ALL

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Adolescents and young adults (AYAs) are less likely than children to survive 8 relatively common types of cancer, according to a long-running study of cancer survival across Europe.

The study showed that AYAs had significantly worse survival rates than children if they were diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin or non-Hodgkin lymphoma (NHL), and 4 types of solid tumor malignancies.

The study’s authors say that variations in survival between age groups are due to a number of factors, including delays in diagnosis and treatment, a lack of treatment guidelines and clinical trials specifically for AYAs, and differences in the biology of some cancers.

“The good news is that the number of children, adolescents, and young adults surviving for at least 5 years after diagnosis has risen steadily over time in Europe,” said author Annalisa Trama, PhD, of The National Institute of Cancer (Istituto Nazionale dei Tumori: Fondazione IRCCS) in Milan, Italy.

“Across all cancers, the level of improvement is similar in these age groups. This contrasts with earlier results that adolescents and young adults diagnosed up to the 1990s were lagging behind children in terms of survival.”

“However, we found that adolescents and young adults still tend to die earlier than children for several cancers common to these age groups, particularly blood cancers like leukemias and non-Hodgkin’s lymphoma.”

Dr Trama and her colleagues reported these findings in The Lancet Oncology.

The researchers compared survival between AYAs (ages 15 to 39), children (ages 0 to 14), and adults (ages 40 to 69) who were diagnosed from 2000 to 2007 and followed up to at least 2008.

The team analyzed data from population-based cancer registries covering all or part of 27 European countries* and estimated 5-year survival for 56,505 cancer cases in children; 312,483 in AYAs; and 3,567,383 in adults. The researchers also analyzed changes in survival over time from 1999 to 2007.

For AYAs, survival at 5 years from diagnosis for all cancers combined was 82% for 2005-2007, which is up from 79% for 1999-2001 (P<0.0001). In children, survival improved from 76% to 79% over the same time period (P<0.0001).

Survival improved significantly in children and AYAs for ALL (P<0.0001) and NHL (P<0.0001 in AYAs and P=0.023 in children). On the other hand, between 1999 and 2007, survival rates remained unchanged for AYAs with AML (around 50%).

Overall, AYAs had slightly better 5-year survival than children because they were diagnosed more often with cancers with fairly good prognoses—Hodgkin lymphoma, NHL, germ cell tumors, melanoma, thyroid cancer, and breast cancer.

However, the overall survival rates conceal differences between specific cancers. Survival was significantly worse for AYAs than for children when it came to 8 relatively common cancers affecting both age groups:

• ALL—55.6% for AYAs and 85.8% for children (P<0.0001)
• AML—49.8% and 60.5%, respectively (P<0.0001)
• Hodgkin lymphoma—92.9% and 95.1%, respectively (P<0.0001)
• NHL—77.4% and 83.0%, respectively (P<0.0001)
• Astrocytomas—46.4% and 61.9%, respectively (P<0.0001)
• Ewing’s sarcoma of bone—49.3% and 66.6%, respectively (P<0.0001)
• Rhabdomyosarcoma—37.8% and 66.6%, respectively (P<0.0001)
• Osteosarcoma—61.5% and 66.8%, respectively (P=0.011).

AYAs had a survival advantage over adults for almost all major cancers affecting both age groups, supporting the idea that younger patients with few other illnesses are likely to fare better than older patients.

There are only 2 types of cancer for which AYAs were at a survival disadvantage—breast (83.5% vs 87.0%) and prostate (79.9% vs 89.8%).

Dr Trama and her colleagues pointed out that this analysis pre-dates recent initiatives to improve outcomes for AYAs that have been implemented in several European countries.

“The European Network for Teenagers and Young Adults with Cancer is advocating collaboration between pediatric and adult oncologists, greater access to clinical trials and research to improve treatments for this specific age group, as well as developing adolescent and young adult-specific practice guidelines, encouraging healthier lifestyles and the greater involvement of patients and patients support groups,” Dr Trama said.

“This study will provide an important starting point from which to evaluate whether these initiatives will reduce the gulf in survival between European adolescents and young adults and children with cancer.”

*Finland, Iceland, Norway, Sweden, England, Ireland, Northern Ireland, Scotland, Wales, Austria, Belgium, France, Germany, Netherlands, Switzerland, Croatia, Italy, Malta, Portugal, Slovenia, Spain, Bulgaria, Estonia, Latvia, Lithuania, Poland, and Slovakia

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Adolescents and young adults (AYAs) are less likely than children to survive 8 relatively common types of cancer, according to a long-running study of cancer survival across Europe.

The study showed that AYAs had significantly worse survival rates than children if they were diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin or non-Hodgkin lymphoma (NHL), and 4 types of solid tumor malignancies.

The study’s authors say that variations in survival between age groups are due to a number of factors, including delays in diagnosis and treatment, a lack of treatment guidelines and clinical trials specifically for AYAs, and differences in the biology of some cancers.

“The good news is that the number of children, adolescents, and young adults surviving for at least 5 years after diagnosis has risen steadily over time in Europe,” said author Annalisa Trama, PhD, of The National Institute of Cancer (Istituto Nazionale dei Tumori: Fondazione IRCCS) in Milan, Italy.

“Across all cancers, the level of improvement is similar in these age groups. This contrasts with earlier results that adolescents and young adults diagnosed up to the 1990s were lagging behind children in terms of survival.”

“However, we found that adolescents and young adults still tend to die earlier than children for several cancers common to these age groups, particularly blood cancers like leukemias and non-Hodgkin’s lymphoma.”

Dr Trama and her colleagues reported these findings in The Lancet Oncology.

The researchers compared survival between AYAs (ages 15 to 39), children (ages 0 to 14), and adults (ages 40 to 69) who were diagnosed from 2000 to 2007 and followed up to at least 2008.

The team analyzed data from population-based cancer registries covering all or part of 27 European countries* and estimated 5-year survival for 56,505 cancer cases in children; 312,483 in AYAs; and 3,567,383 in adults. The researchers also analyzed changes in survival over time from 1999 to 2007.

For AYAs, survival at 5 years from diagnosis for all cancers combined was 82% for 2005-2007, which is up from 79% for 1999-2001 (P<0.0001). In children, survival improved from 76% to 79% over the same time period (P<0.0001).

Survival improved significantly in children and AYAs for ALL (P<0.0001) and NHL (P<0.0001 in AYAs and P=0.023 in children). On the other hand, between 1999 and 2007, survival rates remained unchanged for AYAs with AML (around 50%).

Overall, AYAs had slightly better 5-year survival than children because they were diagnosed more often with cancers with fairly good prognoses—Hodgkin lymphoma, NHL, germ cell tumors, melanoma, thyroid cancer, and breast cancer.

However, the overall survival rates conceal differences between specific cancers. Survival was significantly worse for AYAs than for children when it came to 8 relatively common cancers affecting both age groups:

• ALL—55.6% for AYAs and 85.8% for children (P<0.0001)
• AML—49.8% and 60.5%, respectively (P<0.0001)
• Hodgkin lymphoma—92.9% and 95.1%, respectively (P<0.0001)
• NHL—77.4% and 83.0%, respectively (P<0.0001)
• Astrocytomas—46.4% and 61.9%, respectively (P<0.0001)
• Ewing’s sarcoma of bone—49.3% and 66.6%, respectively (P<0.0001)
• Rhabdomyosarcoma—37.8% and 66.6%, respectively (P<0.0001)
• Osteosarcoma—61.5% and 66.8%, respectively (P=0.011).

AYAs had a survival advantage over adults for almost all major cancers affecting both age groups, supporting the idea that younger patients with few other illnesses are likely to fare better than older patients.

There are only 2 types of cancer for which AYAs were at a survival disadvantage—breast (83.5% vs 87.0%) and prostate (79.9% vs 89.8%).

Dr Trama and her colleagues pointed out that this analysis pre-dates recent initiatives to improve outcomes for AYAs that have been implemented in several European countries.

“The European Network for Teenagers and Young Adults with Cancer is advocating collaboration between pediatric and adult oncologists, greater access to clinical trials and research to improve treatments for this specific age group, as well as developing adolescent and young adult-specific practice guidelines, encouraging healthier lifestyles and the greater involvement of patients and patients support groups,” Dr Trama said.

“This study will provide an important starting point from which to evaluate whether these initiatives will reduce the gulf in survival between European adolescents and young adults and children with cancer.”

*Finland, Iceland, Norway, Sweden, England, Ireland, Northern Ireland, Scotland, Wales, Austria, Belgium, France, Germany, Netherlands, Switzerland, Croatia, Italy, Malta, Portugal, Slovenia, Spain, Bulgaria, Estonia, Latvia, Lithuania, Poland, and Slovakia

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Adolescents and young adults (AYAs) are less likely than children to survive 8 relatively common types of cancer, according to a long-running study of cancer survival across Europe.

The study showed that AYAs had significantly worse survival rates than children if they were diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin or non-Hodgkin lymphoma (NHL), and 4 types of solid tumor malignancies.

The study’s authors say that variations in survival between age groups are due to a number of factors, including delays in diagnosis and treatment, a lack of treatment guidelines and clinical trials specifically for AYAs, and differences in the biology of some cancers.

“The good news is that the number of children, adolescents, and young adults surviving for at least 5 years after diagnosis has risen steadily over time in Europe,” said author Annalisa Trama, PhD, of The National Institute of Cancer (Istituto Nazionale dei Tumori: Fondazione IRCCS) in Milan, Italy.

“Across all cancers, the level of improvement is similar in these age groups. This contrasts with earlier results that adolescents and young adults diagnosed up to the 1990s were lagging behind children in terms of survival.”

“However, we found that adolescents and young adults still tend to die earlier than children for several cancers common to these age groups, particularly blood cancers like leukemias and non-Hodgkin’s lymphoma.”

Dr Trama and her colleagues reported these findings in The Lancet Oncology.

The researchers compared survival between AYAs (ages 15 to 39), children (ages 0 to 14), and adults (ages 40 to 69) who were diagnosed from 2000 to 2007 and followed up to at least 2008.

The team analyzed data from population-based cancer registries covering all or part of 27 European countries* and estimated 5-year survival for 56,505 cancer cases in children; 312,483 in AYAs; and 3,567,383 in adults. The researchers also analyzed changes in survival over time from 1999 to 2007.

For AYAs, survival at 5 years from diagnosis for all cancers combined was 82% for 2005-2007, which is up from 79% for 1999-2001 (P<0.0001). In children, survival improved from 76% to 79% over the same time period (P<0.0001).

Survival improved significantly in children and AYAs for ALL (P<0.0001) and NHL (P<0.0001 in AYAs and P=0.023 in children). On the other hand, between 1999 and 2007, survival rates remained unchanged for AYAs with AML (around 50%).

Overall, AYAs had slightly better 5-year survival than children because they were diagnosed more often with cancers with fairly good prognoses—Hodgkin lymphoma, NHL, germ cell tumors, melanoma, thyroid cancer, and breast cancer.

However, the overall survival rates conceal differences between specific cancers. Survival was significantly worse for AYAs than for children when it came to 8 relatively common cancers affecting both age groups:

• ALL—55.6% for AYAs and 85.8% for children (P<0.0001)
• AML—49.8% and 60.5%, respectively (P<0.0001)
• Hodgkin lymphoma—92.9% and 95.1%, respectively (P<0.0001)
• NHL—77.4% and 83.0%, respectively (P<0.0001)
• Astrocytomas—46.4% and 61.9%, respectively (P<0.0001)
• Ewing’s sarcoma of bone—49.3% and 66.6%, respectively (P<0.0001)
• Rhabdomyosarcoma—37.8% and 66.6%, respectively (P<0.0001)
• Osteosarcoma—61.5% and 66.8%, respectively (P=0.011).

AYAs had a survival advantage over adults for almost all major cancers affecting both age groups, supporting the idea that younger patients with few other illnesses are likely to fare better than older patients.

There are only 2 types of cancer for which AYAs were at a survival disadvantage—breast (83.5% vs 87.0%) and prostate (79.9% vs 89.8%).

Dr Trama and her colleagues pointed out that this analysis pre-dates recent initiatives to improve outcomes for AYAs that have been implemented in several European countries.

“The European Network for Teenagers and Young Adults with Cancer is advocating collaboration between pediatric and adult oncologists, greater access to clinical trials and research to improve treatments for this specific age group, as well as developing adolescent and young adult-specific practice guidelines, encouraging healthier lifestyles and the greater involvement of patients and patients support groups,” Dr Trama said.

“This study will provide an important starting point from which to evaluate whether these initiatives will reduce the gulf in survival between European adolescents and young adults and children with cancer.”

*Finland, Iceland, Norway, Sweden, England, Ireland, Northern Ireland, Scotland, Wales, Austria, Belgium, France, Germany, Netherlands, Switzerland, Croatia, Italy, Malta, Portugal, Slovenia, Spain, Bulgaria, Estonia, Latvia, Lithuania, Poland, and Slovakia

Materials to support the families of children with serious illnesses have been developed by the National Institute of Nursing Research, which is part of the National Institutes of Health. The materials are associated with the NINR’s “Palliative Care: Conversations Matter” campaign.

“Palliative care is often associated with end of life, making it difficult for patients and their families – and even for healthcare providers – to start conversations around the subject. However, palliative care can be incredibly helpful for patients and their families at any stage during an illness. We hope these materials will improve patient and family understanding of pediatric palliative care and facilitate discussion with healthcare teams,” NINR Director Patricia A. Grady said in a written statement.

The resources, which include a fact sheet, a resource card to help families find support, and a series of family stories, are available in both Spanish and English. The NINR developed these materials with feedback from parents of seriously ill children. To learn more, click here

acruz@frontlinemedcom.com

Materials to support the families of children with serious illnesses have been developed by the National Institute of Nursing Research, which is part of the National Institutes of Health. The materials are associated with the NINR’s “Palliative Care: Conversations Matter” campaign.

“Palliative care is often associated with end of life, making it difficult for patients and their families – and even for healthcare providers – to start conversations around the subject. However, palliative care can be incredibly helpful for patients and their families at any stage during an illness. We hope these materials will improve patient and family understanding of pediatric palliative care and facilitate discussion with healthcare teams,” NINR Director Patricia A. Grady said in a written statement.

The resources, which include a fact sheet, a resource card to help families find support, and a series of family stories, are available in both Spanish and English. The NINR developed these materials with feedback from parents of seriously ill children. To learn more, click here

acruz@frontlinemedcom.com

Materials to support the families of children with serious illnesses have been developed by the National Institute of Nursing Research, which is part of the National Institutes of Health. The materials are associated with the NINR’s “Palliative Care: Conversations Matter” campaign.

“Palliative care is often associated with end of life, making it difficult for patients and their families – and even for healthcare providers – to start conversations around the subject. However, palliative care can be incredibly helpful for patients and their families at any stage during an illness. We hope these materials will improve patient and family understanding of pediatric palliative care and facilitate discussion with healthcare teams,” NINR Director Patricia A. Grady said in a written statement.

The resources, which include a fact sheet, a resource card to help families find support, and a series of family stories, are available in both Spanish and English. The NINR developed these materials with feedback from parents of seriously ill children. To learn more, click here

acruz@frontlinemedcom.com

ALL patient

Photo by Bill Branson

New research indicates that survivors of pediatric acute lymphoblastic leukemia (ALL) suffer from brain injury even if they have no history of central nervous system disease or cranial radiation.

The study suggests the neurotoxic effects of chemotherapeutic drugs on the developing brains of young ALL patients may impair their cognitive functioning by disrupting the formation of neural networks that connect brain regions and transfer information.

Shelli Kesler, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these findings in Brain Connectivity.

The researchers used diffusion tensor imaging to analyze and compare the gray matter connectome of 31 pediatric ALL survivors and 39 matched control subjects.

The team found significantly greater cognitive impairment among the ALL survivors (P=0.027), as well as significantly lower connectivity, based on small-worldness (P=0.007) and network clustering coefficient (P=0.019).

The researchers noted that clustered connectivity was altered in the parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions in the ALL survivors.

The team also described a model that can be used to predict cognitive impairment in ALL survivors. The model’s classification accuracy was 89.39% (P<0.0001), its sensitivity was 95.83%, and specificity was 85.71%.

“As survival rates for cancer patients increase, issues related to survivorship, such as chemotherapy-induced cognitive impairment, become more important to the cancer research community,” said Christopher Pawela, PhD, co-editor-in-chief of Brain Connectivity and an assistant professor at the Medical College of Wisconsin in Milwaukee.

“Dr Kesler and colleagues are developing new MRI-based biomarkers to measure brain changes associated with the neurotoxic effects of chemotherapy in the brain. These biomarkers may find utility in providing insight into the mechanisms of brain damage caused by chemotherapeutic drugs and could be used to develop neuroprotective therapies to mitigate the harmful effects of these drugs on the brain.”

ALL patient

Photo by Bill Branson

New research indicates that survivors of pediatric acute lymphoblastic leukemia (ALL) suffer from brain injury even if they have no history of central nervous system disease or cranial radiation.

The study suggests the neurotoxic effects of chemotherapeutic drugs on the developing brains of young ALL patients may impair their cognitive functioning by disrupting the formation of neural networks that connect brain regions and transfer information.

Shelli Kesler, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these findings in Brain Connectivity.

The researchers used diffusion tensor imaging to analyze and compare the gray matter connectome of 31 pediatric ALL survivors and 39 matched control subjects.

The team found significantly greater cognitive impairment among the ALL survivors (P=0.027), as well as significantly lower connectivity, based on small-worldness (P=0.007) and network clustering coefficient (P=0.019).

The researchers noted that clustered connectivity was altered in the parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions in the ALL survivors.

The team also described a model that can be used to predict cognitive impairment in ALL survivors. The model’s classification accuracy was 89.39% (P<0.0001), its sensitivity was 95.83%, and specificity was 85.71%.

“As survival rates for cancer patients increase, issues related to survivorship, such as chemotherapy-induced cognitive impairment, become more important to the cancer research community,” said Christopher Pawela, PhD, co-editor-in-chief of Brain Connectivity and an assistant professor at the Medical College of Wisconsin in Milwaukee.

“Dr Kesler and colleagues are developing new MRI-based biomarkers to measure brain changes associated with the neurotoxic effects of chemotherapy in the brain. These biomarkers may find utility in providing insight into the mechanisms of brain damage caused by chemotherapeutic drugs and could be used to develop neuroprotective therapies to mitigate the harmful effects of these drugs on the brain.”

ALL patient

Photo by Bill Branson

New research indicates that survivors of pediatric acute lymphoblastic leukemia (ALL) suffer from brain injury even if they have no history of central nervous system disease or cranial radiation.

The study suggests the neurotoxic effects of chemotherapeutic drugs on the developing brains of young ALL patients may impair their cognitive functioning by disrupting the formation of neural networks that connect brain regions and transfer information.

Shelli Kesler, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these findings in Brain Connectivity.

The researchers used diffusion tensor imaging to analyze and compare the gray matter connectome of 31 pediatric ALL survivors and 39 matched control subjects.

The team found significantly greater cognitive impairment among the ALL survivors (P=0.027), as well as significantly lower connectivity, based on small-worldness (P=0.007) and network clustering coefficient (P=0.019).

The researchers noted that clustered connectivity was altered in the parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions in the ALL survivors.

The team also described a model that can be used to predict cognitive impairment in ALL survivors. The model’s classification accuracy was 89.39% (P<0.0001), its sensitivity was 95.83%, and specificity was 85.71%.

“As survival rates for cancer patients increase, issues related to survivorship, such as chemotherapy-induced cognitive impairment, become more important to the cancer research community,” said Christopher Pawela, PhD, co-editor-in-chief of Brain Connectivity and an assistant professor at the Medical College of Wisconsin in Milwaukee.

“Dr Kesler and colleagues are developing new MRI-based biomarkers to measure brain changes associated with the neurotoxic effects of chemotherapy in the brain. These biomarkers may find utility in providing insight into the mechanisms of brain damage caused by chemotherapeutic drugs and could be used to develop neuroprotective therapies to mitigate the harmful effects of these drugs on the brain.”

Micrograph showing ALL

Patients with high-risk, relapsed/refractory acute lymphoblastic leukemia (ALL) may be sensitive to treatment with SMAC mimetics, according to researchers.

One SMAC mimetic in particular, birinapant, demonstrated varied activity in samples from ALL patients, but samples from patients with resistant disease were the most sensitive to the drug.

Birinapant also had “marked antileukemic effects” in some mice with ALL.

The researchers found this antileukemic activity was dependent on simultaneous activation of apoptosis and necroptosis.

The team reported these findings in Science Translational Medicine.

“Our research reveals that an alternative cell-death program, necroptosis, can be activated in human ALL cells,” said study author Beat Bornhauser, PhD, of the Children’s Hospital Zurich in Switzerland.

“This enables leukemia cells that barely respond to existing chemotherapeutic drugs to be killed off.”

In vitro and in vivo activity

The researchers tested the efficacy of SMAC mimetics in a set of 51 patient-derived B-cell precursor ALL xenografts, which was enriched for samples from relapsed and drug-resistant disease.

The response to birinapant varied greatly, but samples from high-risk or relapsed patients tended to be highly sensitive to the drug.

The researchers observed similar response profiles with the SMAC mimetic LCL161, although this drug proved less potent than birinapant.

The team also evaluated the antileukemic activity of SMAC mimetics in mouse models of ALL.

Birinapant delayed disease progression and induced complete responses in sensitive ALL cases. LCL161, on the other hand, did not display any in vivo activity.

Determining the mechanism of activity

The researchers used CRISPR-Cas9 to determine how SMAC mimetics fight ALL, and they discovered that the drugs trigger both apoptosis and necroptosis.

If the genes responsible for apoptosis were disabled via genome editing, leukemia cells died due to necroptosis after SMAC mimetics had been administered. If necroptotic genes were disabled, apoptosis led to cell death.

Only the simultaneous deactivation of apoptotic and necroptotic genes resulted in the complete resistance of leukemic cells to SMAC mimetics.

Therefore, the researchers concluded that simultaneous activation of apoptosis and necroptosis is responsible for the strong anti-leukemic effect of SMAC mimetics.

“SMAC mimetics have great potential to eliminate leukemia cells in patients that aren’t sensitive to established chemotherapeutic drugs,” Dr Bornhauser said. “They are effectively a double-edged sword. They kill cells that block apoptosis through necroptosis.”

The researchers are now looking for suitable biomarkers to identify patients who might benefit from treatment with SMAC mimetics in clinical trials.

Micrograph showing ALL

Patients with high-risk, relapsed/refractory acute lymphoblastic leukemia (ALL) may be sensitive to treatment with SMAC mimetics, according to researchers.

One SMAC mimetic in particular, birinapant, demonstrated varied activity in samples from ALL patients, but samples from patients with resistant disease were the most sensitive to the drug.

Birinapant also had “marked antileukemic effects” in some mice with ALL.

The researchers found this antileukemic activity was dependent on simultaneous activation of apoptosis and necroptosis.

The team reported these findings in Science Translational Medicine.

“Our research reveals that an alternative cell-death program, necroptosis, can be activated in human ALL cells,” said study author Beat Bornhauser, PhD, of the Children’s Hospital Zurich in Switzerland.

“This enables leukemia cells that barely respond to existing chemotherapeutic drugs to be killed off.”

In vitro and in vivo activity

The researchers tested the efficacy of SMAC mimetics in a set of 51 patient-derived B-cell precursor ALL xenografts, which was enriched for samples from relapsed and drug-resistant disease.

The response to birinapant varied greatly, but samples from high-risk or relapsed patients tended to be highly sensitive to the drug.

The researchers observed similar response profiles with the SMAC mimetic LCL161, although this drug proved less potent than birinapant.

The team also evaluated the antileukemic activity of SMAC mimetics in mouse models of ALL.

Birinapant delayed disease progression and induced complete responses in sensitive ALL cases. LCL161, on the other hand, did not display any in vivo activity.

Determining the mechanism of activity

The researchers used CRISPR-Cas9 to determine how SMAC mimetics fight ALL, and they discovered that the drugs trigger both apoptosis and necroptosis.

If the genes responsible for apoptosis were disabled via genome editing, leukemia cells died due to necroptosis after SMAC mimetics had been administered. If necroptotic genes were disabled, apoptosis led to cell death.

Only the simultaneous deactivation of apoptotic and necroptotic genes resulted in the complete resistance of leukemic cells to SMAC mimetics.

Therefore, the researchers concluded that simultaneous activation of apoptosis and necroptosis is responsible for the strong anti-leukemic effect of SMAC mimetics.

“SMAC mimetics have great potential to eliminate leukemia cells in patients that aren’t sensitive to established chemotherapeutic drugs,” Dr Bornhauser said. “They are effectively a double-edged sword. They kill cells that block apoptosis through necroptosis.”

The researchers are now looking for suitable biomarkers to identify patients who might benefit from treatment with SMAC mimetics in clinical trials.

Micrograph showing ALL

Patients with high-risk, relapsed/refractory acute lymphoblastic leukemia (ALL) may be sensitive to treatment with SMAC mimetics, according to researchers.

One SMAC mimetic in particular, birinapant, demonstrated varied activity in samples from ALL patients, but samples from patients with resistant disease were the most sensitive to the drug.

Birinapant also had “marked antileukemic effects” in some mice with ALL.

The researchers found this antileukemic activity was dependent on simultaneous activation of apoptosis and necroptosis.

The team reported these findings in Science Translational Medicine.

“Our research reveals that an alternative cell-death program, necroptosis, can be activated in human ALL cells,” said study author Beat Bornhauser, PhD, of the Children’s Hospital Zurich in Switzerland.

“This enables leukemia cells that barely respond to existing chemotherapeutic drugs to be killed off.”

In vitro and in vivo activity

The researchers tested the efficacy of SMAC mimetics in a set of 51 patient-derived B-cell precursor ALL xenografts, which was enriched for samples from relapsed and drug-resistant disease.

The response to birinapant varied greatly, but samples from high-risk or relapsed patients tended to be highly sensitive to the drug.

The researchers observed similar response profiles with the SMAC mimetic LCL161, although this drug proved less potent than birinapant.

The team also evaluated the antileukemic activity of SMAC mimetics in mouse models of ALL.

Birinapant delayed disease progression and induced complete responses in sensitive ALL cases. LCL161, on the other hand, did not display any in vivo activity.

Determining the mechanism of activity

The researchers used CRISPR-Cas9 to determine how SMAC mimetics fight ALL, and they discovered that the drugs trigger both apoptosis and necroptosis.

If the genes responsible for apoptosis were disabled via genome editing, leukemia cells died due to necroptosis after SMAC mimetics had been administered. If necroptotic genes were disabled, apoptosis led to cell death.

Only the simultaneous deactivation of apoptotic and necroptotic genes resulted in the complete resistance of leukemic cells to SMAC mimetics.

Therefore, the researchers concluded that simultaneous activation of apoptosis and necroptosis is responsible for the strong anti-leukemic effect of SMAC mimetics.

“SMAC mimetics have great potential to eliminate leukemia cells in patients that aren’t sensitive to established chemotherapeutic drugs,” Dr Bornhauser said. “They are effectively a double-edged sword. They kill cells that block apoptosis through necroptosis.”

The researchers are now looking for suitable biomarkers to identify patients who might benefit from treatment with SMAC mimetics in clinical trials.

Pediatric cancer patient

Photo by Bill Branson

Adding a physiologic dose of hydrocortisone to treatment with dexamethasone can reduce the severity of certain adverse effects (AEs) in pediatric patients with acute lymphoblastic leukemia (ALL), according to researchers.

Hydrocortisone did not decrease the incidence of psychosocial problems or sleep-related issues in these patients, but the drug did reduce the severity of these problems among patients who experienced them.

Lidewij T. Warris, MD, of Erasmus MC-Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues reported these results in the Journal of Clinical Oncology.

The team conducted this study to determine whether a physiologic dose of hydrocortisone could reduce neuropsychologic and metabolic AEs in children with ALL who were receiving dexamethasone.

The study enrolled 50 patients (ages 3 to 16) who were set to receive 2 consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols.

The patients were randomized to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m²/d) during their first dexamethasone course. During their second course, the patients were assigned to the opposite arm.

The treatment groups were similar with regard to age, type of leukemia, treatment protocol, and CNS status at diagnosis.

Psychosocial problems

The researchers assessed psychosocial problems by having parents complete the Strength and Difficulties Questionnaire (SDQ). Forty-six parents completed the questionnaire at all 4 time points tested.

The results showed that 4 days of dexamethasone treatment significantly increased patient problems, as reported by all SDQ scales and subscales. However, one-third of the population did not have any increase in SDQ total difficulties with dexamethasone.

The addition of hydrocortisone did not affect patients’ total difficulties score (mean difference, -0.8 ± 5.5; P=0.33), emotional symptoms (mean difference, -0.6 ± 2.3; P=0.08), conduct problems (mean difference, 0.0 ± 1.5; P=1.00), or other SDQ subscales.

However, hydrocortisone did have a clinically significant effect in the subset of 16 patients who had clinically relevant dexamethasone-related AEs. This was defined as an increase of ≥5 in their SDQ total difficulties score.

In these patients, hydrocortisone improved the total difficulties delta-score (median difference, -5.0; IQR, -7.8 to -3.0), emotional symptoms score (median difference, -1.5; IQR, -4.0 to -1.0), conduct problems score (median difference, -1.0; IQR, -2.0 to 0.0), and impact of stress score (median difference, -1.0; IQR, -2.0 to 0.0).

Sleep issues

The researchers used the Sleep Disturbance Scale for Children (SDSC) to assess sleep quality and sleep disturbances. Forty-seven parents completed the questionnaire at all 4 time points tested.

Results showed that dexamethasone significantly increased disorders of arousal (P=0.04), sleep-wake transition disorders (P=0.01), and disorders of excessive somnolence (P=0.01).

The addition of hydrocortisone had no significant effect on patients’ total SDSC score (P=0.84), disorders of initiating and maintaining sleep (P=0.74), disorders of excessive somnolence (P=0.29), or sleep-wake transition disorder (P=0.29).

However, hydrocortisone did have a clinically significant effect in the subset of 9 children who had clinically relevant dexamethasone-induced sleeping problems, which were defined as a change of ≥7 in SDSC total score.

Hydrocortisone reduced SDSC total scores (median difference, -11.0; IQR, -16.0 to 0.0) and disorders of initiating and maintaining sleep scores (median difference, -3.0; IQR, -7.0 to –0.5).

Other outcomes

The researchers also found that dexamethasone treatment alone did not affect patients’ attention, visual-spatial functions, memory, or processing speed.

However, the addition of hydrocortisone significantly improved patients’ long-term visual memory (P=0.01).

Hydrocortisone did not have any effect on other neuropsychological tests or on metabolic parameters.

Pediatric cancer patient

Photo by Bill Branson

Adding a physiologic dose of hydrocortisone to treatment with dexamethasone can reduce the severity of certain adverse effects (AEs) in pediatric patients with acute lymphoblastic leukemia (ALL), according to researchers.

Hydrocortisone did not decrease the incidence of psychosocial problems or sleep-related issues in these patients, but the drug did reduce the severity of these problems among patients who experienced them.

Lidewij T. Warris, MD, of Erasmus MC-Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues reported these results in the Journal of Clinical Oncology.

The team conducted this study to determine whether a physiologic dose of hydrocortisone could reduce neuropsychologic and metabolic AEs in children with ALL who were receiving dexamethasone.

The study enrolled 50 patients (ages 3 to 16) who were set to receive 2 consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols.

The patients were randomized to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m²/d) during their first dexamethasone course. During their second course, the patients were assigned to the opposite arm.

The treatment groups were similar with regard to age, type of leukemia, treatment protocol, and CNS status at diagnosis.

Psychosocial problems

The researchers assessed psychosocial problems by having parents complete the Strength and Difficulties Questionnaire (SDQ). Forty-six parents completed the questionnaire at all 4 time points tested.

The results showed that 4 days of dexamethasone treatment significantly increased patient problems, as reported by all SDQ scales and subscales. However, one-third of the population did not have any increase in SDQ total difficulties with dexamethasone.

The addition of hydrocortisone did not affect patients’ total difficulties score (mean difference, -0.8 ± 5.5; P=0.33), emotional symptoms (mean difference, -0.6 ± 2.3; P=0.08), conduct problems (mean difference, 0.0 ± 1.5; P=1.00), or other SDQ subscales.

However, hydrocortisone did have a clinically significant effect in the subset of 16 patients who had clinically relevant dexamethasone-related AEs. This was defined as an increase of ≥5 in their SDQ total difficulties score.

In these patients, hydrocortisone improved the total difficulties delta-score (median difference, -5.0; IQR, -7.8 to -3.0), emotional symptoms score (median difference, -1.5; IQR, -4.0 to -1.0), conduct problems score (median difference, -1.0; IQR, -2.0 to 0.0), and impact of stress score (median difference, -1.0; IQR, -2.0 to 0.0).

Sleep issues

The researchers used the Sleep Disturbance Scale for Children (SDSC) to assess sleep quality and sleep disturbances. Forty-seven parents completed the questionnaire at all 4 time points tested.

Results showed that dexamethasone significantly increased disorders of arousal (P=0.04), sleep-wake transition disorders (P=0.01), and disorders of excessive somnolence (P=0.01).

The addition of hydrocortisone had no significant effect on patients’ total SDSC score (P=0.84), disorders of initiating and maintaining sleep (P=0.74), disorders of excessive somnolence (P=0.29), or sleep-wake transition disorder (P=0.29).

However, hydrocortisone did have a clinically significant effect in the subset of 9 children who had clinically relevant dexamethasone-induced sleeping problems, which were defined as a change of ≥7 in SDSC total score.

Hydrocortisone reduced SDSC total scores (median difference, -11.0; IQR, -16.0 to 0.0) and disorders of initiating and maintaining sleep scores (median difference, -3.0; IQR, -7.0 to –0.5).

Other outcomes

The researchers also found that dexamethasone treatment alone did not affect patients’ attention, visual-spatial functions, memory, or processing speed.

However, the addition of hydrocortisone significantly improved patients’ long-term visual memory (P=0.01).

Hydrocortisone did not have any effect on other neuropsychological tests or on metabolic parameters.

Pediatric cancer patient

Photo by Bill Branson

Adding a physiologic dose of hydrocortisone to treatment with dexamethasone can reduce the severity of certain adverse effects (AEs) in pediatric patients with acute lymphoblastic leukemia (ALL), according to researchers.

Hydrocortisone did not decrease the incidence of psychosocial problems or sleep-related issues in these patients, but the drug did reduce the severity of these problems among patients who experienced them.

Lidewij T. Warris, MD, of Erasmus MC-Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues reported these results in the Journal of Clinical Oncology.

The team conducted this study to determine whether a physiologic dose of hydrocortisone could reduce neuropsychologic and metabolic AEs in children with ALL who were receiving dexamethasone.

The study enrolled 50 patients (ages 3 to 16) who were set to receive 2 consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols.

The patients were randomized to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m²/d) during their first dexamethasone course. During their second course, the patients were assigned to the opposite arm.

The treatment groups were similar with regard to age, type of leukemia, treatment protocol, and CNS status at diagnosis.

Psychosocial problems

The researchers assessed psychosocial problems by having parents complete the Strength and Difficulties Questionnaire (SDQ). Forty-six parents completed the questionnaire at all 4 time points tested.

The results showed that 4 days of dexamethasone treatment significantly increased patient problems, as reported by all SDQ scales and subscales. However, one-third of the population did not have any increase in SDQ total difficulties with dexamethasone.

The addition of hydrocortisone did not affect patients’ total difficulties score (mean difference, -0.8 ± 5.5; P=0.33), emotional symptoms (mean difference, -0.6 ± 2.3; P=0.08), conduct problems (mean difference, 0.0 ± 1.5; P=1.00), or other SDQ subscales.

However, hydrocortisone did have a clinically significant effect in the subset of 16 patients who had clinically relevant dexamethasone-related AEs. This was defined as an increase of ≥5 in their SDQ total difficulties score.

In these patients, hydrocortisone improved the total difficulties delta-score (median difference, -5.0; IQR, -7.8 to -3.0), emotional symptoms score (median difference, -1.5; IQR, -4.0 to -1.0), conduct problems score (median difference, -1.0; IQR, -2.0 to 0.0), and impact of stress score (median difference, -1.0; IQR, -2.0 to 0.0).

Sleep issues

The researchers used the Sleep Disturbance Scale for Children (SDSC) to assess sleep quality and sleep disturbances. Forty-seven parents completed the questionnaire at all 4 time points tested.

Results showed that dexamethasone significantly increased disorders of arousal (P=0.04), sleep-wake transition disorders (P=0.01), and disorders of excessive somnolence (P=0.01).

The addition of hydrocortisone had no significant effect on patients’ total SDSC score (P=0.84), disorders of initiating and maintaining sleep (P=0.74), disorders of excessive somnolence (P=0.29), or sleep-wake transition disorder (P=0.29).

However, hydrocortisone did have a clinically significant effect in the subset of 9 children who had clinically relevant dexamethasone-induced sleeping problems, which were defined as a change of ≥7 in SDSC total score.

Hydrocortisone reduced SDSC total scores (median difference, -11.0; IQR, -16.0 to 0.0) and disorders of initiating and maintaining sleep scores (median difference, -3.0; IQR, -7.0 to –0.5).

Other outcomes

The researchers also found that dexamethasone treatment alone did not affect patients’ attention, visual-spatial functions, memory, or processing speed.

However, the addition of hydrocortisone significantly improved patients’ long-term visual memory (P=0.01).

Hydrocortisone did not have any effect on other neuropsychological tests or on metabolic parameters.

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.

The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.

The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.

‘205 trial

The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.

In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.

Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.

Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.

The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.

The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.

‘205 trial

The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.

In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.

Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.

Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.

The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.

The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.

‘205 trial

The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.

In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.

Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.

Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).

Hagop Kantarjian, MD

Photo from MD Anderson

Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.

Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.

The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.

Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.

Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.

Patients

The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.

Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.

The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.

But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).

Treatment

All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.

The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.

Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.

Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).

Response and survival

Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).

There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).

Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.

The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.

Safety

All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.

The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.

However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).

The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.

Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.

There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.

Hagop Kantarjian, MD

Photo from MD Anderson

Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.

Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.

The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.

Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.

Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.

Patients

The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.

Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.

The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.

But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).

Treatment

All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.

The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.

Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.

Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).

Response and survival

Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).

There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).

Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.

The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.

Safety

All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.

The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.

However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).

The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.

Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.

There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.

Hagop Kantarjian, MD

Photo from MD Anderson

Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.

Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.

The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.

Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.

Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.

Patients

The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.

Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.

The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.

But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).

Treatment

All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.

The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.

Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.

Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).

Response and survival

Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).

There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).

Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.

The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.

Safety

All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.

The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.

However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).

The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.

Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.

There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.

Micrograph showing MCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 as a treatment for several hematologic malignancies.

This includes primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).

KTE-C19 previously received orphan designation from the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity.

KTE-C19 also has breakthrough therapy designation from the FDA as a treatment for DLBCL, PMBCL, and transformed FL.

About KTE-C19

KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target CD19. The product is being developed by Kite Pharma, Inc.

In a study published in the Journal of Clinical Oncology, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

Of the 4 patients with CLL, 3 had a CR, and 1 had a PR. All 3 CRs were ongoing at the time of publication, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the CR was 11 months at the time of publication.

KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

KTE-C19 is currently under investigation in a phase 2 trial of refractory DLBCL, PMBCL, and transformed FL (ZUMA-1), a phase 2 trial of relapsed/refractory MCL (ZUMA-2), a phase 1/2 trial of relapsed/refractory adult ALL (ZUMA-3), and a phase 1/2 trial of relapsed/refractory pediatric ALL (ZUMA-4).

Results from ZUMA-1 were recently presented at the 2016 AACR Annual Meeting (abstract CT135).

Micrograph showing MCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 as a treatment for several hematologic malignancies.

This includes primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).

KTE-C19 previously received orphan designation from the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity.

KTE-C19 also has breakthrough therapy designation from the FDA as a treatment for DLBCL, PMBCL, and transformed FL.

About KTE-C19

KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target CD19. The product is being developed by Kite Pharma, Inc.

In a study published in the Journal of Clinical Oncology, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

Of the 4 patients with CLL, 3 had a CR, and 1 had a PR. All 3 CRs were ongoing at the time of publication, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the CR was 11 months at the time of publication.

KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

KTE-C19 is currently under investigation in a phase 2 trial of refractory DLBCL, PMBCL, and transformed FL (ZUMA-1), a phase 2 trial of relapsed/refractory MCL (ZUMA-2), a phase 1/2 trial of relapsed/refractory adult ALL (ZUMA-3), and a phase 1/2 trial of relapsed/refractory pediatric ALL (ZUMA-4).

Results from ZUMA-1 were recently presented at the 2016 AACR Annual Meeting (abstract CT135).

Micrograph showing MCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 as a treatment for several hematologic malignancies.

This includes primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).

KTE-C19 previously received orphan designation from the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity.

KTE-C19 also has breakthrough therapy designation from the FDA as a treatment for DLBCL, PMBCL, and transformed FL.

About KTE-C19

KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target CD19. The product is being developed by Kite Pharma, Inc.

In a study published in the Journal of Clinical Oncology, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

Of the 4 patients with CLL, 3 had a CR, and 1 had a PR. All 3 CRs were ongoing at the time of publication, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the CR was 11 months at the time of publication.

KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

KTE-C19 is currently under investigation in a phase 2 trial of refractory DLBCL, PMBCL, and transformed FL (ZUMA-1), a phase 2 trial of relapsed/refractory MCL (ZUMA-2), a phase 1/2 trial of relapsed/refractory adult ALL (ZUMA-3), and a phase 1/2 trial of relapsed/refractory pediatric ALL (ZUMA-4).

Results from ZUMA-1 were recently presented at the 2016 AACR Annual Meeting (abstract CT135).

FROM THE AACR ANNUAL MEETING

A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.

Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.

Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.

“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.

Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.

This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.

Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.

A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”

Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.

To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”

One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.

The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.

The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.

FROM THE AACR ANNUAL MEETING

A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.

Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.

Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.

“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.

Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.

This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.

Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.

A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”

Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.

To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”

One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.

The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.

The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.

FROM THE AACR ANNUAL MEETING

A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.

Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.

Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.

“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.

Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.

This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.

Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.

A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”

Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.

To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”

One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.

The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.

The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.