” she said. Another shortcoming of current evidence is a clear understanding of what AFib burden warrants intervention, added Dr. Al-Khatib. “We see high-rate AFib episodes recorded in patients with implanted cardiac devices [and no symptoms], and we don’t know what to do with that either.”

The closest any existing guideline from a medical society comes to currently endorsing screening for AFib by a wearable is the 2016 European Society of Cardiology’s AFib management guidelines, which give “opportunistic screening” among people aged older than 65 years a IB recommendation, but specifically for screening by taking a patient’s pulse or with a ECG recording, with no mention of the screening role for wearables (Eur Heart J. 2016 Oct 7;37[38]:2893-967), Dr. Al-Khatib noted.

The most extensive data on screening for asymptomatic AFib in an unselected population came in the recently reported results from the Apple Heart Study, which enrolled more than 419,000 people monitored by a smart watch for a median of 117 days. During this screening, 2,161 people (0.52%) received a notification of having an irregular pulse (including 3.1% of those who were aged at least 65 years), which triggered more intensive assessment with an ECG patch for a median of 13 days in 450 of the 2,161 screening positives (21%) who agreed to participate in this follow-up. Among those 450 people, the patch test identified 34% as having actual AFib (N Engl J Med. 2019 Nov 14;381[20]:1909-17). But while this study provided evidence that screening for an irregular heartbeat with a wearable can identify AFib with some level of success, the results did not address whether this approach improved short- or long-term patient outcomes.

In addition, what the Apple Heart Study results showed was that this sort of screening results in a relatively large volume of follow-up testing. Of the 2,161 participants who received an irregular pulse notification, 1,376 (64%) returned a 90-day survey. Of these, 787 (57%) reported contact with a health care provider outside the study, 28% were prescribed a new medication, 33% were recommended to see a specialist (such as a cardiologist), and 36% were recommended to have additional testing.

Mitchel L. Zoler/MDedge News

“The results raise the question that a lot of resources were used,” to assess patients with a positive screening result, noted Paul A. Heidenreich, MD, a cardiologist and professor of medicine at Stanford (Calif.) University who studies quality of care for patients with heart disease. He estimated that, in the Apple Heart Study, each of the more than 2,000 patients who screening positive for an irregular heartbeat and underwent subsequent assessment ran up about $700 worth of follow-up testing. But he added that, in the case of AFib, the primary intervention that many previously undiagnosed AFib patients receive is some sort of anticoagulation for stroke prevention. Moreover, because this intervention is so effective there is a lot of money to play with to make AFib screening cost effective, as judged by typical, contemporary metrics of cost efficacy that value a quality-adjusted life-year (QALY) gain as reasonable for society to pay if the cost of an incremental QALY is $50,000-$150,000.

If the benchmark is a cost that’s within $50,000/QALY, then an average follow-up cost of $116/person to assess screened positives can fall within this cost ceiling. If the benchmark is $150,000/QALY, then follow-up costs can run as high as $491/person screened, said Dr. Heidenreich during the same AHA session where Dr. Al-Khatib spoke last November.

Despite this good news for screening for AFib with a wearable from a cost-effectiveness perspective, “there is so much uncertainty regarding the benefit and the consequences of incidental findings that we need an outcomes study before widespread implementation” of this type of screening, Dr. Heidenreich concluded. “We need an outcomes study to feel comfortable” with screening. “There is a huge potential for extra care that we don’t understand.”

Dr. Marrouche agreed that collecting adequate evidence to drive changes in clinical guidelines on how to use data from wearables has lagged behind the rapid spread of wearables and the information they can produce among the American public. “Outcomes and evidence will support guidelines development, but in the meantime, we’re offering education to clinicians, patients, and consumers. Consumers own their data, and they can share them with whomever they choose.”

The document notes that people who use wearables are, in general, “enthusiastic about tracking their data, not only for their own use, but also to share” with others, often on social media websites.

“We cannot control that, but our goal in the document is focused on the clinical relevance [of the data] and to help people better understand their data and use it in a meaningful and safe way,” Dr. Marrouche said.

Dr. Marrouche has been a consultant to, advisor to, or received research support from Abbott, Biosense Webster, Biotronik, GE Healthcare, Medtronic, Preventice, Sanofi-Aventis, Siemens, and Vytronus. Ms. Wurster is an employee of the Heart Rhythm Society. Dr. Al-Khatib has been a consultant to Milestone Pharmaceuticals and Medtronic, and she has also received other financial benefits from Medtronic. Dr. Heidenreich had no disclosures,

mzoler@mdedge.com

With much of the public now wearing devices on their wrists or elsewhere capable of recording a range of vital signs, including heart rate abnormalities, the Heart Rhythm Society launched a guide for American consumers about wearables and the data they collect during a session on Jan. 9 at CES 2020 in Las Vegas.

Mitchel L. Zoler/MDedge News

While providing a succinct but comprehensive overview of the types of wearables and the health metrics they can record, the main and recurring message of the 10-page e-pamphlet is that, when a layperson has a question or concern about their data, the best course is to consult a clinician.

The “Guidance for Wearable Health Solutions,” produced by the Heart Rhythm Society (HRS) along with the Consumer Technology Association (CTA, which presents the annual CES exhibition), cautions that “most wearables are primarily suited for fitness and wellness,” and stresses that wearables “are not a substitute for medical devices prescribed by a clinician.” And in all cases, the document advises, when questions arise about the data – including an apparently high heart rate; a reading the device identifies as abnormal; and when symptoms appear such as a rapid heart rate, dizziness, or fluttering or flopping of the heart – the response that the guidance advocates is consistent: Talk with your clinician.

“Heart Rhythm Society members are seeing more and more patients with their own data collected by wearables,” said Nassir F. Marrouche, MD, professor of medicine and director of electrophysiology at Tulane University, New Orleans, and a member of the panel that wrote the guidance document for the HRS and CTA. “Every provider is dealing with consumer wearable data. The need is important for consumers to be supported. Consumers and patients are buying over-the-counter devices and using them for diagnosis and management, with little to no guidance, and we want to help them feel supported in managing their data and understand what to do with it,” Dr. Marrouche said in an interview.

“This is a new reality in medicine; the direction of information is changing. Consumers are collecting data themselves and coming to physicians already informed. There is a new shift in how information is collected, shared, and used.” Dr. Marrouche was 1 of 5 cardiac electrophysiologists who served on the 11-member writing group.

The new document for consumers “addresses an unmet need,” and the HRS collaboration with the CTA was “a unique opportunity to develop useful guidance that supports education and empowers consumers,” said Christina Wurster, chief strategy officer for the HRS in Washington and a member of the writing panel. “The questions outlined in the document are questions our members receive daily. The document is a resource they can direct people to.”

The HRS and CTA will “partner with consumer advocacy groups and professional societies to further disseminate the document,” added Ms. Wurster. “We’ll also have a strong push on social media to reach consumer audiences and drive awareness of this new resource,” she said in an interview. In addition, HRS “has strategic partnerships with other societies and will aim to work with them for dissemination, including societies related to internal medicine, emergency medicine, cardiology, and nursing, as well as also working with patient and consumer advocacy groups to reach the public.” The CTA will also actively publicize and disseminate the guidance document through their members.
 

Clinical guidelines play catch-up

Ironically, the HRS has issued this guidance to the public and has told people to take their wearable-collected heart data to clinicians before the HRS or any other medical group has advised clinicians on how they should handle, interpret, and use heart rhythm data collected this way.

Presumably, many if not most of the people with questions about their heart data from wearables are asymptomatic, because symptoms are what usually drive patients with a cardiac arrhythmia to consult a physician – they don’t wait to see what their device tells them. But the best way to manage asymptomatic arrhythmias like atrial fibrillation (AFib) remains a big clinical uncertainty today, with no evidence base as a guide, although several studies exploring this question are in progress.

Mitchel L. Zoler/MDedge News

“There are no clear and definitive data showing that treating subclinical atrial fibrillation improves outcomes. That’s what we need, and until we get these data you won’t see strong recommendations in guidelines” to screen patients for asymptomatic AFib or other arrhythmias, said Sana M. Al-Khatib, MD, a cardiac electrophysiologist and professor of medicine at Duke University, Durham, N.C., during the 2019 American Heart Association scientific sessions in Philadelphia in a talk about wearables and guidelines.

“If you intervene with silent AFib, do you improve outcomes? That evidence is lacking,” she said. Another shortcoming of current evidence is a clear understanding of what AFib burden warrants intervention, added Dr. Al-Khatib. “We see high-rate AFib episodes recorded in patients with implanted cardiac devices [and no symptoms], and we don’t know what to do with that either.”

The closest any existing guideline from a medical society comes to currently endorsing screening for AFib by a wearable is the 2016 European Society of Cardiology’s AFib management guidelines, which give “opportunistic screening” among people aged older than 65 years a IB recommendation, but specifically for screening by taking a patient’s pulse or with a ECG recording, with no mention of the screening role for wearables (Eur Heart J. 2016 Oct 7;37[38]:2893-967), Dr. Al-Khatib noted.

The most extensive data on screening for asymptomatic AFib in an unselected population came in the recently reported results from the Apple Heart Study, which enrolled more than 419,000 people monitored by a smart watch for a median of 117 days. During this screening, 2,161 people (0.52%) received a notification of having an irregular pulse (including 3.1% of those who were aged at least 65 years), which triggered more intensive assessment with an ECG patch for a median of 13 days in 450 of the 2,161 screening positives (21%) who agreed to participate in this follow-up. Among those 450 people, the patch test identified 34% as having actual AFib (N Engl J Med. 2019 Nov 14;381[20]:1909-17). But while this study provided evidence that screening for an irregular heartbeat with a wearable can identify AFib with some level of success, the results did not address whether this approach improved short- or long-term patient outcomes.

In addition, what the Apple Heart Study results showed was that this sort of screening results in a relatively large volume of follow-up testing. Of the 2,161 participants who received an irregular pulse notification, 1,376 (64%) returned a 90-day survey. Of these, 787 (57%) reported contact with a health care provider outside the study, 28% were prescribed a new medication, 33% were recommended to see a specialist (such as a cardiologist), and 36% were recommended to have additional testing.

Mitchel L. Zoler/MDedge News

“The results raise the question that a lot of resources were used,” to assess patients with a positive screening result, noted Paul A. Heidenreich, MD, a cardiologist and professor of medicine at Stanford (Calif.) University who studies quality of care for patients with heart disease. He estimated that, in the Apple Heart Study, each of the more than 2,000 patients who screening positive for an irregular heartbeat and underwent subsequent assessment ran up about $700 worth of follow-up testing. But he added that, in the case of AFib, the primary intervention that many previously undiagnosed AFib patients receive is some sort of anticoagulation for stroke prevention. Moreover, because this intervention is so effective there is a lot of money to play with to make AFib screening cost effective, as judged by typical, contemporary metrics of cost efficacy that value a quality-adjusted life-year (QALY) gain as reasonable for society to pay if the cost of an incremental QALY is $50,000-$150,000.

If the benchmark is a cost that’s within $50,000/QALY, then an average follow-up cost of $116/person to assess screened positives can fall within this cost ceiling. If the benchmark is $150,000/QALY, then follow-up costs can run as high as $491/person screened, said Dr. Heidenreich during the same AHA session where Dr. Al-Khatib spoke last November.

Despite this good news for screening for AFib with a wearable from a cost-effectiveness perspective, “there is so much uncertainty regarding the benefit and the consequences of incidental findings that we need an outcomes study before widespread implementation” of this type of screening, Dr. Heidenreich concluded. “We need an outcomes study to feel comfortable” with screening. “There is a huge potential for extra care that we don’t understand.”

Dr. Marrouche agreed that collecting adequate evidence to drive changes in clinical guidelines on how to use data from wearables has lagged behind the rapid spread of wearables and the information they can produce among the American public. “Outcomes and evidence will support guidelines development, but in the meantime, we’re offering education to clinicians, patients, and consumers. Consumers own their data, and they can share them with whomever they choose.”

The document notes that people who use wearables are, in general, “enthusiastic about tracking their data, not only for their own use, but also to share” with others, often on social media websites.

“We cannot control that, but our goal in the document is focused on the clinical relevance [of the data] and to help people better understand their data and use it in a meaningful and safe way,” Dr. Marrouche said.

Dr. Marrouche has been a consultant to, advisor to, or received research support from Abbott, Biosense Webster, Biotronik, GE Healthcare, Medtronic, Preventice, Sanofi-Aventis, Siemens, and Vytronus. Ms. Wurster is an employee of the Heart Rhythm Society. Dr. Al-Khatib has been a consultant to Milestone Pharmaceuticals and Medtronic, and she has also received other financial benefits from Medtronic. Dr. Heidenreich had no disclosures,

mzoler@mdedge.com

An implanted gastric electrical stimulation device significantly improved refractory vomiting but not quality of life in a randomized, multicenter, double-blind crossover trial of 172 patients.

After 4 months of electrical stimulation, frequency of vomiting was significantly improved from baseline in the intervention arm, compared with the control arm, in patients with both delayed (P less than .01) and normal (P = .05) gastric emptying. There was also an improvement in nausea with gastric stimulation. In contrast, there was no significant improvement in the coprimary endpoint of quality of life. Based on these findings, “a limited number of medically resistant patients may benefit from gastroelectric stimulation to relieve nausea and vomiting,” wrote Philippe Ducrotté, MD, of Rouen (France) University Hospital and associates in Gastroenterology.

High-frequency gastric electrical stimulation with the surgically implanted Enterra device is regarded as a treatment option for chronic refractory vomiting in patients with or without gastroparesis. However, only moderate evidence supports the use of this therapy, with level 1 evidence limited to a single study, according to the researchers. For the study, they enrolled 172 adults with at least 12 months of nausea or vomiting that was refractory to antiemetic or prokinetic therapy and was either idiopathic or related to type 1 or 2 diabetes mellitus or surgery (partial gastric resection or vagotomy). Symptoms “had to be severe enough to affect the general condition of the patient, including [causing] weight loss, or the need to change dietary intake to control diabetes,” said the researchers.

The study started with a 4-month run-in period, after which all patients had the device implanted and left off for one month. Patients in the intervention arm then had the device turned on and programmed at standard parameters (5 mA, 14 Hz, 330 micros, cycle on 0.1s, cycle off 5s). Both groups were assessed at 4 months, and 149 patients then crossed over to the other arm and were assessed again at 4 months. Vomiting was evaluated on a 5-point scale ranging from 0 (most severe) to 5 (symptom absent), while quality of life was assessed by means of the 36-question, self-administered Gastrointestinal Quality of Life Index (GIQLI).

During the intervention, 30.6% of patients reported at least a 1-point improvement on the vomiting frequency scale, while 53% reported no change. With the device turned off, 16.5% of patients reported an improvement in vomiting. During both phases of the trial, median vomiting frequency score was improved in the intervention arm compared with the control arm (P less than .001) in patients with (42%) and without (58%) diabetes. “Gastric emptying was not accelerated during the on period compared with the off period,” the investigators wrote. 

A total of 133 (77%) patients in the study had gastroparesis. Most patients were women in their 40s who vomited several times per day. Among 45 device-related events, the most common was abdominal pain at the implantation site (62%), followed by “infectious problems” at the abdominal pouch level (36%) and hematoma (2%). Three of these events “were serious enough to prompt device removal,” the researchers wrote.

The French government funded the study. The investigators reported having no conflicts of interest. They dedicated the paper to the memory of Dr. Ducrotté, who died during the course of the study.

*This story was updated on January 13, 2020.

SOURCE: Ducrotté P et al. Gastroenterology. 2019 Oct 1. https://doi.org/10.1053/j.gastro.2019.10.018

An implanted gastric electrical stimulation device significantly improved refractory vomiting but not quality of life in a randomized, multicenter, double-blind crossover trial of 172 patients.

After 4 months of electrical stimulation, frequency of vomiting was significantly improved from baseline in the intervention arm, compared with the control arm, in patients with both delayed (P less than .01) and normal (P = .05) gastric emptying. There was also an improvement in nausea with gastric stimulation. In contrast, there was no significant improvement in the coprimary endpoint of quality of life. Based on these findings, “a limited number of medically resistant patients may benefit from gastroelectric stimulation to relieve nausea and vomiting,” wrote Philippe Ducrotté, MD, of Rouen (France) University Hospital and associates in Gastroenterology.

High-frequency gastric electrical stimulation with the surgically implanted Enterra device is regarded as a treatment option for chronic refractory vomiting in patients with or without gastroparesis. However, only moderate evidence supports the use of this therapy, with level 1 evidence limited to a single study, according to the researchers. For the study, they enrolled 172 adults with at least 12 months of nausea or vomiting that was refractory to antiemetic or prokinetic therapy and was either idiopathic or related to type 1 or 2 diabetes mellitus or surgery (partial gastric resection or vagotomy). Symptoms “had to be severe enough to affect the general condition of the patient, including [causing] weight loss, or the need to change dietary intake to control diabetes,” said the researchers.

The study started with a 4-month run-in period, after which all patients had the device implanted and left off for one month. Patients in the intervention arm then had the device turned on and programmed at standard parameters (5 mA, 14 Hz, 330 micros, cycle on 0.1s, cycle off 5s). Both groups were assessed at 4 months, and 149 patients then crossed over to the other arm and were assessed again at 4 months. Vomiting was evaluated on a 5-point scale ranging from 0 (most severe) to 5 (symptom absent), while quality of life was assessed by means of the 36-question, self-administered Gastrointestinal Quality of Life Index (GIQLI).

During the intervention, 30.6% of patients reported at least a 1-point improvement on the vomiting frequency scale, while 53% reported no change. With the device turned off, 16.5% of patients reported an improvement in vomiting. During both phases of the trial, median vomiting frequency score was improved in the intervention arm compared with the control arm (P less than .001) in patients with (42%) and without (58%) diabetes. “Gastric emptying was not accelerated during the on period compared with the off period,” the investigators wrote. 

A total of 133 (77%) patients in the study had gastroparesis. Most patients were women in their 40s who vomited several times per day. Among 45 device-related events, the most common was abdominal pain at the implantation site (62%), followed by “infectious problems” at the abdominal pouch level (36%) and hematoma (2%). Three of these events “were serious enough to prompt device removal,” the researchers wrote.

The French government funded the study. The investigators reported having no conflicts of interest. They dedicated the paper to the memory of Dr. Ducrotté, who died during the course of the study.

*This story was updated on January 13, 2020.

SOURCE: Ducrotté P et al. Gastroenterology. 2019 Oct 1. https://doi.org/10.1053/j.gastro.2019.10.018

An implanted gastric electrical stimulation device significantly improved refractory vomiting but not quality of life in a randomized, multicenter, double-blind crossover trial of 172 patients.

After 4 months of electrical stimulation, frequency of vomiting was significantly improved from baseline in the intervention arm, compared with the control arm, in patients with both delayed (P less than .01) and normal (P = .05) gastric emptying. There was also an improvement in nausea with gastric stimulation. In contrast, there was no significant improvement in the coprimary endpoint of quality of life. Based on these findings, “a limited number of medically resistant patients may benefit from gastroelectric stimulation to relieve nausea and vomiting,” wrote Philippe Ducrotté, MD, of Rouen (France) University Hospital and associates in Gastroenterology.

High-frequency gastric electrical stimulation with the surgically implanted Enterra device is regarded as a treatment option for chronic refractory vomiting in patients with or without gastroparesis. However, only moderate evidence supports the use of this therapy, with level 1 evidence limited to a single study, according to the researchers. For the study, they enrolled 172 adults with at least 12 months of nausea or vomiting that was refractory to antiemetic or prokinetic therapy and was either idiopathic or related to type 1 or 2 diabetes mellitus or surgery (partial gastric resection or vagotomy). Symptoms “had to be severe enough to affect the general condition of the patient, including [causing] weight loss, or the need to change dietary intake to control diabetes,” said the researchers.

The study started with a 4-month run-in period, after which all patients had the device implanted and left off for one month. Patients in the intervention arm then had the device turned on and programmed at standard parameters (5 mA, 14 Hz, 330 micros, cycle on 0.1s, cycle off 5s). Both groups were assessed at 4 months, and 149 patients then crossed over to the other arm and were assessed again at 4 months. Vomiting was evaluated on a 5-point scale ranging from 0 (most severe) to 5 (symptom absent), while quality of life was assessed by means of the 36-question, self-administered Gastrointestinal Quality of Life Index (GIQLI).

During the intervention, 30.6% of patients reported at least a 1-point improvement on the vomiting frequency scale, while 53% reported no change. With the device turned off, 16.5% of patients reported an improvement in vomiting. During both phases of the trial, median vomiting frequency score was improved in the intervention arm compared with the control arm (P less than .001) in patients with (42%) and without (58%) diabetes. “Gastric emptying was not accelerated during the on period compared with the off period,” the investigators wrote. 

A total of 133 (77%) patients in the study had gastroparesis. Most patients were women in their 40s who vomited several times per day. Among 45 device-related events, the most common was abdominal pain at the implantation site (62%), followed by “infectious problems” at the abdominal pouch level (36%) and hematoma (2%). Three of these events “were serious enough to prompt device removal,” the researchers wrote.

The French government funded the study. The investigators reported having no conflicts of interest. They dedicated the paper to the memory of Dr. Ducrotté, who died during the course of the study.

*This story was updated on January 13, 2020.

SOURCE: Ducrotté P et al. Gastroenterology. 2019 Oct 1. https://doi.org/10.1053/j.gastro.2019.10.018