SAN ANTONIO – Circulating tumor cell (CTC) counts could serve as a standalone biomarker for determining which patients with newly diagnosed estrogen receptor–positive, HER2-negative metastatic breast cancer are at high risk and should receive first-line chemotherapy and which are at low risk and could safely receive upfront hormonal therapy.

In the phase 3 STIC CTC trial, there were no significant differences in the primary endpoint of progression-free survival (PFS) or a secondary endpoint of overall survival (OS) between patients whose treatments were assigned according to the clinicians’ judgment and those whose treatments were chosen based on CTC count, reported Francois-Clement Bidard, MD, PhD, from Institut Curie in St. Cloud, France.

“CTC count should or may be included in the decision algorithm for hormone receptor–positive, HER2-negative metastatic breast cancer patients,” he said at the San Antonio Breast Cancer Symposium.

The CTC investigators sought to compare CTC-driven clinical decisions with the clinicians choice for first-line therapy in 778 patients with hormone receptor–positive, HER2-negative breast cancer.

Patients were stratified by performance status (0-3), treatment center, and disease-free interval and were randomly assigned to receive therapy based on either the clinician’s judgment of the best course of therapy for each patient or to CTC count, with a cutoff of less than 5 CTC/7.5 mL indicating hormonal therapy and 5 CTC/7.5 mL or above indicating higher-risk disease requiring chemotherapy. In the clinician’s choice arm, the CTC reading was recorded but not implemented, and in the CTC arm, the clinician’s choice was dismissed.

The trial protocol did not specify a chemotherapy regimen, and patients initially assigned to chemotherapy were allowed to have maintenance hormonal therapy.

At 42 months of follow-up, median PFS in the CTC arm was 15.6 months, compared with 14.0 months in the clinician choice arm. The hazard ratio for PFS was 0.92 (90% confidence interval, 0.80-1.06), and the trial met its primary noninferiority endpoint with a prespecified noninferiority margin of 1.25.

The OS rate at 24 months in the CTC group was 82.1%, and in the clinician choice arm was 81.4% (nonsignificant).

Planned subgroup analyses in which the two decision methods were in agreement on whether a patient was at either low or high risk found no significant differences in either PFS or OS, showing that the CTC count complemented the prognostic estimate and isolated patients with either excellent or poor outcomes.


However, when the clinician rated the risk as low but the CTC count rated it as high (196 patients), PFS was significantly higher with CTC (HR, 0.62; P = .002). OS did not differ in this circumstance.

In an exploratory analysis combining all patients with discordant findings (clinician low/CTC high or vice versa), the investigators determined that chemotherapy would offer a significant advantage for both PFS (HR, 0.66; adjusted P = .001) and OS (HR, 0.65; adjusted P = .04).

Virginia Kaklamani, MD, leader of the breast cancer program at the University of Texas, San Antonio, who moderated a briefing where Dr. Bidard discussed the findings prior to presentation in a general session, said that she is not fully convinced that CTC counts can substitute for the clinician’s discretion. “I would probably want to see another study or some more data.”

She noted that for the patient population in this study clinicians today often prescribe cyclin-dependent kinase (CDK) 4/6 inhibitors in the first-line setting over conventional chemotherapy.

“But it is true that CDK 4/6 inhibitors, besides their cost, $10,000 a month, also are toxic to our patients. They cause neutropenias, increase infections, some diarrhea, so if there is a group I can potentially save from taking a CDK 4/6 inhibitor in the first-line setting I’d love to do that. In the metastatic setting what we’re trying to do for years is deescalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is a little foreign to us,” Dr. Kaklamani said.

The strength of the study, however, is that it’s the first to show a survival benefit using CTCs as a diagnostic aid, she added.

Lisa A. Carey, MD, from the University of North Carolina at Chapel Hill, who was not involved in the study, said in an interview that the technology is promising, but not ready for prime time.

“To be honest, it didn’t appear to me that it helped very much, so that particular approach I don’t think is likely to have much benefit for patients. But the concept is an excellent one, and I do think that’s something we need to take home, that this is an area of an unmet need,” she said.

The study was funded by the National Cancer Institute of France, Institut Curie, and Menarini. Dr. Bidard reported receiving research funding and travel grants from Menarini. Dr. Kaklamani and Dr. Carey reported having no relevant conflicts of interest.

SOURCE: Bidard F-C et al. SABCS 2018, Abstract GS3-07.

SAN ANTONIO – Circulating tumor cell (CTC) counts could serve as a standalone biomarker for determining which patients with newly diagnosed estrogen receptor–positive, HER2-negative metastatic breast cancer are at high risk and should receive first-line chemotherapy and which are at low risk and could safely receive upfront hormonal therapy.

In the phase 3 STIC CTC trial, there were no significant differences in the primary endpoint of progression-free survival (PFS) or a secondary endpoint of overall survival (OS) between patients whose treatments were assigned according to the clinicians’ judgment and those whose treatments were chosen based on CTC count, reported Francois-Clement Bidard, MD, PhD, from Institut Curie in St. Cloud, France.

“CTC count should or may be included in the decision algorithm for hormone receptor–positive, HER2-negative metastatic breast cancer patients,” he said at the San Antonio Breast Cancer Symposium.

The CTC investigators sought to compare CTC-driven clinical decisions with the clinicians choice for first-line therapy in 778 patients with hormone receptor–positive, HER2-negative breast cancer.

Patients were stratified by performance status (0-3), treatment center, and disease-free interval and were randomly assigned to receive therapy based on either the clinician’s judgment of the best course of therapy for each patient or to CTC count, with a cutoff of less than 5 CTC/7.5 mL indicating hormonal therapy and 5 CTC/7.5 mL or above indicating higher-risk disease requiring chemotherapy. In the clinician’s choice arm, the CTC reading was recorded but not implemented, and in the CTC arm, the clinician’s choice was dismissed.

The trial protocol did not specify a chemotherapy regimen, and patients initially assigned to chemotherapy were allowed to have maintenance hormonal therapy.

At 42 months of follow-up, median PFS in the CTC arm was 15.6 months, compared with 14.0 months in the clinician choice arm. The hazard ratio for PFS was 0.92 (90% confidence interval, 0.80-1.06), and the trial met its primary noninferiority endpoint with a prespecified noninferiority margin of 1.25.

The OS rate at 24 months in the CTC group was 82.1%, and in the clinician choice arm was 81.4% (nonsignificant).

Planned subgroup analyses in which the two decision methods were in agreement on whether a patient was at either low or high risk found no significant differences in either PFS or OS, showing that the CTC count complemented the prognostic estimate and isolated patients with either excellent or poor outcomes.


However, when the clinician rated the risk as low but the CTC count rated it as high (196 patients), PFS was significantly higher with CTC (HR, 0.62; P = .002). OS did not differ in this circumstance.

In an exploratory analysis combining all patients with discordant findings (clinician low/CTC high or vice versa), the investigators determined that chemotherapy would offer a significant advantage for both PFS (HR, 0.66; adjusted P = .001) and OS (HR, 0.65; adjusted P = .04).

Virginia Kaklamani, MD, leader of the breast cancer program at the University of Texas, San Antonio, who moderated a briefing where Dr. Bidard discussed the findings prior to presentation in a general session, said that she is not fully convinced that CTC counts can substitute for the clinician’s discretion. “I would probably want to see another study or some more data.”

She noted that for the patient population in this study clinicians today often prescribe cyclin-dependent kinase (CDK) 4/6 inhibitors in the first-line setting over conventional chemotherapy.

“But it is true that CDK 4/6 inhibitors, besides their cost, $10,000 a month, also are toxic to our patients. They cause neutropenias, increase infections, some diarrhea, so if there is a group I can potentially save from taking a CDK 4/6 inhibitor in the first-line setting I’d love to do that. In the metastatic setting what we’re trying to do for years is deescalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is a little foreign to us,” Dr. Kaklamani said.

The strength of the study, however, is that it’s the first to show a survival benefit using CTCs as a diagnostic aid, she added.

Lisa A. Carey, MD, from the University of North Carolina at Chapel Hill, who was not involved in the study, said in an interview that the technology is promising, but not ready for prime time.

“To be honest, it didn’t appear to me that it helped very much, so that particular approach I don’t think is likely to have much benefit for patients. But the concept is an excellent one, and I do think that’s something we need to take home, that this is an area of an unmet need,” she said.

The study was funded by the National Cancer Institute of France, Institut Curie, and Menarini. Dr. Bidard reported receiving research funding and travel grants from Menarini. Dr. Kaklamani and Dr. Carey reported having no relevant conflicts of interest.

SOURCE: Bidard F-C et al. SABCS 2018, Abstract GS3-07.

SAN ANTONIO – Circulating tumor cell (CTC) counts could serve as a standalone biomarker for determining which patients with newly diagnosed estrogen receptor–positive, HER2-negative metastatic breast cancer are at high risk and should receive first-line chemotherapy and which are at low risk and could safely receive upfront hormonal therapy.

In the phase 3 STIC CTC trial, there were no significant differences in the primary endpoint of progression-free survival (PFS) or a secondary endpoint of overall survival (OS) between patients whose treatments were assigned according to the clinicians’ judgment and those whose treatments were chosen based on CTC count, reported Francois-Clement Bidard, MD, PhD, from Institut Curie in St. Cloud, France.

“CTC count should or may be included in the decision algorithm for hormone receptor–positive, HER2-negative metastatic breast cancer patients,” he said at the San Antonio Breast Cancer Symposium.

The CTC investigators sought to compare CTC-driven clinical decisions with the clinicians choice for first-line therapy in 778 patients with hormone receptor–positive, HER2-negative breast cancer.

Patients were stratified by performance status (0-3), treatment center, and disease-free interval and were randomly assigned to receive therapy based on either the clinician’s judgment of the best course of therapy for each patient or to CTC count, with a cutoff of less than 5 CTC/7.5 mL indicating hormonal therapy and 5 CTC/7.5 mL or above indicating higher-risk disease requiring chemotherapy. In the clinician’s choice arm, the CTC reading was recorded but not implemented, and in the CTC arm, the clinician’s choice was dismissed.

The trial protocol did not specify a chemotherapy regimen, and patients initially assigned to chemotherapy were allowed to have maintenance hormonal therapy.

At 42 months of follow-up, median PFS in the CTC arm was 15.6 months, compared with 14.0 months in the clinician choice arm. The hazard ratio for PFS was 0.92 (90% confidence interval, 0.80-1.06), and the trial met its primary noninferiority endpoint with a prespecified noninferiority margin of 1.25.

The OS rate at 24 months in the CTC group was 82.1%, and in the clinician choice arm was 81.4% (nonsignificant).

Planned subgroup analyses in which the two decision methods were in agreement on whether a patient was at either low or high risk found no significant differences in either PFS or OS, showing that the CTC count complemented the prognostic estimate and isolated patients with either excellent or poor outcomes.


However, when the clinician rated the risk as low but the CTC count rated it as high (196 patients), PFS was significantly higher with CTC (HR, 0.62; P = .002). OS did not differ in this circumstance.

In an exploratory analysis combining all patients with discordant findings (clinician low/CTC high or vice versa), the investigators determined that chemotherapy would offer a significant advantage for both PFS (HR, 0.66; adjusted P = .001) and OS (HR, 0.65; adjusted P = .04).

Virginia Kaklamani, MD, leader of the breast cancer program at the University of Texas, San Antonio, who moderated a briefing where Dr. Bidard discussed the findings prior to presentation in a general session, said that she is not fully convinced that CTC counts can substitute for the clinician’s discretion. “I would probably want to see another study or some more data.”

She noted that for the patient population in this study clinicians today often prescribe cyclin-dependent kinase (CDK) 4/6 inhibitors in the first-line setting over conventional chemotherapy.

“But it is true that CDK 4/6 inhibitors, besides their cost, $10,000 a month, also are toxic to our patients. They cause neutropenias, increase infections, some diarrhea, so if there is a group I can potentially save from taking a CDK 4/6 inhibitor in the first-line setting I’d love to do that. In the metastatic setting what we’re trying to do for years is deescalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is a little foreign to us,” Dr. Kaklamani said.

The strength of the study, however, is that it’s the first to show a survival benefit using CTCs as a diagnostic aid, she added.

Lisa A. Carey, MD, from the University of North Carolina at Chapel Hill, who was not involved in the study, said in an interview that the technology is promising, but not ready for prime time.

“To be honest, it didn’t appear to me that it helped very much, so that particular approach I don’t think is likely to have much benefit for patients. But the concept is an excellent one, and I do think that’s something we need to take home, that this is an area of an unmet need,” she said.

The study was funded by the National Cancer Institute of France, Institut Curie, and Menarini. Dr. Bidard reported receiving research funding and travel grants from Menarini. Dr. Kaklamani and Dr. Carey reported having no relevant conflicts of interest.

SOURCE: Bidard F-C et al. SABCS 2018, Abstract GS3-07.

SAN DIEGO – A couple years ago, hematologist-oncologist Norman E. “Ned” Sharpless, MD, was gobsmacked by a groundbreaking study into treatments for acute myeloid leukemia. While the findings offered valuable new insight into the best drug options, they left Dr. Sharpless quaking, and not with delight. “I can recall that my knees buckled,” he said.

Courtesy University of North Carolina

Why? Because the findings, he told colleagues at the annual meeting of the American Society of Hematology, came too late for many patients to benefit. “One could say that’s great news, this is medical progress,” he said. “But I saw this as a clear failure of data aggregation.”

Now, Dr. Sharpless is in a position to do more than fume and speak out. He became the director of the National Cancer Institute in 2017 and he’s made “big data” one of his four priorities for the NCI under his leadership.

“While data security is crucial, there are also costs to not aggregating data and sharing it,” he said. “It means giving patients the wrong drug, it means patients having to die.”

While Dr. Sharpless said he’s disappointed by the progress on data in medicine, he had praise to offer, too. In conversations over his first year-plus on the job, he said, he’s learned that “it’s a great time to be a cancer scientist and a cancer doctor in the United States. ... It’s undeniably a great time to be a blood doctor or blood scientist. We’re making progress at a rate that is faster and greater than at any point in my career as an oncologist. Just look at all the new stuff we’ve got!”

In hematology, great strides are being made in areas such as the treatment of leukemia and lymphoma, he said. Progress is also boosting treatment in areas such as melanoma and lung, breast, ovarian, and head and neck cancer.

“Some of you will correctly point out that this progress is not enough. In some cases, treatments are moderately effective and not curative. These are singles or even doubles, but we still need home runs. We still have too many patients dying of cancer, including blood cancer,” he said. “From my perspective, it’s important to be very clear-eyed. While we have a long way to go to end suffering in all patients, we have to be willing to admit that progress has been impressive.”

Dr. Sharpless touted the Cancer Moonshot, which will allocate $1.8 billion in federal funds for cancer research over 7 years. And he mentioned his four priority areas at NCI: Workforce development, basic science, big data, and clinical trials. Initiatives in these areas include prioritization of research by early-career investigators and increased funding for trials, he said.

As for data, he said, “I’ve been trying to explain to congressional leaders why getting control of our data is important.”

Dr. Sharpless likes to point to his own encounter in his kitchen in 2016 – the one that buckled his knees – with an issue of the New England Journal of Medicine. There he found a study that examined molecular determinants of response to decitabine in acute myeloid leukemia and myelodysplastic syndromes (N Engl J Med. 2016 Nov 24;375[21]:2023-36).

“I can still close my eyes now and literally see the faces of patients whom I gave ... a very toxic regimen, some of whom had very bad outcomes,” he said. “I know in retrospect, based on certain statistics, I probably used the wrong drug in some of these patients. If we’d been aggregating data in a deliberate way, from the get-go of AML, a result like this would have fallen out immediately. I’m concerned we’re still making these types of mistakes for other cancer subtypes today.”

Moving forward, he said, the goal is “to create large, multimodal data sets ... And put them in the cloud and make them available to the research community in the most useful format possible, in a way that’s safe and secure. We have to do these things because the costs of not harnessing data are too great.”

Dr. Sharpless reported several past financial relationships with G1 Therapeutics, Healthspan Diagnostics, and Unity Biotechnology.

SAN DIEGO – A couple years ago, hematologist-oncologist Norman E. “Ned” Sharpless, MD, was gobsmacked by a groundbreaking study into treatments for acute myeloid leukemia. While the findings offered valuable new insight into the best drug options, they left Dr. Sharpless quaking, and not with delight. “I can recall that my knees buckled,” he said.

Courtesy University of North Carolina

Why? Because the findings, he told colleagues at the annual meeting of the American Society of Hematology, came too late for many patients to benefit. “One could say that’s great news, this is medical progress,” he said. “But I saw this as a clear failure of data aggregation.”

Now, Dr. Sharpless is in a position to do more than fume and speak out. He became the director of the National Cancer Institute in 2017 and he’s made “big data” one of his four priorities for the NCI under his leadership.

“While data security is crucial, there are also costs to not aggregating data and sharing it,” he said. “It means giving patients the wrong drug, it means patients having to die.”

While Dr. Sharpless said he’s disappointed by the progress on data in medicine, he had praise to offer, too. In conversations over his first year-plus on the job, he said, he’s learned that “it’s a great time to be a cancer scientist and a cancer doctor in the United States. ... It’s undeniably a great time to be a blood doctor or blood scientist. We’re making progress at a rate that is faster and greater than at any point in my career as an oncologist. Just look at all the new stuff we’ve got!”

In hematology, great strides are being made in areas such as the treatment of leukemia and lymphoma, he said. Progress is also boosting treatment in areas such as melanoma and lung, breast, ovarian, and head and neck cancer.

“Some of you will correctly point out that this progress is not enough. In some cases, treatments are moderately effective and not curative. These are singles or even doubles, but we still need home runs. We still have too many patients dying of cancer, including blood cancer,” he said. “From my perspective, it’s important to be very clear-eyed. While we have a long way to go to end suffering in all patients, we have to be willing to admit that progress has been impressive.”

Dr. Sharpless touted the Cancer Moonshot, which will allocate $1.8 billion in federal funds for cancer research over 7 years. And he mentioned his four priority areas at NCI: Workforce development, basic science, big data, and clinical trials. Initiatives in these areas include prioritization of research by early-career investigators and increased funding for trials, he said.

As for data, he said, “I’ve been trying to explain to congressional leaders why getting control of our data is important.”

Dr. Sharpless likes to point to his own encounter in his kitchen in 2016 – the one that buckled his knees – with an issue of the New England Journal of Medicine. There he found a study that examined molecular determinants of response to decitabine in acute myeloid leukemia and myelodysplastic syndromes (N Engl J Med. 2016 Nov 24;375[21]:2023-36).

“I can still close my eyes now and literally see the faces of patients whom I gave ... a very toxic regimen, some of whom had very bad outcomes,” he said. “I know in retrospect, based on certain statistics, I probably used the wrong drug in some of these patients. If we’d been aggregating data in a deliberate way, from the get-go of AML, a result like this would have fallen out immediately. I’m concerned we’re still making these types of mistakes for other cancer subtypes today.”

Moving forward, he said, the goal is “to create large, multimodal data sets ... And put them in the cloud and make them available to the research community in the most useful format possible, in a way that’s safe and secure. We have to do these things because the costs of not harnessing data are too great.”

Dr. Sharpless reported several past financial relationships with G1 Therapeutics, Healthspan Diagnostics, and Unity Biotechnology.

SAN DIEGO – A couple years ago, hematologist-oncologist Norman E. “Ned” Sharpless, MD, was gobsmacked by a groundbreaking study into treatments for acute myeloid leukemia. While the findings offered valuable new insight into the best drug options, they left Dr. Sharpless quaking, and not with delight. “I can recall that my knees buckled,” he said.

Courtesy University of North Carolina

Why? Because the findings, he told colleagues at the annual meeting of the American Society of Hematology, came too late for many patients to benefit. “One could say that’s great news, this is medical progress,” he said. “But I saw this as a clear failure of data aggregation.”

Now, Dr. Sharpless is in a position to do more than fume and speak out. He became the director of the National Cancer Institute in 2017 and he’s made “big data” one of his four priorities for the NCI under his leadership.

“While data security is crucial, there are also costs to not aggregating data and sharing it,” he said. “It means giving patients the wrong drug, it means patients having to die.”

While Dr. Sharpless said he’s disappointed by the progress on data in medicine, he had praise to offer, too. In conversations over his first year-plus on the job, he said, he’s learned that “it’s a great time to be a cancer scientist and a cancer doctor in the United States. ... It’s undeniably a great time to be a blood doctor or blood scientist. We’re making progress at a rate that is faster and greater than at any point in my career as an oncologist. Just look at all the new stuff we’ve got!”

In hematology, great strides are being made in areas such as the treatment of leukemia and lymphoma, he said. Progress is also boosting treatment in areas such as melanoma and lung, breast, ovarian, and head and neck cancer.

“Some of you will correctly point out that this progress is not enough. In some cases, treatments are moderately effective and not curative. These are singles or even doubles, but we still need home runs. We still have too many patients dying of cancer, including blood cancer,” he said. “From my perspective, it’s important to be very clear-eyed. While we have a long way to go to end suffering in all patients, we have to be willing to admit that progress has been impressive.”

Dr. Sharpless touted the Cancer Moonshot, which will allocate $1.8 billion in federal funds for cancer research over 7 years. And he mentioned his four priority areas at NCI: Workforce development, basic science, big data, and clinical trials. Initiatives in these areas include prioritization of research by early-career investigators and increased funding for trials, he said.

As for data, he said, “I’ve been trying to explain to congressional leaders why getting control of our data is important.”

Dr. Sharpless likes to point to his own encounter in his kitchen in 2016 – the one that buckled his knees – with an issue of the New England Journal of Medicine. There he found a study that examined molecular determinants of response to decitabine in acute myeloid leukemia and myelodysplastic syndromes (N Engl J Med. 2016 Nov 24;375[21]:2023-36).

“I can still close my eyes now and literally see the faces of patients whom I gave ... a very toxic regimen, some of whom had very bad outcomes,” he said. “I know in retrospect, based on certain statistics, I probably used the wrong drug in some of these patients. If we’d been aggregating data in a deliberate way, from the get-go of AML, a result like this would have fallen out immediately. I’m concerned we’re still making these types of mistakes for other cancer subtypes today.”

Moving forward, he said, the goal is “to create large, multimodal data sets ... And put them in the cloud and make them available to the research community in the most useful format possible, in a way that’s safe and secure. We have to do these things because the costs of not harnessing data are too great.”

Dr. Sharpless reported several past financial relationships with G1 Therapeutics, Healthspan Diagnostics, and Unity Biotechnology.

Single neurons in the human medial frontal cortex appear to be involved in the signaling of self-monitored errors, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.

Epifantsev/Thinkstock

“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.

The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.

“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”

Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).

Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”

The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.

As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.

In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).

The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.

SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016

Single neurons in the human medial frontal cortex appear to be involved in the signaling of self-monitored errors, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.

Epifantsev/Thinkstock

“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.

The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.

“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”

Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).

Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”

The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.

As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.

In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).

The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.

SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016

Single neurons in the human medial frontal cortex appear to be involved in the signaling of self-monitored errors, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.

Epifantsev/Thinkstock

“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.

The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.

“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”

Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).

Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”

The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.

As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.

In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).

The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.

SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016

While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.

Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program. 

By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.

The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.

“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.

However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.

In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.

Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.

Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).

Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.

Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.

While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.

“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.

Dr. Bratslavsky and his coauthors listed no disclosures related to their research.

SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.

While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.

Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program. 

By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.

The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.

“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.

However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.

In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.

Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.

Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).

Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.

Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.

While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.

“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.

Dr. Bratslavsky and his coauthors listed no disclosures related to their research.

SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.

While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.

Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program. 

By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.

The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.

“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.

However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.

In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.

Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.

Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).

Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.

Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.

While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.

“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.

Dr. Bratslavsky and his coauthors listed no disclosures related to their research.

SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.

In this episode, Roberto Lewis-Fernandez, MD, joins MDedge Psychiatry Editor-in-Chief, Lorenzo Norris, MD, to talk about how cultural assessments work and why they’re imperative to person-centered care. More from Dr. Lewis-Fernandez, Curbside Consult: Chinese American man with high risk of psychosis.

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In this episode, Roberto Lewis-Fernandez, MD, joins MDedge Psychiatry Editor-in-Chief, Lorenzo Norris, MD, to talk about how cultural assessments work and why they’re imperative to person-centered care. More from Dr. Lewis-Fernandez, Curbside Consult: Chinese American man with high risk of psychosis.

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Spotify
 

In this episode, Roberto Lewis-Fernandez, MD, joins MDedge Psychiatry Editor-in-Chief, Lorenzo Norris, MD, to talk about how cultural assessments work and why they’re imperative to person-centered care. More from Dr. Lewis-Fernandez, Curbside Consult: Chinese American man with high risk of psychosis.

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Spotify
 

According to a scientific statement by the AHA on Arteriosclerosis, Thrombosis, and Vascular Biology, the benefits of statins highly offset the associated risks in appropriate patients. Also today, acute stroke thrombolysis worked safely despite GI bleed or malignancy, legal advice on what to do if a patient sues you, and the link between childhood asthma and obesity.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

According to a scientific statement by the AHA on Arteriosclerosis, Thrombosis, and Vascular Biology, the benefits of statins highly offset the associated risks in appropriate patients. Also today, acute stroke thrombolysis worked safely despite GI bleed or malignancy, legal advice on what to do if a patient sues you, and the link between childhood asthma and obesity.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

According to a scientific statement by the AHA on Arteriosclerosis, Thrombosis, and Vascular Biology, the benefits of statins highly offset the associated risks in appropriate patients. Also today, acute stroke thrombolysis worked safely despite GI bleed or malignancy, legal advice on what to do if a patient sues you, and the link between childhood asthma and obesity.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

©ASH/Scott Morgan 2018

SAN DIEGO—In a phase 3 trial, ibrutinib plus rituximab (IR) improved survival when compared with standard chemoimmunotherapy in patients younger than 70 with untreated chronic lymphocytic leukemia (CLL).

Patients who received IR had superior progression-free survival (PFS) and overall survival compared to patients who received fludarabine, cyclophosphamide, and rituximab (FCR).

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” said Tait D. Shanafelt, MD, of Stanford University in California.

In fact, the study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

He presented the results during the late-breaking abstract session at the 2018 ASH Annual Meeting (abstract LBA-4*).

The trial (NCT02048813) included 529 patients age 70 or younger with previously untreated CLL. They were randomized on a 2:1 basis to either six cycles of FCR according to standard protocols (n=175) or IR (n=354).

IR consisted of ibrutinib given at 420 mg daily for each 28-day cycle and rituximab given at 50 mg/m² on day 1 of cycle 2, at 325 mg/m² on day 2 of cycle 2, and at 500 mg/m² on day 1 for cycles 3 to 7.

From cycle 8 on, patients in the IR arm received daily ibrutinib at 420 mg until disease progression.

Dr. Shanafelt said patient characteristics were well-balanced between the treatment arms.

He presented results from both an intent-to-treat (ITT) analysis and a per-protocol analysis excluding 22 patients in the IR arm and nine patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

PFS

In the ITT analysis, there were 37 cases of progression or death in the IR arm and 40 cases in the FCR arm. This difference translated into a hazard ratio (HR) for progression or death of 0.35 with IR (P<0.00001).

In the per-protocol analysis, there were 33 cases of progression or death in the IR arm and 39 cases in the FCR arm. The HR was 0.32 favoring IR (P<0.00001).

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was significantly better with IR in patients with unmutated IGHV (HR= 0.26, P<0.00001) but not in patients with mutated IGHV (HR=0.44, P=0.07).

Overall survival

In the ITT analysis, there were four deaths in the IR arm and 10 in the FCR arm (HR=0.17, P<0.0003).

In the per-protocol analysis, there were three deaths in the IR arm and 10 deaths in the FCR arm (HR=0.13, P<0.0001).

Dr. Shanafelt noted that, although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning the rate of death in the FCR arm was five-fold higher than in the IR arm.

Safety and cost

Grade 3 or greater treatment-related adverse events (AEs) occurred in 58.5% of patients in the IR arm and 72.1% of patients in the FCR arm (P=0.004).

Specific AEs that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P<0.001 for all comparisons).

AEs that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P=0.04) and hypertension (7.4% vs. 1.9%, P=0.01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost. The monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, AbbVie, Pharmacyclics, and Janssen.

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Preliminary data on UCART19—the first off-the-shelf, anti-CD19, allogeneic chimeric antigen receptor (CAR) T-cell therapy—suggest it can produce complete responses (CRs) and minimal residual disease (MRD) negativity, and side effects are manageable.

Investigators pooled data from the phase 1 pediatric (PALL) and adult (CALM) trials of UCART19 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and observed a 67% CR rate in the overall population and an 82% CR rate in patients who received a three-drug lymphodepleting regimen.

Additionally, investigators reported no instance of moderate or severe acute graft-versus-host disease (GVHD) with UCART19.

“We’ve been blessed with the new treatments that have emerged in recent years,” said Reuben Benjamin, MD, PhD, “that include BiTEs, antibody-drug conjugates, and most excitingly, the autologous CAR T-cell therapies.”

Nevertheless, some logistical issues with the autologous CAR T cells leave an unmet need in this group of patients, he noted.

“So an off-the-shelf approach using a product like UCART19 may potentially overcome some of these hurdles that we see in the autologous CAR T-cell therapy field,” he said.

Dr. Benjamin, of King’s College Hospital in London, U.K., presented the analysis of PALL and CALM data at the 2018 ASH Annual Meeting as abstract 896.*

UCART19 product

UCART19 is an allogeneic, genetically modified, CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells.

It has a safety switch—RQR8, which is a CD20 mimotope—that allows the CAR T cells to be targeted by rituximab.

“And importantly,” Dr. Benjamin explained, “the T-cell alpha gene has been knocked out using TALEN® gene-editing technology to prevent T-cell receptor-mediated graft-versus-host disease.”

The CD52 gene is also knocked out, which permits an anti-CD52 monoclonal antibody, such as alemtuzumab, to be used in lymphodepletion.

Study design

The primary objective of both the adult (NCT02746952) and pediatric (NCT02808442) studies was to determine the safety and tolerability of UCART19. Also, the adult study was to determine the maximum tolerated dose of UCART19 and the optimal lymphodepleting regimen.

A secondary objective of both studies was to determine the remission rate at day 28.

Eligible patients received a lymphodepleting regimen for 7 days, followed by a single infusion of UCART19.

Lymphodepletion in the pediatric trial consisted of fludarabine (F) at 150 mg/m² and cyclophosphamide (C) at 120 mg/kg, with or without alemtuzumab (A) at 1 mg/kg capped at 40 mg.

Adults received lower doses of each agent—90 mg/m², 1,500 mg/m², and (optionally) 1 mg/kg or 40 mg, respectively.

Investigators included alemtuzumab in the regimen to minimize viral infections.

The UCART19 dose was weight-banded in the pediatric trial and ranged from 1.1 to 2.3 x 10⁶ cells/kg.

The adult trial included three UCART19 dose levels:

• 6 x 10⁶ cells (≈1 x 10⁵ cells/kg)
• 6 or 8 x 10⁷ cells (≈1 x 10⁶ cells/kg)
• 8 or 2.4 x 10⁸ cells (≈3 x 10⁶ cells/kg).

Patients were assessed for safety and response at day 28 and regularly thereafter for up to 12 months. Patients had the option during the follow-up period to receive a second dose if they did not respond or lost their response.

Patient characteristics/status

Twenty-one patients were enrolled in the trials—seven children and 14 adults. Median ages were 2.7 years (PALL; range, 0.8–16.4) and 29.5 years (CALM; range, 18–62).

Both studies included high-risk, heavily pretreated populations, Dr. Benjamin noted.

The pooled population had a median of 4 prior lines of therapy (range, 1–6), and nine patients had a high-risk cytogenetics, including complex karyotypes, MLL rearrangements, and Ph+ disease.

Thirteen patients had prior allogeneic stem cell transplants.

Nine patients had a bone marrow tumor burden of more than 25% blasts prior to lymphodepletion.

As of the cutoff date of October 23, all patients had been treated with UCART19.

Four of the pediatric patients are still on the trial. Two are in remission, one has relapsed, and one is refractory.

Eight adult patients are still on trial. Three are in remission, three are relapsed, and two are refractory.

Safety

“UCART19 appears to show an acceptable safety profile based on the adverse events reported so far,” Dr. Benjamin said.

Nineteen patients experienced cytokine release syndrome (CRS), primarily grades 1 and 2. Eight patients had grade 1 and 2 neurotoxicity events, and two patients had grade 1 acute skin GVHD.

“In keeping with what is seen in some of the autologous CAR T-cell trials,” Dr. Benjamin explained, “prolonged cytopenias were seen, which we defined in these studies as grade 4 neutropenia or thrombocytopenia occurring at 42 days post-UCART infusion.”

Six of 21 patients developed prolonged cytopenia.

There was also an increased incidence of viral infections occurring in eight patients, including cytomegalovirus, adenovirus, BK virus, and metapneumovirus.

“Most of these infections, however, were manageable,” Dr. Benjamin said.

Two patients developed neutropenic sepsis, one grade 5, which was one of the treatment-related deaths in the CALM trial.

No treatment-related deaths occurred in the PALL study, but there were two in the CALM study—one from pulmonary hemorrhage and the other from neutropenic sepsis and grade 4 CRS.

Twelve patients are still alive, five of whom are in CR.

Efficacy

Of the patients who received FCA lymphodepletion, 82% (14/17) achieved CR/CR with incomplete hematologic recovery (CRi), and 71% (10/14) achieved MRD negativity.

An additional patient gained MRD-negative status after the second dose of UCART19.

Of the 14 patients who achieved a CR/CRi, 78% (n=11) went on to receive an allogeneic transplant.

In the entire pooled population, 67% (14/21) achieved CR/CRi.

Three patients received a second UCART19 dose, and five patients remain in CR/CRi.

UCART19 expansion

UCART19 expansion, as measured by quantitative polymerase chain reaction in PALL and flow-based methods in CALM, occurred primarily in the first 28 days in the FCA-treated population.

Investigators observed expansion in 15 of 17 patients treated with FCA. None of the patients who received FC alone (n=4) had expansion detectable in blood or bone marrow, Dr. Benjamin noted.

“The response we’ve seen in the study so far,” Dr. Benjamin clarified, “is linked to the expansion observed within the first 28-day period.”

UCART cells persisted in three patients beyond day 42. In one patient, they persisted up to day 120.

“Of interest is the T-cell recovery seen in the study,” Dr. Benjamin elaborated. “We only have data from the adult study here—14 patients. And you’ll see that, in the FCA-treated arm (n=11), you have a deeper and more sustained lymphodepletion compared to the FC-treated patients (n=3). And this may play a role in the subsequent UCART19 expansion and disease response.”

Re-dosing

Of the three patients who were re-dosed, two achieved MRD negativity.

One patient achieved MRD-negative status at day 28 but relapsed and received a second infusion 3 months after the first dose. The second expansion was not as deep as the first, but the patient nevertheless achieved MRD negativity after the second dose.

The second patient received FC lymphodepletion and was refractory at day 28.

“The second time around, he received FCA, had a slightly better expansion, and achieved molecular remission,” Dr. Benjamin said.

And the third patient had FCA lymphodepletion but was refractory at day 28.

“We elected to give a second dose at 2.4 months later, but unfortunately, there wasn’t very much expansion, even the second time around, and the patient progressed,” Dr. Benjamin said.

FCA lymphodepletion appears to be required for UCART19 expansion. There was no UCART19 expansion and no response in all four patients lymphodepleted with FC.

The evaluation of UCART19 is ongoing in pediatric and adult B-cell ALL, and “there is a plan for moving into the lymphoma space as well,” Dr. Benjamin added.

Dr. Benjamin disclosed honoraria from Amgen, Takeda, Novartis, Gilead, and Celgene, and research funding from Servier and Pfizer.

Servier and Allogene are supporting the UCART19 trials. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Preliminary data on UCART19—the first off-the-shelf, anti-CD19, allogeneic chimeric antigen receptor (CAR) T-cell therapy—suggest it can produce complete responses (CRs) and minimal residual disease (MRD) negativity, and side effects are manageable.

Investigators pooled data from the phase 1 pediatric (PALL) and adult (CALM) trials of UCART19 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and observed a 67% CR rate in the overall population and an 82% CR rate in patients who received a three-drug lymphodepleting regimen.

Additionally, investigators reported no instance of moderate or severe acute graft-versus-host disease (GVHD) with UCART19.

“We’ve been blessed with the new treatments that have emerged in recent years,” said Reuben Benjamin, MD, PhD, “that include BiTEs, antibody-drug conjugates, and most excitingly, the autologous CAR T-cell therapies.”

Nevertheless, some logistical issues with the autologous CAR T cells leave an unmet need in this group of patients, he noted.

“So an off-the-shelf approach using a product like UCART19 may potentially overcome some of these hurdles that we see in the autologous CAR T-cell therapy field,” he said.

Dr. Benjamin, of King’s College Hospital in London, U.K., presented the analysis of PALL and CALM data at the 2018 ASH Annual Meeting as abstract 896.*

UCART19 product

UCART19 is an allogeneic, genetically modified, CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells.

It has a safety switch—RQR8, which is a CD20 mimotope—that allows the CAR T cells to be targeted by rituximab.

“And importantly,” Dr. Benjamin explained, “the T-cell alpha gene has been knocked out using TALEN® gene-editing technology to prevent T-cell receptor-mediated graft-versus-host disease.”

The CD52 gene is also knocked out, which permits an anti-CD52 monoclonal antibody, such as alemtuzumab, to be used in lymphodepletion.

Study design

The primary objective of both the adult (NCT02746952) and pediatric (NCT02808442) studies was to determine the safety and tolerability of UCART19. Also, the adult study was to determine the maximum tolerated dose of UCART19 and the optimal lymphodepleting regimen.

A secondary objective of both studies was to determine the remission rate at day 28.

Eligible patients received a lymphodepleting regimen for 7 days, followed by a single infusion of UCART19.

Lymphodepletion in the pediatric trial consisted of fludarabine (F) at 150 mg/m² and cyclophosphamide (C) at 120 mg/kg, with or without alemtuzumab (A) at 1 mg/kg capped at 40 mg.

Adults received lower doses of each agent—90 mg/m², 1,500 mg/m², and (optionally) 1 mg/kg or 40 mg, respectively.

Investigators included alemtuzumab in the regimen to minimize viral infections.

The UCART19 dose was weight-banded in the pediatric trial and ranged from 1.1 to 2.3 x 10⁶ cells/kg.

The adult trial included three UCART19 dose levels:

• 6 x 10⁶ cells (≈1 x 10⁵ cells/kg)
• 6 or 8 x 10⁷ cells (≈1 x 10⁶ cells/kg)
• 8 or 2.4 x 10⁸ cells (≈3 x 10⁶ cells/kg).

Patients were assessed for safety and response at day 28 and regularly thereafter for up to 12 months. Patients had the option during the follow-up period to receive a second dose if they did not respond or lost their response.

Patient characteristics/status

Twenty-one patients were enrolled in the trials—seven children and 14 adults. Median ages were 2.7 years (PALL; range, 0.8–16.4) and 29.5 years (CALM; range, 18–62).

Both studies included high-risk, heavily pretreated populations, Dr. Benjamin noted.

The pooled population had a median of 4 prior lines of therapy (range, 1–6), and nine patients had a high-risk cytogenetics, including complex karyotypes, MLL rearrangements, and Ph+ disease.

Thirteen patients had prior allogeneic stem cell transplants.

Nine patients had a bone marrow tumor burden of more than 25% blasts prior to lymphodepletion.

As of the cutoff date of October 23, all patients had been treated with UCART19.

Four of the pediatric patients are still on the trial. Two are in remission, one has relapsed, and one is refractory.

Eight adult patients are still on trial. Three are in remission, three are relapsed, and two are refractory.

Safety

“UCART19 appears to show an acceptable safety profile based on the adverse events reported so far,” Dr. Benjamin said.

Nineteen patients experienced cytokine release syndrome (CRS), primarily grades 1 and 2. Eight patients had grade 1 and 2 neurotoxicity events, and two patients had grade 1 acute skin GVHD.

“In keeping with what is seen in some of the autologous CAR T-cell trials,” Dr. Benjamin explained, “prolonged cytopenias were seen, which we defined in these studies as grade 4 neutropenia or thrombocytopenia occurring at 42 days post-UCART infusion.”

Six of 21 patients developed prolonged cytopenia.

There was also an increased incidence of viral infections occurring in eight patients, including cytomegalovirus, adenovirus, BK virus, and metapneumovirus.

“Most of these infections, however, were manageable,” Dr. Benjamin said.

Two patients developed neutropenic sepsis, one grade 5, which was one of the treatment-related deaths in the CALM trial.

No treatment-related deaths occurred in the PALL study, but there were two in the CALM study—one from pulmonary hemorrhage and the other from neutropenic sepsis and grade 4 CRS.

Twelve patients are still alive, five of whom are in CR.

Efficacy

Of the patients who received FCA lymphodepletion, 82% (14/17) achieved CR/CR with incomplete hematologic recovery (CRi), and 71% (10/14) achieved MRD negativity.

An additional patient gained MRD-negative status after the second dose of UCART19.

Of the 14 patients who achieved a CR/CRi, 78% (n=11) went on to receive an allogeneic transplant.

In the entire pooled population, 67% (14/21) achieved CR/CRi.

Three patients received a second UCART19 dose, and five patients remain in CR/CRi.

UCART19 expansion

UCART19 expansion, as measured by quantitative polymerase chain reaction in PALL and flow-based methods in CALM, occurred primarily in the first 28 days in the FCA-treated population.

Investigators observed expansion in 15 of 17 patients treated with FCA. None of the patients who received FC alone (n=4) had expansion detectable in blood or bone marrow, Dr. Benjamin noted.

“The response we’ve seen in the study so far,” Dr. Benjamin clarified, “is linked to the expansion observed within the first 28-day period.”

UCART cells persisted in three patients beyond day 42. In one patient, they persisted up to day 120.

“Of interest is the T-cell recovery seen in the study,” Dr. Benjamin elaborated. “We only have data from the adult study here—14 patients. And you’ll see that, in the FCA-treated arm (n=11), you have a deeper and more sustained lymphodepletion compared to the FC-treated patients (n=3). And this may play a role in the subsequent UCART19 expansion and disease response.”

Re-dosing

Of the three patients who were re-dosed, two achieved MRD negativity.

One patient achieved MRD-negative status at day 28 but relapsed and received a second infusion 3 months after the first dose. The second expansion was not as deep as the first, but the patient nevertheless achieved MRD negativity after the second dose.

The second patient received FC lymphodepletion and was refractory at day 28.

“The second time around, he received FCA, had a slightly better expansion, and achieved molecular remission,” Dr. Benjamin said.

And the third patient had FCA lymphodepletion but was refractory at day 28.

“We elected to give a second dose at 2.4 months later, but unfortunately, there wasn’t very much expansion, even the second time around, and the patient progressed,” Dr. Benjamin said.

FCA lymphodepletion appears to be required for UCART19 expansion. There was no UCART19 expansion and no response in all four patients lymphodepleted with FC.

The evaluation of UCART19 is ongoing in pediatric and adult B-cell ALL, and “there is a plan for moving into the lymphoma space as well,” Dr. Benjamin added.

Dr. Benjamin disclosed honoraria from Amgen, Takeda, Novartis, Gilead, and Celgene, and research funding from Servier and Pfizer.

Servier and Allogene are supporting the UCART19 trials. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Preliminary data on UCART19—the first off-the-shelf, anti-CD19, allogeneic chimeric antigen receptor (CAR) T-cell therapy—suggest it can produce complete responses (CRs) and minimal residual disease (MRD) negativity, and side effects are manageable.

Investigators pooled data from the phase 1 pediatric (PALL) and adult (CALM) trials of UCART19 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and observed a 67% CR rate in the overall population and an 82% CR rate in patients who received a three-drug lymphodepleting regimen.

Additionally, investigators reported no instance of moderate or severe acute graft-versus-host disease (GVHD) with UCART19.

“We’ve been blessed with the new treatments that have emerged in recent years,” said Reuben Benjamin, MD, PhD, “that include BiTEs, antibody-drug conjugates, and most excitingly, the autologous CAR T-cell therapies.”

Nevertheless, some logistical issues with the autologous CAR T cells leave an unmet need in this group of patients, he noted.

“So an off-the-shelf approach using a product like UCART19 may potentially overcome some of these hurdles that we see in the autologous CAR T-cell therapy field,” he said.

Dr. Benjamin, of King’s College Hospital in London, U.K., presented the analysis of PALL and CALM data at the 2018 ASH Annual Meeting as abstract 896.*

UCART19 product

UCART19 is an allogeneic, genetically modified, CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells.

It has a safety switch—RQR8, which is a CD20 mimotope—that allows the CAR T cells to be targeted by rituximab.

“And importantly,” Dr. Benjamin explained, “the T-cell alpha gene has been knocked out using TALEN® gene-editing technology to prevent T-cell receptor-mediated graft-versus-host disease.”

The CD52 gene is also knocked out, which permits an anti-CD52 monoclonal antibody, such as alemtuzumab, to be used in lymphodepletion.

Study design

The primary objective of both the adult (NCT02746952) and pediatric (NCT02808442) studies was to determine the safety and tolerability of UCART19. Also, the adult study was to determine the maximum tolerated dose of UCART19 and the optimal lymphodepleting regimen.

A secondary objective of both studies was to determine the remission rate at day 28.

Eligible patients received a lymphodepleting regimen for 7 days, followed by a single infusion of UCART19.

Lymphodepletion in the pediatric trial consisted of fludarabine (F) at 150 mg/m² and cyclophosphamide (C) at 120 mg/kg, with or without alemtuzumab (A) at 1 mg/kg capped at 40 mg.

Adults received lower doses of each agent—90 mg/m², 1,500 mg/m², and (optionally) 1 mg/kg or 40 mg, respectively.

Investigators included alemtuzumab in the regimen to minimize viral infections.

The UCART19 dose was weight-banded in the pediatric trial and ranged from 1.1 to 2.3 x 10⁶ cells/kg.

The adult trial included three UCART19 dose levels:

• 6 x 10⁶ cells (≈1 x 10⁵ cells/kg)
• 6 or 8 x 10⁷ cells (≈1 x 10⁶ cells/kg)
• 8 or 2.4 x 10⁸ cells (≈3 x 10⁶ cells/kg).

Patients were assessed for safety and response at day 28 and regularly thereafter for up to 12 months. Patients had the option during the follow-up period to receive a second dose if they did not respond or lost their response.

Patient characteristics/status

Twenty-one patients were enrolled in the trials—seven children and 14 adults. Median ages were 2.7 years (PALL; range, 0.8–16.4) and 29.5 years (CALM; range, 18–62).

Both studies included high-risk, heavily pretreated populations, Dr. Benjamin noted.

The pooled population had a median of 4 prior lines of therapy (range, 1–6), and nine patients had a high-risk cytogenetics, including complex karyotypes, MLL rearrangements, and Ph+ disease.

Thirteen patients had prior allogeneic stem cell transplants.

Nine patients had a bone marrow tumor burden of more than 25% blasts prior to lymphodepletion.

As of the cutoff date of October 23, all patients had been treated with UCART19.

Four of the pediatric patients are still on the trial. Two are in remission, one has relapsed, and one is refractory.

Eight adult patients are still on trial. Three are in remission, three are relapsed, and two are refractory.

Safety

“UCART19 appears to show an acceptable safety profile based on the adverse events reported so far,” Dr. Benjamin said.

Nineteen patients experienced cytokine release syndrome (CRS), primarily grades 1 and 2. Eight patients had grade 1 and 2 neurotoxicity events, and two patients had grade 1 acute skin GVHD.

“In keeping with what is seen in some of the autologous CAR T-cell trials,” Dr. Benjamin explained, “prolonged cytopenias were seen, which we defined in these studies as grade 4 neutropenia or thrombocytopenia occurring at 42 days post-UCART infusion.”

Six of 21 patients developed prolonged cytopenia.

There was also an increased incidence of viral infections occurring in eight patients, including cytomegalovirus, adenovirus, BK virus, and metapneumovirus.

“Most of these infections, however, were manageable,” Dr. Benjamin said.

Two patients developed neutropenic sepsis, one grade 5, which was one of the treatment-related deaths in the CALM trial.

No treatment-related deaths occurred in the PALL study, but there were two in the CALM study—one from pulmonary hemorrhage and the other from neutropenic sepsis and grade 4 CRS.

Twelve patients are still alive, five of whom are in CR.

Efficacy

Of the patients who received FCA lymphodepletion, 82% (14/17) achieved CR/CR with incomplete hematologic recovery (CRi), and 71% (10/14) achieved MRD negativity.

An additional patient gained MRD-negative status after the second dose of UCART19.

Of the 14 patients who achieved a CR/CRi, 78% (n=11) went on to receive an allogeneic transplant.

In the entire pooled population, 67% (14/21) achieved CR/CRi.

Three patients received a second UCART19 dose, and five patients remain in CR/CRi.

UCART19 expansion

UCART19 expansion, as measured by quantitative polymerase chain reaction in PALL and flow-based methods in CALM, occurred primarily in the first 28 days in the FCA-treated population.

Investigators observed expansion in 15 of 17 patients treated with FCA. None of the patients who received FC alone (n=4) had expansion detectable in blood or bone marrow, Dr. Benjamin noted.

“The response we’ve seen in the study so far,” Dr. Benjamin clarified, “is linked to the expansion observed within the first 28-day period.”

UCART cells persisted in three patients beyond day 42. In one patient, they persisted up to day 120.

“Of interest is the T-cell recovery seen in the study,” Dr. Benjamin elaborated. “We only have data from the adult study here—14 patients. And you’ll see that, in the FCA-treated arm (n=11), you have a deeper and more sustained lymphodepletion compared to the FC-treated patients (n=3). And this may play a role in the subsequent UCART19 expansion and disease response.”

Re-dosing

Of the three patients who were re-dosed, two achieved MRD negativity.

One patient achieved MRD-negative status at day 28 but relapsed and received a second infusion 3 months after the first dose. The second expansion was not as deep as the first, but the patient nevertheless achieved MRD negativity after the second dose.

The second patient received FC lymphodepletion and was refractory at day 28.

“The second time around, he received FCA, had a slightly better expansion, and achieved molecular remission,” Dr. Benjamin said.

And the third patient had FCA lymphodepletion but was refractory at day 28.

“We elected to give a second dose at 2.4 months later, but unfortunately, there wasn’t very much expansion, even the second time around, and the patient progressed,” Dr. Benjamin said.

FCA lymphodepletion appears to be required for UCART19 expansion. There was no UCART19 expansion and no response in all four patients lymphodepleted with FC.

The evaluation of UCART19 is ongoing in pediatric and adult B-cell ALL, and “there is a plan for moving into the lymphoma space as well,” Dr. Benjamin added.

Dr. Benjamin disclosed honoraria from Amgen, Takeda, Novartis, Gilead, and Celgene, and research funding from Servier and Pfizer.

Servier and Allogene are supporting the UCART19 trials. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—The combination of melflufen and dexamethasone demonstrated activity in patients with multi-resistant multiple myeloma (MM) in a phase 2 trial.

Melflufen-dexamethasone produced an overall response rate of 33% in patients who had quad- or penta-refractory MM.

The combination was considered well tolerated, although 13% of patients discontinued treatment due to adverse events (AEs).

Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented these results, from the HORIZON trial (NCT02963493), at the 2018 ASH Annual Meeting (abstract 600*).

Dr. Richardson reported results with melflufen-dexamethasone in 83 MM patients. They had a median age of 63 (range, 35-86), and 59% were male. Their median time since diagnosis was 6.5 years (range, 0.7-25) at baseline.

The patients had received a median of 5 prior lines of therapy (range, 2-13). All patients were refractory to pomalidomide or daratumumab, and 60% were refractory to both drugs. Eighty percent of patients were refractory to a monoclonal antibody, and 55% were refractory to an alkylator.

Eighty-six percent of patients were refractory to both a proteasome inhibitor and an immunomodulatory drug. Sixty percent of patients were refractory to a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 therapy.

Ninety-three percent of patients were refractory to their last line of therapy. Sixty-nine percent had received a transplant, and 25% had received two transplants.

“[I]f you look at the refractoriness of these patients, 46% had used three or more prior regimens within the last 12 months before entering the trial, and I think that reflects a real challenge in these patients,” Dr. Richardson said.

Results

The patients received melflufen at 40 mg on day 1 of each 28-day cycle and dexamethasone at 40 mg weekly (20 mg for patients age 75 and older). Patients were treated until progression, consent withdrawal, or unacceptable toxicity.

The overall response rate (partial response or better) was 33%, the clinical benefit rate (minimal response or better) was 39%, and 84% of patients had stable disease or better.

Twenty seven patients responded, including one stringent complete response, nine very good partial responses, and 17 partial responses.

Five patients had a minimal response, 37 had stable disease, and 12 progressed. One patient was not evaluable, and one had data pending.

Dr. Richardson noted that melflufen-dexamethasone demonstrated activity regardless of a patient’s underlying refractory status, but serum albumin was a strong predictor of response. Specifically, patients with higher albumin levels were more likely to respond.

“We do not think it’s a mechanism-of-action issue with [melflufen], but we will be evaluating that,” Dr. Richardson said.

He went on to say that the median progression-free survival was 4.0 months overall, 6.4 months among patients with a partial response or better, and 1 month in patients with progressive disease.

Treatment-related grade 3/4 AEs occurred in 75% of patients. This included neutropenia (61%), thrombocytopenia (59%), anemia (25%), febrile neutropenia (6%), leukopenia (5%), lymphopenia (5%), infections and infestations (7%), and pneumonia (2%).

There were no treatment-related deaths. Thirteen percent of patients discontinued treatment due to AEs, most due to thrombocytopenia (8/11).

In closing, Dr. Richardson said toxicity was “generally manageable” with this treatment, which “has promising activity in multi-resistant, relapsed/refractory myeloma.”

He added that, in the phase 3 OCEAN trial (NCT03151811), researchers are comparing melflufen-dexamethasone to pomalidomide-dexamethasone in a less heavily pretreated MM population.

In the phase 1/2 ANCHOR trial (NCT03481556), researchers are testing melflufen-dexamethasone in combination with daratumumab or bortezomib.

Dr. Richardson disclosed relationships with Karyopharm Pharmaceuticals, Bristol-Myers Squibb, Janssen, Amgen, Jazz Pharmaceuticals, Takeda, Celgene, and Oncopeptides AB. The HORIZON trial is supported by Oncopeptides AB in collaboration with Precision Oncology.

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—The combination of melflufen and dexamethasone demonstrated activity in patients with multi-resistant multiple myeloma (MM) in a phase 2 trial.

Melflufen-dexamethasone produced an overall response rate of 33% in patients who had quad- or penta-refractory MM.

The combination was considered well tolerated, although 13% of patients discontinued treatment due to adverse events (AEs).

Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented these results, from the HORIZON trial (NCT02963493), at the 2018 ASH Annual Meeting (abstract 600*).

Dr. Richardson reported results with melflufen-dexamethasone in 83 MM patients. They had a median age of 63 (range, 35-86), and 59% were male. Their median time since diagnosis was 6.5 years (range, 0.7-25) at baseline.

The patients had received a median of 5 prior lines of therapy (range, 2-13). All patients were refractory to pomalidomide or daratumumab, and 60% were refractory to both drugs. Eighty percent of patients were refractory to a monoclonal antibody, and 55% were refractory to an alkylator.

Eighty-six percent of patients were refractory to both a proteasome inhibitor and an immunomodulatory drug. Sixty percent of patients were refractory to a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 therapy.

Ninety-three percent of patients were refractory to their last line of therapy. Sixty-nine percent had received a transplant, and 25% had received two transplants.

“[I]f you look at the refractoriness of these patients, 46% had used three or more prior regimens within the last 12 months before entering the trial, and I think that reflects a real challenge in these patients,” Dr. Richardson said.

Results

The patients received melflufen at 40 mg on day 1 of each 28-day cycle and dexamethasone at 40 mg weekly (20 mg for patients age 75 and older). Patients were treated until progression, consent withdrawal, or unacceptable toxicity.

The overall response rate (partial response or better) was 33%, the clinical benefit rate (minimal response or better) was 39%, and 84% of patients had stable disease or better.

Twenty seven patients responded, including one stringent complete response, nine very good partial responses, and 17 partial responses.

Five patients had a minimal response, 37 had stable disease, and 12 progressed. One patient was not evaluable, and one had data pending.

Dr. Richardson noted that melflufen-dexamethasone demonstrated activity regardless of a patient’s underlying refractory status, but serum albumin was a strong predictor of response. Specifically, patients with higher albumin levels were more likely to respond.

“We do not think it’s a mechanism-of-action issue with [melflufen], but we will be evaluating that,” Dr. Richardson said.

He went on to say that the median progression-free survival was 4.0 months overall, 6.4 months among patients with a partial response or better, and 1 month in patients with progressive disease.

Treatment-related grade 3/4 AEs occurred in 75% of patients. This included neutropenia (61%), thrombocytopenia (59%), anemia (25%), febrile neutropenia (6%), leukopenia (5%), lymphopenia (5%), infections and infestations (7%), and pneumonia (2%).

There were no treatment-related deaths. Thirteen percent of patients discontinued treatment due to AEs, most due to thrombocytopenia (8/11).

In closing, Dr. Richardson said toxicity was “generally manageable” with this treatment, which “has promising activity in multi-resistant, relapsed/refractory myeloma.”

He added that, in the phase 3 OCEAN trial (NCT03151811), researchers are comparing melflufen-dexamethasone to pomalidomide-dexamethasone in a less heavily pretreated MM population.

In the phase 1/2 ANCHOR trial (NCT03481556), researchers are testing melflufen-dexamethasone in combination with daratumumab or bortezomib.

Dr. Richardson disclosed relationships with Karyopharm Pharmaceuticals, Bristol-Myers Squibb, Janssen, Amgen, Jazz Pharmaceuticals, Takeda, Celgene, and Oncopeptides AB. The HORIZON trial is supported by Oncopeptides AB in collaboration with Precision Oncology.

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—The combination of melflufen and dexamethasone demonstrated activity in patients with multi-resistant multiple myeloma (MM) in a phase 2 trial.

Melflufen-dexamethasone produced an overall response rate of 33% in patients who had quad- or penta-refractory MM.

The combination was considered well tolerated, although 13% of patients discontinued treatment due to adverse events (AEs).

Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented these results, from the HORIZON trial (NCT02963493), at the 2018 ASH Annual Meeting (abstract 600*).

Dr. Richardson reported results with melflufen-dexamethasone in 83 MM patients. They had a median age of 63 (range, 35-86), and 59% were male. Their median time since diagnosis was 6.5 years (range, 0.7-25) at baseline.

The patients had received a median of 5 prior lines of therapy (range, 2-13). All patients were refractory to pomalidomide or daratumumab, and 60% were refractory to both drugs. Eighty percent of patients were refractory to a monoclonal antibody, and 55% were refractory to an alkylator.

Eighty-six percent of patients were refractory to both a proteasome inhibitor and an immunomodulatory drug. Sixty percent of patients were refractory to a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 therapy.

Ninety-three percent of patients were refractory to their last line of therapy. Sixty-nine percent had received a transplant, and 25% had received two transplants.

“[I]f you look at the refractoriness of these patients, 46% had used three or more prior regimens within the last 12 months before entering the trial, and I think that reflects a real challenge in these patients,” Dr. Richardson said.

Results

The patients received melflufen at 40 mg on day 1 of each 28-day cycle and dexamethasone at 40 mg weekly (20 mg for patients age 75 and older). Patients were treated until progression, consent withdrawal, or unacceptable toxicity.

The overall response rate (partial response or better) was 33%, the clinical benefit rate (minimal response or better) was 39%, and 84% of patients had stable disease or better.

Twenty seven patients responded, including one stringent complete response, nine very good partial responses, and 17 partial responses.

Five patients had a minimal response, 37 had stable disease, and 12 progressed. One patient was not evaluable, and one had data pending.

Dr. Richardson noted that melflufen-dexamethasone demonstrated activity regardless of a patient’s underlying refractory status, but serum albumin was a strong predictor of response. Specifically, patients with higher albumin levels were more likely to respond.

“We do not think it’s a mechanism-of-action issue with [melflufen], but we will be evaluating that,” Dr. Richardson said.

He went on to say that the median progression-free survival was 4.0 months overall, 6.4 months among patients with a partial response or better, and 1 month in patients with progressive disease.

Treatment-related grade 3/4 AEs occurred in 75% of patients. This included neutropenia (61%), thrombocytopenia (59%), anemia (25%), febrile neutropenia (6%), leukopenia (5%), lymphopenia (5%), infections and infestations (7%), and pneumonia (2%).

There were no treatment-related deaths. Thirteen percent of patients discontinued treatment due to AEs, most due to thrombocytopenia (8/11).

In closing, Dr. Richardson said toxicity was “generally manageable” with this treatment, which “has promising activity in multi-resistant, relapsed/refractory myeloma.”

He added that, in the phase 3 OCEAN trial (NCT03151811), researchers are comparing melflufen-dexamethasone to pomalidomide-dexamethasone in a less heavily pretreated MM population.

In the phase 1/2 ANCHOR trial (NCT03481556), researchers are testing melflufen-dexamethasone in combination with daratumumab or bortezomib.

Dr. Richardson disclosed relationships with Karyopharm Pharmaceuticals, Bristol-Myers Squibb, Janssen, Amgen, Jazz Pharmaceuticals, Takeda, Celgene, and Oncopeptides AB. The HORIZON trial is supported by Oncopeptides AB in collaboration with Precision Oncology.

*Data in the abstract differ from the presentation.

Just 15% of U.S. physician practices report using telemedicine for patient care, with use of the technology varying widely by specialty.

Carol Kane, director of economic and health policy research, and Kurt Gillis, principal economist, both of the American Medical Association, evaluated the responses of 3,500 physicians about their telemedicine usage through data from the AMA’s 2016 Physician Practice Benchmark Survey. They took into account physicians’ specialty, age, sex, practice setting, and region, as well as the type of telemedicine services employed, if any.

In a research article published in Health Affairs, they found that in 2016, 15% of medical practices used telemedicine for patient interactions – including e-visits and store and forward services – while 11% used the technology to communicate with other health professionals.

Of the primary three telemedicine modalities, physicians used videoconferencing most often (13%), followed by store and forward of data (9%), and remote patient monitoring (7%).

Of specialists, 40% of radiologists, 28% of psychiatrists, and 24% of cardiologists used telemedicine for patient interactions, Ms. Kane and Mr. Gillis found. Emergency physicians were most likely to use telemedicine for interactions with other health professionals (39%), followed by pathologists (30%), and radiologists 26%). On the lower end of the spectrum, 6% of immunologists, 9% of ob.gyns., and 10% of general surgeons used telemedicine for patient care.

Remote patient monitoring was the least used telemedicine modality, with less than 10% of physicians in every broad specialty group using the service, with the exception of internal medicine subspecialties. Cardiologists reported the highest use of remote patient monitoring, followed by nephrologists.

Practice size and setting markedly influenced the practice of telemedicine. Use for patient interactions ranged from 8% among physicians in practices with one to four doctors to 27% among physician practices with at least 50 physicians. Similarly, telemedicine use between physicians and other health care professionals ranged from 4% among doctors in the smallest practice category to 23% in the largest practice category. Physicians in solo practice were less likely to use telemedicine for patient interactions than physicians in single- or multispecialty group practices.

Unsurprisingly, rural physicians were more likely to use telemedicine to consult with other doctors and to use video conferencing with patients than were physicians in metropolitan areas. No significant differences in telemedicine use were observed between physicians in states with parity laws. Such laws generally require that commercial insurers cover and reimburse for telemedicine services as they would for in-person services.

SOURCE: Kane et al. Health Affairs. 2018. doi: 10.1377/hlthaff.2018.05077.

Just 15% of U.S. physician practices report using telemedicine for patient care, with use of the technology varying widely by specialty.

Carol Kane, director of economic and health policy research, and Kurt Gillis, principal economist, both of the American Medical Association, evaluated the responses of 3,500 physicians about their telemedicine usage through data from the AMA’s 2016 Physician Practice Benchmark Survey. They took into account physicians’ specialty, age, sex, practice setting, and region, as well as the type of telemedicine services employed, if any.

In a research article published in Health Affairs, they found that in 2016, 15% of medical practices used telemedicine for patient interactions – including e-visits and store and forward services – while 11% used the technology to communicate with other health professionals.

Of the primary three telemedicine modalities, physicians used videoconferencing most often (13%), followed by store and forward of data (9%), and remote patient monitoring (7%).

Of specialists, 40% of radiologists, 28% of psychiatrists, and 24% of cardiologists used telemedicine for patient interactions, Ms. Kane and Mr. Gillis found. Emergency physicians were most likely to use telemedicine for interactions with other health professionals (39%), followed by pathologists (30%), and radiologists 26%). On the lower end of the spectrum, 6% of immunologists, 9% of ob.gyns., and 10% of general surgeons used telemedicine for patient care.

Remote patient monitoring was the least used telemedicine modality, with less than 10% of physicians in every broad specialty group using the service, with the exception of internal medicine subspecialties. Cardiologists reported the highest use of remote patient monitoring, followed by nephrologists.

Practice size and setting markedly influenced the practice of telemedicine. Use for patient interactions ranged from 8% among physicians in practices with one to four doctors to 27% among physician practices with at least 50 physicians. Similarly, telemedicine use between physicians and other health care professionals ranged from 4% among doctors in the smallest practice category to 23% in the largest practice category. Physicians in solo practice were less likely to use telemedicine for patient interactions than physicians in single- or multispecialty group practices.

Unsurprisingly, rural physicians were more likely to use telemedicine to consult with other doctors and to use video conferencing with patients than were physicians in metropolitan areas. No significant differences in telemedicine use were observed between physicians in states with parity laws. Such laws generally require that commercial insurers cover and reimburse for telemedicine services as they would for in-person services.

SOURCE: Kane et al. Health Affairs. 2018. doi: 10.1377/hlthaff.2018.05077.

Just 15% of U.S. physician practices report using telemedicine for patient care, with use of the technology varying widely by specialty.

Carol Kane, director of economic and health policy research, and Kurt Gillis, principal economist, both of the American Medical Association, evaluated the responses of 3,500 physicians about their telemedicine usage through data from the AMA’s 2016 Physician Practice Benchmark Survey. They took into account physicians’ specialty, age, sex, practice setting, and region, as well as the type of telemedicine services employed, if any.

In a research article published in Health Affairs, they found that in 2016, 15% of medical practices used telemedicine for patient interactions – including e-visits and store and forward services – while 11% used the technology to communicate with other health professionals.

Of the primary three telemedicine modalities, physicians used videoconferencing most often (13%), followed by store and forward of data (9%), and remote patient monitoring (7%).

Of specialists, 40% of radiologists, 28% of psychiatrists, and 24% of cardiologists used telemedicine for patient interactions, Ms. Kane and Mr. Gillis found. Emergency physicians were most likely to use telemedicine for interactions with other health professionals (39%), followed by pathologists (30%), and radiologists 26%). On the lower end of the spectrum, 6% of immunologists, 9% of ob.gyns., and 10% of general surgeons used telemedicine for patient care.

Remote patient monitoring was the least used telemedicine modality, with less than 10% of physicians in every broad specialty group using the service, with the exception of internal medicine subspecialties. Cardiologists reported the highest use of remote patient monitoring, followed by nephrologists.

Practice size and setting markedly influenced the practice of telemedicine. Use for patient interactions ranged from 8% among physicians in practices with one to four doctors to 27% among physician practices with at least 50 physicians. Similarly, telemedicine use between physicians and other health care professionals ranged from 4% among doctors in the smallest practice category to 23% in the largest practice category. Physicians in solo practice were less likely to use telemedicine for patient interactions than physicians in single- or multispecialty group practices.

Unsurprisingly, rural physicians were more likely to use telemedicine to consult with other doctors and to use video conferencing with patients than were physicians in metropolitan areas. No significant differences in telemedicine use were observed between physicians in states with parity laws. Such laws generally require that commercial insurers cover and reimburse for telemedicine services as they would for in-person services.

SOURCE: Kane et al. Health Affairs. 2018. doi: 10.1377/hlthaff.2018.05077.