Leukemia, Myelodysplasia, Transplantation

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

One-time treatment with the hallucinogenic drug psilocybin may provide long-term relief of existential anxiety in patients with life-threatening cancers, according to a small study.

After receiving a single high dose of the drug, most of the patients studied reported decreases in depression and anxiety as well as increases in quality of life and optimism.

These improvements were sustained at 6 months of follow-up.

“The most interesting and remarkable finding is that a single dose of psilocybin, which lasts 4 to 6 hours, produced enduring decreases in depression and anxiety symptoms, and this may represent a fascinating new model for treating some psychiatric conditions,” said study author Roland Griffiths, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Griffiths said this study grew out of a decade of research at Johns Hopkins on the effects of psilocybin in healthy volunteers, which showed that psilocybin can consistently produce positive changes in mood, behavior, and spirituality when administered to carefully screened and prepared participants.

The current study was designed to see if psilocybin could produce similar results in psychologically distressed cancer patients.

The results were published in the Journal of Psychopharmacology alongside a similar study and 11 accompanying editorials.

For their study, Dr Griffiths and his colleagues recruited 51 participants diagnosed with life-threatening cancers, most of which were recurrent or metastatic.

Types of cancer included breast (n=13), upper aerodigestive (n=7), gastrointestinal (n=4), genitourinary (n=18), and “other” cancers (n=1), as well as hematologic malignancies (n=8).

All participants had been given a formal psychiatric diagnosis, including an anxiety or depressive disorder.

Half of the participants were female, and they had an average age of 56. Ninety-two percent were white, 4% were black, and 2% were Asian.

Treatment

Each participant had 2 treatment sessions scheduled 5 weeks apart. In 1 session, they received a capsule containing a very low dose (1 or 3 mg per 70 kg) of psilocybin that was meant to act as a “control” because the dose was too low to produce effects.

In the other session, participants received a capsule with what is considered a moderate or high dose (22 or 30 mg per 70 kg).

To minimize expectancy effects, the participants and the staff members supervising the sessions were told that participants would receive psilocybin on both sessions, but they did not know that all participants would receive a high dose and a low dose.

Blood pressure and mood were monitored throughout the sessions.

Two monitors aided participants during each session, encouraging them to lie down, wear an eye mask, listen to music through headphones, and direct their attention on their inner experience. If anxiety or confusion arose, the monitors provided reassurance to the participants.

Participants, staff, and community observers rated participants’ moods, attitudes, and behaviors throughout the study.

The researchers assessed each participant via questionnaires and structured interviews before the first session, 7 hours after taking the psilocybin, 5 weeks after each session, and 6 months after the second session.

Adverse events

Thirty-four percent of participants had an episode of elevated systolic blood pressure (>160 mm Hg at 1 or more time-point) in the high-dose psilocybin session, and 17% of participants had such an episode in the low-dose session.

Thirteen percent and 2%, respectively, had an episode of elevated diastolic blood pressure (>100 mm Hg at 1 or more time-point). None of these episodes met criteria for medical intervention.

During the high-dose psilocybin session, 15% of patients experienced nausea or vomiting. There were no such events during the low-dose session.

Three participants reported mild to moderate headaches after the high-dose session.

Twenty-one percent of patients reported physical discomfort during the high-dose session, as did 8% of patients during the low-dose session.

Psychological discomfort occurred in 32% and 12% of participants, respectively. The researchers said there were no cases of hallucinogen persisting perception disorder or prolonged psychosis.

Efficacy outcomes

Most participants reported experiencing changes in visual perception, emotions, and thinking after taking high-dose psilocybin. They also reported experiences of psychological insight and profound, deeply meaningful experiences.

Six months after the final session of treatment, about 80% of participants continued to show clinically significant decreases in depressed mood and anxiety, according to clinician assessment.

According to the participants themselves, 83% had increases in well-being or life satisfaction at 6 months after treatment.

Sixty-seven percent of participants rated the experience as one of the top 5 meaningful experiences in their lives, and 70% rated the experience as one of their top 5 spiritually significant lifetime events.

“Before beginning the study, it wasn’t clear to me that this treatment would be helpful, since cancer patients may experience profound hopelessness in response to their diagnosis, which is often followed by multiple surgeries and prolonged chemotherapy,” Dr Griffiths said.

“I could imagine that cancer patients would receive psilocybin, look into the existential void, and come out even more fearful. However, the positive changes in attitudes, moods, and behavior that we documented in healthy volunteers were replicated in cancer patients.”

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

One-time treatment with the hallucinogenic drug psilocybin may provide long-term relief of existential anxiety in patients with life-threatening cancers, according to a small study.

After receiving a single high dose of the drug, most of the patients studied reported decreases in depression and anxiety as well as increases in quality of life and optimism.

These improvements were sustained at 6 months of follow-up.

“The most interesting and remarkable finding is that a single dose of psilocybin, which lasts 4 to 6 hours, produced enduring decreases in depression and anxiety symptoms, and this may represent a fascinating new model for treating some psychiatric conditions,” said study author Roland Griffiths, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Griffiths said this study grew out of a decade of research at Johns Hopkins on the effects of psilocybin in healthy volunteers, which showed that psilocybin can consistently produce positive changes in mood, behavior, and spirituality when administered to carefully screened and prepared participants.

The current study was designed to see if psilocybin could produce similar results in psychologically distressed cancer patients.

The results were published in the Journal of Psychopharmacology alongside a similar study and 11 accompanying editorials.

For their study, Dr Griffiths and his colleagues recruited 51 participants diagnosed with life-threatening cancers, most of which were recurrent or metastatic.

Types of cancer included breast (n=13), upper aerodigestive (n=7), gastrointestinal (n=4), genitourinary (n=18), and “other” cancers (n=1), as well as hematologic malignancies (n=8).

All participants had been given a formal psychiatric diagnosis, including an anxiety or depressive disorder.

Half of the participants were female, and they had an average age of 56. Ninety-two percent were white, 4% were black, and 2% were Asian.

Treatment

Each participant had 2 treatment sessions scheduled 5 weeks apart. In 1 session, they received a capsule containing a very low dose (1 or 3 mg per 70 kg) of psilocybin that was meant to act as a “control” because the dose was too low to produce effects.

In the other session, participants received a capsule with what is considered a moderate or high dose (22 or 30 mg per 70 kg).

To minimize expectancy effects, the participants and the staff members supervising the sessions were told that participants would receive psilocybin on both sessions, but they did not know that all participants would receive a high dose and a low dose.

Blood pressure and mood were monitored throughout the sessions.

Two monitors aided participants during each session, encouraging them to lie down, wear an eye mask, listen to music through headphones, and direct their attention on their inner experience. If anxiety or confusion arose, the monitors provided reassurance to the participants.

Participants, staff, and community observers rated participants’ moods, attitudes, and behaviors throughout the study.

The researchers assessed each participant via questionnaires and structured interviews before the first session, 7 hours after taking the psilocybin, 5 weeks after each session, and 6 months after the second session.

Adverse events

Thirty-four percent of participants had an episode of elevated systolic blood pressure (>160 mm Hg at 1 or more time-point) in the high-dose psilocybin session, and 17% of participants had such an episode in the low-dose session.

Thirteen percent and 2%, respectively, had an episode of elevated diastolic blood pressure (>100 mm Hg at 1 or more time-point). None of these episodes met criteria for medical intervention.

During the high-dose psilocybin session, 15% of patients experienced nausea or vomiting. There were no such events during the low-dose session.

Three participants reported mild to moderate headaches after the high-dose session.

Twenty-one percent of patients reported physical discomfort during the high-dose session, as did 8% of patients during the low-dose session.

Psychological discomfort occurred in 32% and 12% of participants, respectively. The researchers said there were no cases of hallucinogen persisting perception disorder or prolonged psychosis.

Efficacy outcomes

Most participants reported experiencing changes in visual perception, emotions, and thinking after taking high-dose psilocybin. They also reported experiences of psychological insight and profound, deeply meaningful experiences.

Six months after the final session of treatment, about 80% of participants continued to show clinically significant decreases in depressed mood and anxiety, according to clinician assessment.

According to the participants themselves, 83% had increases in well-being or life satisfaction at 6 months after treatment.

Sixty-seven percent of participants rated the experience as one of the top 5 meaningful experiences in their lives, and 70% rated the experience as one of their top 5 spiritually significant lifetime events.

“Before beginning the study, it wasn’t clear to me that this treatment would be helpful, since cancer patients may experience profound hopelessness in response to their diagnosis, which is often followed by multiple surgeries and prolonged chemotherapy,” Dr Griffiths said.

“I could imagine that cancer patients would receive psilocybin, look into the existential void, and come out even more fearful. However, the positive changes in attitudes, moods, and behavior that we documented in healthy volunteers were replicated in cancer patients.”

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

One-time treatment with the hallucinogenic drug psilocybin may provide long-term relief of existential anxiety in patients with life-threatening cancers, according to a small study.

After receiving a single high dose of the drug, most of the patients studied reported decreases in depression and anxiety as well as increases in quality of life and optimism.

These improvements were sustained at 6 months of follow-up.

“The most interesting and remarkable finding is that a single dose of psilocybin, which lasts 4 to 6 hours, produced enduring decreases in depression and anxiety symptoms, and this may represent a fascinating new model for treating some psychiatric conditions,” said study author Roland Griffiths, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Griffiths said this study grew out of a decade of research at Johns Hopkins on the effects of psilocybin in healthy volunteers, which showed that psilocybin can consistently produce positive changes in mood, behavior, and spirituality when administered to carefully screened and prepared participants.

The current study was designed to see if psilocybin could produce similar results in psychologically distressed cancer patients.

The results were published in the Journal of Psychopharmacology alongside a similar study and 11 accompanying editorials.

For their study, Dr Griffiths and his colleagues recruited 51 participants diagnosed with life-threatening cancers, most of which were recurrent or metastatic.

Types of cancer included breast (n=13), upper aerodigestive (n=7), gastrointestinal (n=4), genitourinary (n=18), and “other” cancers (n=1), as well as hematologic malignancies (n=8).

All participants had been given a formal psychiatric diagnosis, including an anxiety or depressive disorder.

Half of the participants were female, and they had an average age of 56. Ninety-two percent were white, 4% were black, and 2% were Asian.

Treatment

Each participant had 2 treatment sessions scheduled 5 weeks apart. In 1 session, they received a capsule containing a very low dose (1 or 3 mg per 70 kg) of psilocybin that was meant to act as a “control” because the dose was too low to produce effects.

In the other session, participants received a capsule with what is considered a moderate or high dose (22 or 30 mg per 70 kg).

To minimize expectancy effects, the participants and the staff members supervising the sessions were told that participants would receive psilocybin on both sessions, but they did not know that all participants would receive a high dose and a low dose.

Blood pressure and mood were monitored throughout the sessions.

Two monitors aided participants during each session, encouraging them to lie down, wear an eye mask, listen to music through headphones, and direct their attention on their inner experience. If anxiety or confusion arose, the monitors provided reassurance to the participants.

Participants, staff, and community observers rated participants’ moods, attitudes, and behaviors throughout the study.

The researchers assessed each participant via questionnaires and structured interviews before the first session, 7 hours after taking the psilocybin, 5 weeks after each session, and 6 months after the second session.

Adverse events

Thirty-four percent of participants had an episode of elevated systolic blood pressure (>160 mm Hg at 1 or more time-point) in the high-dose psilocybin session, and 17% of participants had such an episode in the low-dose session.

Thirteen percent and 2%, respectively, had an episode of elevated diastolic blood pressure (>100 mm Hg at 1 or more time-point). None of these episodes met criteria for medical intervention.

During the high-dose psilocybin session, 15% of patients experienced nausea or vomiting. There were no such events during the low-dose session.

Three participants reported mild to moderate headaches after the high-dose session.

Twenty-one percent of patients reported physical discomfort during the high-dose session, as did 8% of patients during the low-dose session.

Psychological discomfort occurred in 32% and 12% of participants, respectively. The researchers said there were no cases of hallucinogen persisting perception disorder or prolonged psychosis.

Efficacy outcomes

Most participants reported experiencing changes in visual perception, emotions, and thinking after taking high-dose psilocybin. They also reported experiences of psychological insight and profound, deeply meaningful experiences.

Six months after the final session of treatment, about 80% of participants continued to show clinically significant decreases in depressed mood and anxiety, according to clinician assessment.

According to the participants themselves, 83% had increases in well-being or life satisfaction at 6 months after treatment.

Sixty-seven percent of participants rated the experience as one of the top 5 meaningful experiences in their lives, and 70% rated the experience as one of their top 5 spiritually significant lifetime events.

“Before beginning the study, it wasn’t clear to me that this treatment would be helpful, since cancer patients may experience profound hopelessness in response to their diagnosis, which is often followed by multiple surgeries and prolonged chemotherapy,” Dr Griffiths said.

“I could imagine that cancer patients would receive psilocybin, look into the existential void, and come out even more fearful. However, the positive changes in attitudes, moods, and behavior that we documented in healthy volunteers were replicated in cancer patients.”

Micrograph showing MDS

Preclinical research has revealed potential therapeutic targets for

myelodysplastic syndromes (MDS).

Investigators

found evidence to suggest that TRAF6, a toll-like receptor effector

with ubiquitin ligase activity, plays a key role in MDS.

So TRAF6 and

proteins regulated by TRAF6 may be therapeutic targets for MDS.

Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.

The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.

To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.

“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.

Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.

This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.

All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.

“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.

Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.

TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.

Micrograph showing MDS

Preclinical research has revealed potential therapeutic targets for

myelodysplastic syndromes (MDS).

Investigators

found evidence to suggest that TRAF6, a toll-like receptor effector

with ubiquitin ligase activity, plays a key role in MDS.

So TRAF6 and

proteins regulated by TRAF6 may be therapeutic targets for MDS.

Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.

The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.

To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.

“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.

Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.

This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.

All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.

“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.

Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.

TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.

Micrograph showing MDS

Preclinical research has revealed potential therapeutic targets for

myelodysplastic syndromes (MDS).

Investigators

found evidence to suggest that TRAF6, a toll-like receptor effector

with ubiquitin ligase activity, plays a key role in MDS.

So TRAF6 and

proteins regulated by TRAF6 may be therapeutic targets for MDS.

Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.

The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.

To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.

“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.

Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.

This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.

All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.

“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.

Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.

TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.

ALL cells
Image by Vashi Donsk

Researchers say they have characterized a subpopulation of leukemia cells that are responsible for relapse in acute lymphoblastic leukemia (ALL).

The team identified these dormant, therapy-resistant cells in mouse models of ALL and found that removing the cells from their environment makes them sensitive to treatment.

The researchers believe these findings could pave the way to better relapse prevention in patients with ALL.

“Previously, the biological principles responsible for a relapse in leukemia were not fully understood,” said study author Irmela Jeremias, MD, PhD, of Helmholtz Zentrum München in Munich, Germany.

“Our new approach is to isolate dormant cells, which gives us the first possibility of developing therapies that switch off these cells.”

Dr Jeremias and colleagues described this approach in Cancer Cell.

First, the researchers created mouse models recapitulating minimal residual disease (MRD) and relapse in ALL patients.

The team then used genetic engineering and proliferation-sensitive dyes to isolate and characterize relapse-inducing cells.

This revealed a subpopulation of leukemia cells that exhibited long-term dormancy, treatment resistance, and stemness. These cells were similar to primary ALL cells isolated from pediatric and adult patients with MRD.

However, the dormant leukemia cells found in the mice changed once they were removed from the in vivo environment. They began to proliferate and became sensitive to ex vivo treatment with chemotherapy drugs.

“[T]hese cells, once they have been dissolved out of their surroundings, are indeed susceptible to therapy and react well to therapeutics,” said study author Erbey Özdemir, a doctoral candidate at Helmholtz Zentrum München.

The researchers therefore believe that therapeutic strategies aimed at dissociating dormant leukemia cells from their protective niche might prevent relapse in ALL patients.

“This has brought us a small step closer to the global goal of preventing disease relapse in patients suffering from leukemia,” Dr Jeremias said. “It might serve as basis for new therapies that destroy resistant leukemia cells before they induce relapse.”

ALL cells
Image by Vashi Donsk

Researchers say they have characterized a subpopulation of leukemia cells that are responsible for relapse in acute lymphoblastic leukemia (ALL).

The team identified these dormant, therapy-resistant cells in mouse models of ALL and found that removing the cells from their environment makes them sensitive to treatment.

The researchers believe these findings could pave the way to better relapse prevention in patients with ALL.

“Previously, the biological principles responsible for a relapse in leukemia were not fully understood,” said study author Irmela Jeremias, MD, PhD, of Helmholtz Zentrum München in Munich, Germany.

“Our new approach is to isolate dormant cells, which gives us the first possibility of developing therapies that switch off these cells.”

Dr Jeremias and colleagues described this approach in Cancer Cell.

First, the researchers created mouse models recapitulating minimal residual disease (MRD) and relapse in ALL patients.

The team then used genetic engineering and proliferation-sensitive dyes to isolate and characterize relapse-inducing cells.

This revealed a subpopulation of leukemia cells that exhibited long-term dormancy, treatment resistance, and stemness. These cells were similar to primary ALL cells isolated from pediatric and adult patients with MRD.

However, the dormant leukemia cells found in the mice changed once they were removed from the in vivo environment. They began to proliferate and became sensitive to ex vivo treatment with chemotherapy drugs.

“[T]hese cells, once they have been dissolved out of their surroundings, are indeed susceptible to therapy and react well to therapeutics,” said study author Erbey Özdemir, a doctoral candidate at Helmholtz Zentrum München.

The researchers therefore believe that therapeutic strategies aimed at dissociating dormant leukemia cells from their protective niche might prevent relapse in ALL patients.

“This has brought us a small step closer to the global goal of preventing disease relapse in patients suffering from leukemia,” Dr Jeremias said. “It might serve as basis for new therapies that destroy resistant leukemia cells before they induce relapse.”

ALL cells
Image by Vashi Donsk

Researchers say they have characterized a subpopulation of leukemia cells that are responsible for relapse in acute lymphoblastic leukemia (ALL).

The team identified these dormant, therapy-resistant cells in mouse models of ALL and found that removing the cells from their environment makes them sensitive to treatment.

The researchers believe these findings could pave the way to better relapse prevention in patients with ALL.

“Previously, the biological principles responsible for a relapse in leukemia were not fully understood,” said study author Irmela Jeremias, MD, PhD, of Helmholtz Zentrum München in Munich, Germany.

“Our new approach is to isolate dormant cells, which gives us the first possibility of developing therapies that switch off these cells.”

Dr Jeremias and colleagues described this approach in Cancer Cell.

First, the researchers created mouse models recapitulating minimal residual disease (MRD) and relapse in ALL patients.

The team then used genetic engineering and proliferation-sensitive dyes to isolate and characterize relapse-inducing cells.

This revealed a subpopulation of leukemia cells that exhibited long-term dormancy, treatment resistance, and stemness. These cells were similar to primary ALL cells isolated from pediatric and adult patients with MRD.

However, the dormant leukemia cells found in the mice changed once they were removed from the in vivo environment. They began to proliferate and became sensitive to ex vivo treatment with chemotherapy drugs.

“[T]hese cells, once they have been dissolved out of their surroundings, are indeed susceptible to therapy and react well to therapeutics,” said study author Erbey Özdemir, a doctoral candidate at Helmholtz Zentrum München.

The researchers therefore believe that therapeutic strategies aimed at dissociating dormant leukemia cells from their protective niche might prevent relapse in ALL patients.

“This has brought us a small step closer to the global goal of preventing disease relapse in patients suffering from leukemia,” Dr Jeremias said. “It might serve as basis for new therapies that destroy resistant leukemia cells before they induce relapse.”

Drug release in a cancer cell

Image courtesy of PNAS

A diabetes medication and an antihypertensive drug may prove effective in the treatment of hematologic malignancies and other cancers, according to preclinical research published in Science Advances.

Past research has shown that metformin, a drug used to treat type 2 diabetes, has anticancer properties.

However, the usual therapeutic dose is too low to effectively fight cancer, and higher doses of metformin could be too toxic.

With the current study, researchers found that the antihypertensive drug syrosingopine enhances the anticancer efficacy of metformin without harming normal blood cells.

The team screened over a thousand drugs to find one that could boost metformin’s efficacy against cancers.

They identified syrosingopine and tested it in combination with metformin—at concentrations substantially below the drugs’ therapeutic thresholds—on a range of cancer cell lines and in mouse models of liver cancer.

Thirty-five of the 43 cell lines tested were susceptible to both syrosingopine and metformin. This included leukemia, lymphoma, and multiple myeloma cell lines.

In addition, the mice given a short course of syrosingopine and metformin experienced a reduction in the number of visible liver tumors.

The researchers also tested syrosingopine and metformin in peripheral blasts from 12 patients with acute myeloid leukemia and a patient with blast crisis chronic myeloid leukemia. All 13 samples responded to the treatment.

On the other hand, syrosingopine and metformin did not affect peripheral blood cells from healthy subjects.

“[A]lmost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells,” said study author Don Benjamin, of the University of Basel in Switzerland.

“And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment.”

The researchers believe metformin functions by lowering blood glucose levels for cancer cells, starving them of essential nutrients needed for their survival. However, it is not clear how syrosingopine works in conjunction with metformin.

The team emphasized the need for more research evaluating the drugs in combination.

“We have been able to show that the 2 known drugs lead to more profound effects on cancer cell proliferation than each drug alone,” Dr Benjamin said. “The data from this study support the development of combination approaches for the treatment of cancer patients.”

Drug release in a cancer cell

Image courtesy of PNAS

A diabetes medication and an antihypertensive drug may prove effective in the treatment of hematologic malignancies and other cancers, according to preclinical research published in Science Advances.

Past research has shown that metformin, a drug used to treat type 2 diabetes, has anticancer properties.

However, the usual therapeutic dose is too low to effectively fight cancer, and higher doses of metformin could be too toxic.

With the current study, researchers found that the antihypertensive drug syrosingopine enhances the anticancer efficacy of metformin without harming normal blood cells.

The team screened over a thousand drugs to find one that could boost metformin’s efficacy against cancers.

They identified syrosingopine and tested it in combination with metformin—at concentrations substantially below the drugs’ therapeutic thresholds—on a range of cancer cell lines and in mouse models of liver cancer.

Thirty-five of the 43 cell lines tested were susceptible to both syrosingopine and metformin. This included leukemia, lymphoma, and multiple myeloma cell lines.

In addition, the mice given a short course of syrosingopine and metformin experienced a reduction in the number of visible liver tumors.

The researchers also tested syrosingopine and metformin in peripheral blasts from 12 patients with acute myeloid leukemia and a patient with blast crisis chronic myeloid leukemia. All 13 samples responded to the treatment.

On the other hand, syrosingopine and metformin did not affect peripheral blood cells from healthy subjects.

“[A]lmost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells,” said study author Don Benjamin, of the University of Basel in Switzerland.

“And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment.”

The researchers believe metformin functions by lowering blood glucose levels for cancer cells, starving them of essential nutrients needed for their survival. However, it is not clear how syrosingopine works in conjunction with metformin.

The team emphasized the need for more research evaluating the drugs in combination.

“We have been able to show that the 2 known drugs lead to more profound effects on cancer cell proliferation than each drug alone,” Dr Benjamin said. “The data from this study support the development of combination approaches for the treatment of cancer patients.”

Drug release in a cancer cell

Image courtesy of PNAS

A diabetes medication and an antihypertensive drug may prove effective in the treatment of hematologic malignancies and other cancers, according to preclinical research published in Science Advances.

Past research has shown that metformin, a drug used to treat type 2 diabetes, has anticancer properties.

However, the usual therapeutic dose is too low to effectively fight cancer, and higher doses of metformin could be too toxic.

With the current study, researchers found that the antihypertensive drug syrosingopine enhances the anticancer efficacy of metformin without harming normal blood cells.

The team screened over a thousand drugs to find one that could boost metformin’s efficacy against cancers.

They identified syrosingopine and tested it in combination with metformin—at concentrations substantially below the drugs’ therapeutic thresholds—on a range of cancer cell lines and in mouse models of liver cancer.

Thirty-five of the 43 cell lines tested were susceptible to both syrosingopine and metformin. This included leukemia, lymphoma, and multiple myeloma cell lines.

In addition, the mice given a short course of syrosingopine and metformin experienced a reduction in the number of visible liver tumors.

The researchers also tested syrosingopine and metformin in peripheral blasts from 12 patients with acute myeloid leukemia and a patient with blast crisis chronic myeloid leukemia. All 13 samples responded to the treatment.

On the other hand, syrosingopine and metformin did not affect peripheral blood cells from healthy subjects.

“[A]lmost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells,” said study author Don Benjamin, of the University of Basel in Switzerland.

“And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment.”

The researchers believe metformin functions by lowering blood glucose levels for cancer cells, starving them of essential nutrients needed for their survival. However, it is not clear how syrosingopine works in conjunction with metformin.

The team emphasized the need for more research evaluating the drugs in combination.

“We have been able to show that the 2 known drugs lead to more profound effects on cancer cell proliferation than each drug alone,” Dr Benjamin said. “The data from this study support the development of combination approaches for the treatment of cancer patients.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Gedeon Richter Plc. has withdrawn its marketing authorization application (MAA) for the biosimilar pegfilgrastim product Cavoley from the European Medicines Agency (EMA).

Richter was seeking approval of Cavoley for the same indications as the reference product, Neulasta, a pegylated recombinant granulocyte-colony stimulating factor used to reduce the duration of neutropenia and the occurrence of febrile neutropenia in adults receiving cytotoxic chemotherapy to treat malignancies (except chronic myeloid leukemia and myelodysplastic syndromes).

The MAA filing for Cavoley was based on data from Richter’s completed biosimilar development program.

The company presented to the EMA results of studies in healthy volunteers designed to show that Cavoley is highly similar to Neulasta in terms of chemical structure, purity, the way it works, and how the body handles the drug.

Richter also presented results of a study comparing the safety and effectiveness of Cavoley and Neulasta in breast cancer patients receiving cytotoxic chemotherapy (EudraCT 2013-003166-14).

Richter withdrew the MAA for Cavoley after the EMA’s Committee for Medicinal Products for Human Use (CHMP) evaluated the documentation provided by the company and formulated lists of questions.

After the CHMP had assessed the company’s responses to the last round of questions, there were still some unresolved issues.

Based on the review of the data and Richter’s response to the CHMP’s list of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Cavoley could not have been approved.

The CHMP said the company had not demonstrated that Cavoley is highly similar to Neulasta.

In its letter notifying the EMA of the MAA withdrawal, Richter said it would continue developing Cavoley and follow the CHMP’s advice to eliminate the remaining uncertainty that Cavoley is highly similar to Neulasta.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Gedeon Richter Plc. has withdrawn its marketing authorization application (MAA) for the biosimilar pegfilgrastim product Cavoley from the European Medicines Agency (EMA).

Richter was seeking approval of Cavoley for the same indications as the reference product, Neulasta, a pegylated recombinant granulocyte-colony stimulating factor used to reduce the duration of neutropenia and the occurrence of febrile neutropenia in adults receiving cytotoxic chemotherapy to treat malignancies (except chronic myeloid leukemia and myelodysplastic syndromes).

The MAA filing for Cavoley was based on data from Richter’s completed biosimilar development program.

The company presented to the EMA results of studies in healthy volunteers designed to show that Cavoley is highly similar to Neulasta in terms of chemical structure, purity, the way it works, and how the body handles the drug.

Richter also presented results of a study comparing the safety and effectiveness of Cavoley and Neulasta in breast cancer patients receiving cytotoxic chemotherapy (EudraCT 2013-003166-14).

Richter withdrew the MAA for Cavoley after the EMA’s Committee for Medicinal Products for Human Use (CHMP) evaluated the documentation provided by the company and formulated lists of questions.

After the CHMP had assessed the company’s responses to the last round of questions, there were still some unresolved issues.

Based on the review of the data and Richter’s response to the CHMP’s list of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Cavoley could not have been approved.

The CHMP said the company had not demonstrated that Cavoley is highly similar to Neulasta.

In its letter notifying the EMA of the MAA withdrawal, Richter said it would continue developing Cavoley and follow the CHMP’s advice to eliminate the remaining uncertainty that Cavoley is highly similar to Neulasta.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

Gedeon Richter Plc. has withdrawn its marketing authorization application (MAA) for the biosimilar pegfilgrastim product Cavoley from the European Medicines Agency (EMA).

Richter was seeking approval of Cavoley for the same indications as the reference product, Neulasta, a pegylated recombinant granulocyte-colony stimulating factor used to reduce the duration of neutropenia and the occurrence of febrile neutropenia in adults receiving cytotoxic chemotherapy to treat malignancies (except chronic myeloid leukemia and myelodysplastic syndromes).

The MAA filing for Cavoley was based on data from Richter’s completed biosimilar development program.

The company presented to the EMA results of studies in healthy volunteers designed to show that Cavoley is highly similar to Neulasta in terms of chemical structure, purity, the way it works, and how the body handles the drug.

Richter also presented results of a study comparing the safety and effectiveness of Cavoley and Neulasta in breast cancer patients receiving cytotoxic chemotherapy (EudraCT 2013-003166-14).

Richter withdrew the MAA for Cavoley after the EMA’s Committee for Medicinal Products for Human Use (CHMP) evaluated the documentation provided by the company and formulated lists of questions.

After the CHMP had assessed the company’s responses to the last round of questions, there were still some unresolved issues.

Based on the review of the data and Richter’s response to the CHMP’s list of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Cavoley could not have been approved.

The CHMP said the company had not demonstrated that Cavoley is highly similar to Neulasta.

In its letter notifying the EMA of the MAA withdrawal, Richter said it would continue developing Cavoley and follow the CHMP’s advice to eliminate the remaining uncertainty that Cavoley is highly similar to Neulasta.

Micrograph showing AML

The US Food and Drug Administration (FDA) has placed holds on 3 early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML).

A phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant patients has been placed on full clinical hold.

This means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.

Two phase 1 trials of vadastuximab talirine have been placed on partial clinical hold. This means no new subjects can be enrolled, but existing patients may continue treatment with re-consent.

In one of the trials on partial hold, researchers are investigating vadastuximab talirine alone and in combination with hypomethylating agents in AML patients who either relapsed after induction/consolidation or declined treatment with high-dose induction/consolidation.

In the other trial on partial hold, researchers are testing vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed AML patients. Results from this trial were presented at the 2016 ASH Annual Meeting.

All 3 clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment.

There have been 6 patients with hepatotoxicity, including several cases of veno-occlusive disease, with 4 fatal events.

Seattle Genetics, Inc., the company developing vadastuximab talirine, said it is working with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine to identify appropriate protocol amendments for patient safety and to enable continuation of these trials.

No new studies of vadastuximab talirine will be initiated until the clinical holds are lifted.

Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase 3 CASCADE trial in older AML patients and phase 1/2 trial in patients with myelodysplastic syndrome (MDS), are proceeding with enrollment.

Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings.

Vadastuximab talirine is an investigational antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).

PBD dimers are said to be significantly more potent than systemic chemotherapeutic drugs, and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its PBD agent upon internalization into CD33-expressing cells.

Micrograph showing AML

The US Food and Drug Administration (FDA) has placed holds on 3 early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML).

A phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant patients has been placed on full clinical hold.

This means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.

Two phase 1 trials of vadastuximab talirine have been placed on partial clinical hold. This means no new subjects can be enrolled, but existing patients may continue treatment with re-consent.

In one of the trials on partial hold, researchers are investigating vadastuximab talirine alone and in combination with hypomethylating agents in AML patients who either relapsed after induction/consolidation or declined treatment with high-dose induction/consolidation.

In the other trial on partial hold, researchers are testing vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed AML patients. Results from this trial were presented at the 2016 ASH Annual Meeting.

All 3 clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment.

There have been 6 patients with hepatotoxicity, including several cases of veno-occlusive disease, with 4 fatal events.

Seattle Genetics, Inc., the company developing vadastuximab talirine, said it is working with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine to identify appropriate protocol amendments for patient safety and to enable continuation of these trials.

No new studies of vadastuximab talirine will be initiated until the clinical holds are lifted.

Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase 3 CASCADE trial in older AML patients and phase 1/2 trial in patients with myelodysplastic syndrome (MDS), are proceeding with enrollment.

Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings.

Vadastuximab talirine is an investigational antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).

PBD dimers are said to be significantly more potent than systemic chemotherapeutic drugs, and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its PBD agent upon internalization into CD33-expressing cells.

Micrograph showing AML

The US Food and Drug Administration (FDA) has placed holds on 3 early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML).

A phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant patients has been placed on full clinical hold.

This means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.

Two phase 1 trials of vadastuximab talirine have been placed on partial clinical hold. This means no new subjects can be enrolled, but existing patients may continue treatment with re-consent.

In one of the trials on partial hold, researchers are investigating vadastuximab talirine alone and in combination with hypomethylating agents in AML patients who either relapsed after induction/consolidation or declined treatment with high-dose induction/consolidation.

In the other trial on partial hold, researchers are testing vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed AML patients. Results from this trial were presented at the 2016 ASH Annual Meeting.

All 3 clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment.

There have been 6 patients with hepatotoxicity, including several cases of veno-occlusive disease, with 4 fatal events.

Seattle Genetics, Inc., the company developing vadastuximab talirine, said it is working with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine to identify appropriate protocol amendments for patient safety and to enable continuation of these trials.

No new studies of vadastuximab talirine will be initiated until the clinical holds are lifted.

Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase 3 CASCADE trial in older AML patients and phase 1/2 trial in patients with myelodysplastic syndrome (MDS), are proceeding with enrollment.

Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings.

Vadastuximab talirine is an investigational antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).

PBD dimers are said to be significantly more potent than systemic chemotherapeutic drugs, and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its PBD agent upon internalization into CD33-expressing cells.

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

ALL patient

Photo by Bill Branson

SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).

Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.

The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.

Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).

Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.

At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.

The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).

Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.

The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.

Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.

All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.

Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.

Efficacy

The median follow-up was 18.7 months.

Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.

The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.

The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.

“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.

However, he noted superior response and overall survival rates among patients who received a   fludarabine/cyclophosphamide preparative regimen.

“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.

The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.

For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.

Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.

Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)

Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.

The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.

The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.

CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.

Toxicity

“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.

Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.

Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade

3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).

“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”

In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),

dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).

ALL patient

Photo by Bill Branson

SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).

Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.

The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.

Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).

Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.

At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.

The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).

Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.

The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.

Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.

All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.

Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.

Efficacy

The median follow-up was 18.7 months.

Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.

The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.

The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.

“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.

However, he noted superior response and overall survival rates among patients who received a   fludarabine/cyclophosphamide preparative regimen.

“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.

The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.

For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.

Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.

Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)

Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.

The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.

The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.

CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.

Toxicity

“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.

Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.

Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade

3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).

“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”

In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),

dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).

ALL patient

Photo by Bill Branson

SAN DIEGO—Trial results suggest treatment with the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 is feasible for most young patients with high-risk B-cell acute lymphoblastic leukemia (ALL).

Nearly all ALL patients in this trial were able to receive their assigned dose of KTE-C19 after a preparative chemotherapy regimen.

The complete response (CR) rate in these patients was 62%, and the rate of severe cytokine release syndrome (CRS) was low.

Daniel W. Lee III, MD, of the University of Virginia in Charlottesville, presented these results at the 2016 ASH Annual Meeting (abstract 218).

Dr Lee noted that CAR T cells have shown promise in early studies, but morbidity related to high-grade CRS and/or neurotoxicity could limit wide applicability of this treatment in patients with high disease burden. Among those who achieve CR to CD19 CAR T-cell therapy, nearly half of patients relapse in the first year.

At ASH, Dr Lee reported results of a non-randomized clinical trial of KTE-C19, a CD19 CAR T-cell therapy under development by Kite Pharmaceuticals. The company did not sponsor this study, although investigators reported relationships with Kite and other companies. The trial was sponsored by the National Cancer Institute.

The trial included 53 children and young adults with relapsed/refractory ALL (n=51) or diffuse large B-cell lymphoma (n=2). The patients’ median age was 13 (range, 4-30), and most were male (n=41).

Of the ALL patients, 11 had primary refractory disease, 5 had Ph-positive ALL, 3 had Down syndrome, 6 had central nervous system (CNS) disease (2 with CNS3, 4 with CNS2), and 2 had MLL-rearranged ALL. The median ALL disease burden was 27%.

The first 21 patients received a low-dose fludarabine/cyclophosphamide preparative regimen, and the subsequent 32 patients received an alternative intensified preparative regimen in an attempt to mitigate severe CRS risk and improve response.

Possible intensive preparative regimens included higher-dose fludarabine/cyclophosphamide, fludarabine/high-dose cytarabine/G-CSF, and ifosfamide/etoposide.

All 53 patients had peripheral blood cells collected, and 52 were infused with CAR T cells. One patient did not receive an infusion due to progressive fungal pneumonia, and 2 patients received less than their assigned dose.

Therefore, Dr Lee said KTE-C19 was feasible in 94% of patients.

Efficacy

The median follow-up was 18.7 months.

Dr Lee said KTE-C19 “produced robust responses in very high-risk ALL patients.” He noted, however, that the CR rate was lower among patients with high disease burden.

The CR rate among the ALL patients was 62%. Of the 31 patients who achieved a CR, 28 had a minimal residual disease (MRD)-negative remission.

The rate of MRD-negative CR was 100% among the 11 patients with primary refractory ALL, 100% among the 6 patients with CNS disease, 60% among the 5 patients with Ph+ ALL, and 67% among the 3 with Down syndrome. Neither of the 2 patients with MLL-rearranged ALL responded.

“Attempts to increase response rate by modifying the preparative regimen have not yet been successful,” Dr Lee pointed out.

However, he noted superior response and overall survival rates among patients who received a   fludarabine/cyclophosphamide preparative regimen.

“Median overall survival in all enrolled patients is 13.3 months with fludarabine/cyclophosphamide prep versus 5.5 months with other regimens,” he said.

The overall survival rate for the ALL patients was 28%, and the median overall survival was 11.2 months.

For patients who achieved an MRD-negative remission, the leukemia-free survival (LFS) rate was 56%. The median LFS was not reached.

Dr Lee noted that hematopoietic stem cell transplant (HSCT) after KTE-C19 correlated with decreased relapse rates and led to superior LFS.

Of the 28 patients who achieved MRD-negative CR, 21 went on to HSCT after KTE-C19. The median time to HSCT after CAR T-cell dose was 54 days. (Ten of the 28 patients had HSCT before receiving KTE-C19.)

Nineteen (91%) of the patients who proceeded to HSCT after KTE-C19 did not relapse, compared to 1 (14%) of the patients who did not have a post-CAR T transplant.

The median LFS was 4.9 months among the MRD responders who did not proceed to HSCT and undefined among MRD responders with a transplant after KTE-C19.

The probability of survival was 65% beginning at 18 months among patients who underwent HSCT and 14% beginning at 9.8 months among patients without a post-KTE-C19 transplant.

CD19 escape remains a challenge, Dr Lee said. The risk may be diminished, but not eradicated, with HSCT.

Toxicity

“There was a low rate of CRS, which was successfully managed with a grade-driven algorithm,” Dr Lee noted.

Five patients (10%) had grade 3 CRS, and 2 (4%) had grade 4 CRS.

Other grade 3/4 adverse events that were considered at least possibly related to therapy included fever (38% grade 3), febrile neutropenia (23% grade

3), hypotension (9% grade 3, 4% grade 4), LV systolic dysfunction (9% grade 3), prolonged QTc (2% grade 3), dysphasia (2% grade 3), cardiac arrest (2% grade 4), multi-organ failure (2% grade 3), hypoxia (2% grade 3, 2% grade 4), and pulmonary embolism (2% grade 3).

“There were no severe or permanent neurologic toxicities,” Dr Lee said. “Intensive neuropsychological testing in 13 patients revealed no consistent treatment-related neurocognitive decline, and several patients improved following therapy.”

In all, there were 46 cases of neurotoxicity, including visual hallucination (8 grade 1, 17%), headache (1 grade 3 [2%], 3 grade 2 [6%]), confusion (2 grade 1, 4%),

dysphasia (1 grade 3, 2%), delirium (1 grade 3, 2%), seizure (1 grade 2, 1 grade 1 [2% each]), ataxia (1 grade 2, 2%), tremor (1 grade 2, 2%), dysesthesia (1 grade 2, 2%), and dysarthria (1 grade 1, 2%).