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Pulmonary complications affect cancer survivors long-term
Photo by Bill Branson
A new study suggests that survivors of childhood cancer may be plagued by pulmonary complications related to treatment well into their adult lives.
The research indicated that the cumulative incidence of pulmonary complications continues to increase up to 25 years from a patient’s initial cancer diagnosis.
In addition, platinum-based chemotherapy and higher doses of radiation were linked to an increased risk of death from pulmonary causes.
Andrew C. Dietz, MD, of Children’s Hospital Los Angeles in California, and his colleagues reported these findings in Cancer.
The researchers analyzed data from 20,690 five-year cancer survivors who participated in the Childhood Cancer Survivor Study to determine the incidence of death from pulmonary causes.
The team also assessed the incidence of various pulmonary complications in 14,316 of those cancer survivors (who completed a baseline survey and/or 1 of 2 follow-up surveys years later), comparing the results to those seen in a control group of 4027 cancer survivor siblings.
About 34% of the 14,316 cancer survivors had been diagnosed with acute leukemia, and about 21% were diagnosed with Hodgkin or non-Hodgkin lymphoma.
The cancer survivors’ median age at diagnosis was 7 (range, 0-21), and their median age at evaluation was 32 (range, 6-59). The median time from diagnosis was 25 years (range, 5-39).
Compared with controls, cancer survivors were more likely to be male, black, and Hispanic. Cancer survivors were slightly younger and more likely to report a history of congestive heart failure, but they were less likely to be overweight/obese or have ever smoked at the time of the baseline survey.
Results
By age 45, the cumulative incidence of any pulmonary condition was 29.6% among cancer survivors and 26.5% among controls (P=0.001).
The cancer survivors were more likely than controls to report chronic cough (rate ratio [RR]=1.6), the need for extra oxygen (RR=1.8), lung fibrosis (RR=3.5), and recurrent pneumonia (RR=2.0).
Among cancer survivors, the risk of asthma was significantly associated with exposure to asparaginase. Chronic cough was significantly associated with chest wall or lung surgery, anthracyclines, hydroxyurea, and lung radiation doses ≥15 Gy.
Emphysema was significantly associated with lomustine. The need for extra oxygen was significantly associated with hematopoietic stem cell transplant, chest wall or lung surgery, and lung radiation doses ≥10 Gy.
Lung fibrosis was significantly associated with chest wall or lung surgery, asparaginase, platinum-based chemotherapy, and lung radiation doses ≥10 Gy. Recurrent pneumonia was significantly associated with lung radiation doses ≥15 Gy.
The standardized mortality ratio for death from pulmonary causes among all eligible cancer survivors (n=20,690) was 5.9. Pulmonary death was significantly associated with exposure to platinum-based agents and lung radiation doses ≥10 Gy.
“This study adds to our understanding of specific, long-term risks to pulmonary health for survivors of childhood cancer and will help refine guidelines for appropriate screening, health surveillance, and counseling,” said study author Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
He added that this knowledge could potentially contribute to the design and testing of better, targeted interventions to decrease adverse pulmonary events in this population. 
Photo by Bill Branson
A new study suggests that survivors of childhood cancer may be plagued by pulmonary complications related to treatment well into their adult lives.
The research indicated that the cumulative incidence of pulmonary complications continues to increase up to 25 years from a patient’s initial cancer diagnosis.
In addition, platinum-based chemotherapy and higher doses of radiation were linked to an increased risk of death from pulmonary causes.
Andrew C. Dietz, MD, of Children’s Hospital Los Angeles in California, and his colleagues reported these findings in Cancer.
The researchers analyzed data from 20,690 five-year cancer survivors who participated in the Childhood Cancer Survivor Study to determine the incidence of death from pulmonary causes.
The team also assessed the incidence of various pulmonary complications in 14,316 of those cancer survivors (who completed a baseline survey and/or 1 of 2 follow-up surveys years later), comparing the results to those seen in a control group of 4027 cancer survivor siblings.
About 34% of the 14,316 cancer survivors had been diagnosed with acute leukemia, and about 21% were diagnosed with Hodgkin or non-Hodgkin lymphoma.
The cancer survivors’ median age at diagnosis was 7 (range, 0-21), and their median age at evaluation was 32 (range, 6-59). The median time from diagnosis was 25 years (range, 5-39).
Compared with controls, cancer survivors were more likely to be male, black, and Hispanic. Cancer survivors were slightly younger and more likely to report a history of congestive heart failure, but they were less likely to be overweight/obese or have ever smoked at the time of the baseline survey.
Results
By age 45, the cumulative incidence of any pulmonary condition was 29.6% among cancer survivors and 26.5% among controls (P=0.001).
The cancer survivors were more likely than controls to report chronic cough (rate ratio [RR]=1.6), the need for extra oxygen (RR=1.8), lung fibrosis (RR=3.5), and recurrent pneumonia (RR=2.0).
Among cancer survivors, the risk of asthma was significantly associated with exposure to asparaginase. Chronic cough was significantly associated with chest wall or lung surgery, anthracyclines, hydroxyurea, and lung radiation doses ≥15 Gy.
Emphysema was significantly associated with lomustine. The need for extra oxygen was significantly associated with hematopoietic stem cell transplant, chest wall or lung surgery, and lung radiation doses ≥10 Gy.
Lung fibrosis was significantly associated with chest wall or lung surgery, asparaginase, platinum-based chemotherapy, and lung radiation doses ≥10 Gy. Recurrent pneumonia was significantly associated with lung radiation doses ≥15 Gy.
The standardized mortality ratio for death from pulmonary causes among all eligible cancer survivors (n=20,690) was 5.9. Pulmonary death was significantly associated with exposure to platinum-based agents and lung radiation doses ≥10 Gy.
“This study adds to our understanding of specific, long-term risks to pulmonary health for survivors of childhood cancer and will help refine guidelines for appropriate screening, health surveillance, and counseling,” said study author Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
He added that this knowledge could potentially contribute to the design and testing of better, targeted interventions to decrease adverse pulmonary events in this population.
Photo by Bill Branson
A new study suggests that survivors of childhood cancer may be plagued by pulmonary complications related to treatment well into their adult lives.
The research indicated that the cumulative incidence of pulmonary complications continues to increase up to 25 years from a patient’s initial cancer diagnosis.
In addition, platinum-based chemotherapy and higher doses of radiation were linked to an increased risk of death from pulmonary causes.
Andrew C. Dietz, MD, of Children’s Hospital Los Angeles in California, and his colleagues reported these findings in Cancer.
The researchers analyzed data from 20,690 five-year cancer survivors who participated in the Childhood Cancer Survivor Study to determine the incidence of death from pulmonary causes.
The team also assessed the incidence of various pulmonary complications in 14,316 of those cancer survivors (who completed a baseline survey and/or 1 of 2 follow-up surveys years later), comparing the results to those seen in a control group of 4027 cancer survivor siblings.
About 34% of the 14,316 cancer survivors had been diagnosed with acute leukemia, and about 21% were diagnosed with Hodgkin or non-Hodgkin lymphoma.
The cancer survivors’ median age at diagnosis was 7 (range, 0-21), and their median age at evaluation was 32 (range, 6-59). The median time from diagnosis was 25 years (range, 5-39).
Compared with controls, cancer survivors were more likely to be male, black, and Hispanic. Cancer survivors were slightly younger and more likely to report a history of congestive heart failure, but they were less likely to be overweight/obese or have ever smoked at the time of the baseline survey.
Results
By age 45, the cumulative incidence of any pulmonary condition was 29.6% among cancer survivors and 26.5% among controls (P=0.001).
The cancer survivors were more likely than controls to report chronic cough (rate ratio [RR]=1.6), the need for extra oxygen (RR=1.8), lung fibrosis (RR=3.5), and recurrent pneumonia (RR=2.0).
Among cancer survivors, the risk of asthma was significantly associated with exposure to asparaginase. Chronic cough was significantly associated with chest wall or lung surgery, anthracyclines, hydroxyurea, and lung radiation doses ≥15 Gy.
Emphysema was significantly associated with lomustine. The need for extra oxygen was significantly associated with hematopoietic stem cell transplant, chest wall or lung surgery, and lung radiation doses ≥10 Gy.
Lung fibrosis was significantly associated with chest wall or lung surgery, asparaginase, platinum-based chemotherapy, and lung radiation doses ≥10 Gy. Recurrent pneumonia was significantly associated with lung radiation doses ≥15 Gy.
The standardized mortality ratio for death from pulmonary causes among all eligible cancer survivors (n=20,690) was 5.9. Pulmonary death was significantly associated with exposure to platinum-based agents and lung radiation doses ≥10 Gy.
“This study adds to our understanding of specific, long-term risks to pulmonary health for survivors of childhood cancer and will help refine guidelines for appropriate screening, health surveillance, and counseling,” said study author Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
He added that this knowledge could potentially contribute to the design and testing of better, targeted interventions to decrease adverse pulmonary events in this population.
Research provides new insight into CLL
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
Venetoclax can produce short-term responses in AML
Results of a phase 2 trial suggest the BCL2 inhibitor venetoclax can produce responses in patients with acute myelogenous leukemia (AML) who do not respond to or cannot tolerate chemotherapy.
However, the overall response rate in this trial was low, and responses were not durable.
All of the patients studied discontinued venetoclax, most due to disease progression.
The study was published in Cancer Discovery. It was funded by AbbVie in collaboration with Genentech/Roche.
The trial included 32 patients with AML and a median age of 71 (range, 19–84). Thirteen patients had an antecedent hematologic disorder or myeloproliferative neoplasm, and 4 had therapy-related AML with complex cytogenetics.
Twelve patients had mutations in IDH genes, and 6 had a high BCL2-sensitive protein index.
Thirty patients had received at least 1 prior therapy, and 13 had received at least 3 prior treatment regimens. Two patients were considered unfit for intensive chemotherapy and were treatment-naive at study entry.
The patients received venetoclax at 800 mg daily. All 32 patients received at least 1 dose, and 26 patients received at least 4 weeks of therapy.
Efficacy
The overall response rate was 19%. Two patients had a complete response (CR), and 4 had a CR with incomplete blood count recovery. Three of the 6 responders had an antecedent hematologic disorder.
“[E]ven among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL2 inhibition, even to the point of complete remissions,” said study author Anthony Letai, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days.
The 4 patients who had CRs with incomplete count recovery had IDH mutations. Response to the drug correlated with biomarker results, including indices of BCL2 protein expression and BH3 profiling.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL2,” Dr Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
Safety and discontinuation
All of the patients discontinued therapy—29 due to progressive disease and 1 due to an adverse event (terminal ileitis). One patient withdrew consent, and 1 proceeded to allogeneic transplant after achieving stable disease.
All of the patients experienced treatment-emergent adverse events. The most common were nausea (59%), diarrhea (56%), hypokalemia (41%), vomiting (41%), fatigue (34%), headache (34%), hypomagnesemia (34%), febrile neutropenia (31%), and hypophosphatemia (31%).
Serious adverse events occurred in 84% of patients. These included febrile neutropenia (28%), pneumonia (16%), abdominal pain (6%), acute renal failure (6%), failure to thrive (6%), hypotension (6%), sepsis (6%), and urinary tract infection (6%).
Based on the results of this trial, the researchers concluded that venetoclax may be a viable treatment option for AML patients when used in combination with other therapies.
“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combinations with hypomethylating agents and other approaches,” said study author Marina Konopleva, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”
Results of a phase 2 trial suggest the BCL2 inhibitor venetoclax can produce responses in patients with acute myelogenous leukemia (AML) who do not respond to or cannot tolerate chemotherapy.
However, the overall response rate in this trial was low, and responses were not durable.
All of the patients studied discontinued venetoclax, most due to disease progression.
The study was published in Cancer Discovery. It was funded by AbbVie in collaboration with Genentech/Roche.
The trial included 32 patients with AML and a median age of 71 (range, 19–84). Thirteen patients had an antecedent hematologic disorder or myeloproliferative neoplasm, and 4 had therapy-related AML with complex cytogenetics.
Twelve patients had mutations in IDH genes, and 6 had a high BCL2-sensitive protein index.
Thirty patients had received at least 1 prior therapy, and 13 had received at least 3 prior treatment regimens. Two patients were considered unfit for intensive chemotherapy and were treatment-naive at study entry.
The patients received venetoclax at 800 mg daily. All 32 patients received at least 1 dose, and 26 patients received at least 4 weeks of therapy.
Efficacy
The overall response rate was 19%. Two patients had a complete response (CR), and 4 had a CR with incomplete blood count recovery. Three of the 6 responders had an antecedent hematologic disorder.
“[E]ven among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL2 inhibition, even to the point of complete remissions,” said study author Anthony Letai, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days.
The 4 patients who had CRs with incomplete count recovery had IDH mutations. Response to the drug correlated with biomarker results, including indices of BCL2 protein expression and BH3 profiling.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL2,” Dr Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
Safety and discontinuation
All of the patients discontinued therapy—29 due to progressive disease and 1 due to an adverse event (terminal ileitis). One patient withdrew consent, and 1 proceeded to allogeneic transplant after achieving stable disease.
All of the patients experienced treatment-emergent adverse events. The most common were nausea (59%), diarrhea (56%), hypokalemia (41%), vomiting (41%), fatigue (34%), headache (34%), hypomagnesemia (34%), febrile neutropenia (31%), and hypophosphatemia (31%).
Serious adverse events occurred in 84% of patients. These included febrile neutropenia (28%), pneumonia (16%), abdominal pain (6%), acute renal failure (6%), failure to thrive (6%), hypotension (6%), sepsis (6%), and urinary tract infection (6%).
Based on the results of this trial, the researchers concluded that venetoclax may be a viable treatment option for AML patients when used in combination with other therapies.
“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combinations with hypomethylating agents and other approaches,” said study author Marina Konopleva, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”
Results of a phase 2 trial suggest the BCL2 inhibitor venetoclax can produce responses in patients with acute myelogenous leukemia (AML) who do not respond to or cannot tolerate chemotherapy.
However, the overall response rate in this trial was low, and responses were not durable.
All of the patients studied discontinued venetoclax, most due to disease progression.
The study was published in Cancer Discovery. It was funded by AbbVie in collaboration with Genentech/Roche.
The trial included 32 patients with AML and a median age of 71 (range, 19–84). Thirteen patients had an antecedent hematologic disorder or myeloproliferative neoplasm, and 4 had therapy-related AML with complex cytogenetics.
Twelve patients had mutations in IDH genes, and 6 had a high BCL2-sensitive protein index.
Thirty patients had received at least 1 prior therapy, and 13 had received at least 3 prior treatment regimens. Two patients were considered unfit for intensive chemotherapy and were treatment-naive at study entry.
The patients received venetoclax at 800 mg daily. All 32 patients received at least 1 dose, and 26 patients received at least 4 weeks of therapy.
Efficacy
The overall response rate was 19%. Two patients had a complete response (CR), and 4 had a CR with incomplete blood count recovery. Three of the 6 responders had an antecedent hematologic disorder.
“[E]ven among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL2 inhibition, even to the point of complete remissions,” said study author Anthony Letai, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days.
The 4 patients who had CRs with incomplete count recovery had IDH mutations. Response to the drug correlated with biomarker results, including indices of BCL2 protein expression and BH3 profiling.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL2,” Dr Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
Safety and discontinuation
All of the patients discontinued therapy—29 due to progressive disease and 1 due to an adverse event (terminal ileitis). One patient withdrew consent, and 1 proceeded to allogeneic transplant after achieving stable disease.
All of the patients experienced treatment-emergent adverse events. The most common were nausea (59%), diarrhea (56%), hypokalemia (41%), vomiting (41%), fatigue (34%), headache (34%), hypomagnesemia (34%), febrile neutropenia (31%), and hypophosphatemia (31%).
Serious adverse events occurred in 84% of patients. These included febrile neutropenia (28%), pneumonia (16%), abdominal pain (6%), acute renal failure (6%), failure to thrive (6%), hypotension (6%), sepsis (6%), and urinary tract infection (6%).
Based on the results of this trial, the researchers concluded that venetoclax may be a viable treatment option for AML patients when used in combination with other therapies.
“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combinations with hypomethylating agents and other approaches,” said study author Marina Konopleva, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”
Chemo during pregnancy may impact baby’s fertility
Photo by Nina Matthews
Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.
Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.
However, if the drug is given after ovarian follicles have developed, the damage is not significant.
The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.
“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.
“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”
Dr Spears and her colleagues reported these findings in BMC Cancer.
The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.
A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.
Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.
The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.
When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.
In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.
“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.
She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.
Photo by Nina Matthews
Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.
Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.
However, if the drug is given after ovarian follicles have developed, the damage is not significant.
The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.
“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.
“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”
Dr Spears and her colleagues reported these findings in BMC Cancer.
The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.
A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.
Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.
The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.
When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.
In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.
“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.
She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.
Photo by Nina Matthews
Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.
Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.
However, if the drug is given after ovarian follicles have developed, the damage is not significant.
The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.
“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.
“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”
Dr Spears and her colleagues reported these findings in BMC Cancer.
The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.
A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.
Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.
The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.
When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.
In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.
“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.
She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.
FDA approves drug for prevention of CINV
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved granisetron extended-release injection (Sustol®) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults.
Extended-release granisetron is a serotonin-3 (5-HT3) receptor antagonist that utilizes Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for at least 5 days, covering both the acute and delayed phases of CINV.
The product is intended for use in combination with other anti-emetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.
“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” said Ralph V. Boccia, MD, of the Center for Cancer and Blood Disorders in Bethesda, Maryland.
“In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”
Extended-release granisetron (formerly known as APF530) is a product of Heron Therapeutics, Inc. The US commercial launch of the drug is planned for the fourth quarter of 2016.
Phase 3 trials
The global phase 3 development program of extended-release granisetron consisted of 2 large, guideline-based clinical trials of more than 2000 cancer patients.
In one trial, researchers compared extended-release granisetron to palonosetron for the prevention of acute and delayed CINV after MEC or highly emetogenic chemotherapy (HEC).
Results suggested extended-release granisetron was non-inferior to palonosetron. The most common adverse events observed in patients receiving granisetron were injection-site reactions and constipation.
In another trial, researchers compared extended-release granisetron to ondansetron for control of delayed CINV after HEC. Patients received extended-release granisetron, dexamethasone, and fosaprepitant or ondansetron, dexamethasone, and fosaprepitant.
A higher percentage of patients in the granisetron arm had delayed-phase complete response. The incidence of treatment-emergent adverse events was similar between the treatment arms.
“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, of North Shore Hematology Oncology Associates in East Setauket, New York.
“Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”
For more details on the drug, access the full prescribing information at www.SUSTOL.com.
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved granisetron extended-release injection (Sustol®) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults.
Extended-release granisetron is a serotonin-3 (5-HT3) receptor antagonist that utilizes Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for at least 5 days, covering both the acute and delayed phases of CINV.
The product is intended for use in combination with other anti-emetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.
“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” said Ralph V. Boccia, MD, of the Center for Cancer and Blood Disorders in Bethesda, Maryland.
“In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”
Extended-release granisetron (formerly known as APF530) is a product of Heron Therapeutics, Inc. The US commercial launch of the drug is planned for the fourth quarter of 2016.
Phase 3 trials
The global phase 3 development program of extended-release granisetron consisted of 2 large, guideline-based clinical trials of more than 2000 cancer patients.
In one trial, researchers compared extended-release granisetron to palonosetron for the prevention of acute and delayed CINV after MEC or highly emetogenic chemotherapy (HEC).
Results suggested extended-release granisetron was non-inferior to palonosetron. The most common adverse events observed in patients receiving granisetron were injection-site reactions and constipation.
In another trial, researchers compared extended-release granisetron to ondansetron for control of delayed CINV after HEC. Patients received extended-release granisetron, dexamethasone, and fosaprepitant or ondansetron, dexamethasone, and fosaprepitant.
A higher percentage of patients in the granisetron arm had delayed-phase complete response. The incidence of treatment-emergent adverse events was similar between the treatment arms.
“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, of North Shore Hematology Oncology Associates in East Setauket, New York.
“Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”
For more details on the drug, access the full prescribing information at www.SUSTOL.com.
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved granisetron extended-release injection (Sustol®) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults.
Extended-release granisetron is a serotonin-3 (5-HT3) receptor antagonist that utilizes Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for at least 5 days, covering both the acute and delayed phases of CINV.
The product is intended for use in combination with other anti-emetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.
“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” said Ralph V. Boccia, MD, of the Center for Cancer and Blood Disorders in Bethesda, Maryland.
“In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”
Extended-release granisetron (formerly known as APF530) is a product of Heron Therapeutics, Inc. The US commercial launch of the drug is planned for the fourth quarter of 2016.
Phase 3 trials
The global phase 3 development program of extended-release granisetron consisted of 2 large, guideline-based clinical trials of more than 2000 cancer patients.
In one trial, researchers compared extended-release granisetron to palonosetron for the prevention of acute and delayed CINV after MEC or highly emetogenic chemotherapy (HEC).
Results suggested extended-release granisetron was non-inferior to palonosetron. The most common adverse events observed in patients receiving granisetron were injection-site reactions and constipation.
In another trial, researchers compared extended-release granisetron to ondansetron for control of delayed CINV after HEC. Patients received extended-release granisetron, dexamethasone, and fosaprepitant or ondansetron, dexamethasone, and fosaprepitant.
A higher percentage of patients in the granisetron arm had delayed-phase complete response. The incidence of treatment-emergent adverse events was similar between the treatment arms.
“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, of North Shore Hematology Oncology Associates in East Setauket, New York.
“Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”
For more details on the drug, access the full prescribing information at www.SUSTOL.com.
Teva launches generic imatinib tablets in US
Photo by Steven Harbour
Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.
In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+
chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.
Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.
In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.
Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.
For more details on imatinib, see the full prescribing information.
Photo by Steven Harbour
Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.
In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+
chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.
Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.
In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.
Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.
For more details on imatinib, see the full prescribing information.
Photo by Steven Harbour
Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.
In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+
chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.
Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.
In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.
Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.
For more details on imatinib, see the full prescribing information.
Products granted orphan designation for use in HSCT
The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.
If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About orphan designation
Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.
In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.
BPX-501/rimiducid development
BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.
The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.
These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.
Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.
The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.
BP-004 trial
BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.
One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.
The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.”
The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.
If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About orphan designation
Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.
In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.
BPX-501/rimiducid development
BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.
The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.
These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.
Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.
The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.
BP-004 trial
BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.
One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.
The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.”
The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.
If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About orphan designation
Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.
In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.
BPX-501/rimiducid development
BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.
The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.
These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.
Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.
The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.
BP-004 trial
BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.
One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.
The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.”
SB-generated CAR T cells show promise
Image by NIAID
Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.
These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).
In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.
The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.
The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).
The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.
The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.
Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.
Safety
The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.
Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.
The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.
There were 5 other deaths, all of them due to disease relapse.
Efficacy: Autologous HSCT
Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.
Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).
The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.
Efficacy: Allogeneic HSCT
Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.
Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.
The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.
“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.
“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”
Image by NIAID
Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.
These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).
In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.
The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.
The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).
The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.
The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.
Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.
Safety
The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.
Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.
The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.
There were 5 other deaths, all of them due to disease relapse.
Efficacy: Autologous HSCT
Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.
Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).
The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.
Efficacy: Allogeneic HSCT
Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.
Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.
The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.
“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.
“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”
Image by NIAID
Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.
These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).
In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.
The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.
The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).
The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.
The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.
Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.
Safety
The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.
Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.
The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.
There were 5 other deaths, all of them due to disease relapse.
Efficacy: Autologous HSCT
Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.
Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).
The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.
Efficacy: Allogeneic HSCT
Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.
Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.
The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.
“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.
“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”
Method provides more accurate diagnosis of MDS, team says
Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.
The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.
And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.
The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.
For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.
The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.
In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.
NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.
Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).
The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.
Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.
The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.
And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.
The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.
For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.
The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.
In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.
NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.
Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).
The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.
Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.
The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.
And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.
The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.
For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.
The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.
In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.
NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.
Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).
The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.
HDAC inhibitor granted breakthrough designation
Image by Eric Smith
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the histone deacetylase (HDAC) inhibitor pracinostat to be used in combination with azacitidine to treat newly diagnosed acute myeloid leukemia (AML) patients who are 75 and older or unfit for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The breakthrough therapy designation for pracinostat is supported by data from a phase 2 study of the HDAC inhibitor in combination with azacitidine in elderly patients with newly diagnosed AML who were not candidates for induction chemotherapy.
Detailed results from this trial were presented at the 20th Congress of the European Hematology Association last year. The research was sponsored by MEI Pharma, the company developing pracinostat.
The study included 50 AML patients who had a median age of 75 (range, 66-84).
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
According to updated data from MEI Pharma, the complete response rate was 42% (n=21), and the median overall survival was 19.1 months.
The company said these data compare favorably to a phase 3 study of azacitidine (AZA-AML-0011), which showed a median overall survival of 10.4 months with azacitidine alone and a complete response rate of 19.5% in a similar patient population.
The combination of pracinostat and azacitidine was thought to be well tolerated overall, with no unexpected toxicities. The most common grade 3-4 treatment-emergent adverse events included febrile neutropenia, thrombocytopenia, anemia, and fatigue.
Image by Eric Smith
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the histone deacetylase (HDAC) inhibitor pracinostat to be used in combination with azacitidine to treat newly diagnosed acute myeloid leukemia (AML) patients who are 75 and older or unfit for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The breakthrough therapy designation for pracinostat is supported by data from a phase 2 study of the HDAC inhibitor in combination with azacitidine in elderly patients with newly diagnosed AML who were not candidates for induction chemotherapy.
Detailed results from this trial were presented at the 20th Congress of the European Hematology Association last year. The research was sponsored by MEI Pharma, the company developing pracinostat.
The study included 50 AML patients who had a median age of 75 (range, 66-84).
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
According to updated data from MEI Pharma, the complete response rate was 42% (n=21), and the median overall survival was 19.1 months.
The company said these data compare favorably to a phase 3 study of azacitidine (AZA-AML-0011), which showed a median overall survival of 10.4 months with azacitidine alone and a complete response rate of 19.5% in a similar patient population.
The combination of pracinostat and azacitidine was thought to be well tolerated overall, with no unexpected toxicities. The most common grade 3-4 treatment-emergent adverse events included febrile neutropenia, thrombocytopenia, anemia, and fatigue.
Image by Eric Smith
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the histone deacetylase (HDAC) inhibitor pracinostat to be used in combination with azacitidine to treat newly diagnosed acute myeloid leukemia (AML) patients who are 75 and older or unfit for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The breakthrough therapy designation for pracinostat is supported by data from a phase 2 study of the HDAC inhibitor in combination with azacitidine in elderly patients with newly diagnosed AML who were not candidates for induction chemotherapy.
Detailed results from this trial were presented at the 20th Congress of the European Hematology Association last year. The research was sponsored by MEI Pharma, the company developing pracinostat.
The study included 50 AML patients who had a median age of 75 (range, 66-84).
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
According to updated data from MEI Pharma, the complete response rate was 42% (n=21), and the median overall survival was 19.1 months.
The company said these data compare favorably to a phase 3 study of azacitidine (AZA-AML-0011), which showed a median overall survival of 10.4 months with azacitidine alone and a complete response rate of 19.5% in a similar patient population.
The combination of pracinostat and azacitidine was thought to be well tolerated overall, with no unexpected toxicities. The most common grade 3-4 treatment-emergent adverse events included febrile neutropenia, thrombocytopenia, anemia, and fatigue.