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Product appears safe, effective in rel/ref ALL
Credit: Bill Branson
Eryaspase, a product consisting of L-asparaginase encapsulated in red blood cells, may be safer and more effective than native E coli L-asparaginase, results of a phase 2/3 study suggest.
In patients with relapsed or refractory acute lymphoblastic leukemia (ALL), eryaspase given in combination with chemotherapy produced a higher complete response rate and fewer allergic reactions than native E coli L-asparaginase in combination with chemotherapy.
Eryaspase was also well-tolerated in patients who had previously experienced allergic reactions to L-asparaginase.
ERYTECH Pharma, the company developing eryaspase, recently announced these results from the GRASPIVOTALL trial.
The study included 80 children and adults with relapsed or refractory ALL, who were randomized to 1 of 3 treatment arms.
In the first 2 arms, researchers compared eryaspase to native E coli L-asparaginase, both in combination with standard chemotherapy (COOPRALL), in patients without prior allergies to L-asparaginase. In the third arm, the team evaluated eryaspase for patients who have experienced allergic reactions related to asparaginase in their first-line treatment.
The primary endpoint of the study consisted of 2 objectives: (a) superior safety, expressed as a significant reduction of the incidence of allergic reactions with eryaspase compared to native L-asparaginase, and (b) noninferior duration of asparaginase activity above the threshold of 100 IU/L during the induction phase in the nonallergic patients. Both endpoints needed to be met for the study to be considered positive.
The main secondary efficacy endpoints included complete response, minimal residual disease, event-free survival, and overall survival.
At 1 year of follow-up, both primary endpoints were met. There was a significant reduction of allergic reactions in the eryaspase arm compared to the native L-asparaginase arm—0% (0/26) and 42.9% (12/28), respectively (P<0.001).
And there was a significant increase in the duration of circulating asparaginase activity in the eryaspase arm compared to the native L-asparaginase arm. Asparaginase levels were maintained above 100 IU/L for an average of 20.5 days with up to 2 injections during the first month of treatment with eryaspase, compared to 9.2 days in the native L-asparaginase arm, with up to 8 injections of L-asparaginase (P<0.001).
In addition, the complete response rate was higher with eryaspase. At the end of the induction phase, 71.4% of patients (n=15) in the eryaspase arm had a complete response, compared to 42.3% of patients (n=11) in the native L-asparaginase arm.
Finally, the study showed that eryaspase is well-tolerated by patients with previous allergies to L-asparaginase. Two of the 26 patients with prior allergies to L-asparaginase experienced mild allergic reactions to eryaspase.
“The results of this study are an important step forward for the treatment of ALL patients that are at risk to receive L-asparaginase, which remains an important unmet medical need,” said Yves Betrand, MD, of the Institute for Pediatric Hematology and Oncology in Lyon, France.
“The virtual absence of allergic reactions, also in patients with prior allergies to L-asparaginase, is very encouraging.”
The analysis of additional secondary and exploratory endpoints for this study is ongoing. ERYTECH said results will be available later this year and are set to be presented at an upcoming scientific conference.
Based on the results of this and earlier studies of eryaspase, ERYTECH intends to submit its application for European Marketing Authorization in the first half of 2015.
The company also plans to accelerate the product’s development in ALL in the US and to launch phase 2 clinical trials in additional oncology indications with high unmet medical need. A phase 2b study of eryaspase in acute myeloid leukemia is already underway, with more than half of the patients enrolled. 
Credit: Bill Branson
Eryaspase, a product consisting of L-asparaginase encapsulated in red blood cells, may be safer and more effective than native E coli L-asparaginase, results of a phase 2/3 study suggest.
In patients with relapsed or refractory acute lymphoblastic leukemia (ALL), eryaspase given in combination with chemotherapy produced a higher complete response rate and fewer allergic reactions than native E coli L-asparaginase in combination with chemotherapy.
Eryaspase was also well-tolerated in patients who had previously experienced allergic reactions to L-asparaginase.
ERYTECH Pharma, the company developing eryaspase, recently announced these results from the GRASPIVOTALL trial.
The study included 80 children and adults with relapsed or refractory ALL, who were randomized to 1 of 3 treatment arms.
In the first 2 arms, researchers compared eryaspase to native E coli L-asparaginase, both in combination with standard chemotherapy (COOPRALL), in patients without prior allergies to L-asparaginase. In the third arm, the team evaluated eryaspase for patients who have experienced allergic reactions related to asparaginase in their first-line treatment.
The primary endpoint of the study consisted of 2 objectives: (a) superior safety, expressed as a significant reduction of the incidence of allergic reactions with eryaspase compared to native L-asparaginase, and (b) noninferior duration of asparaginase activity above the threshold of 100 IU/L during the induction phase in the nonallergic patients. Both endpoints needed to be met for the study to be considered positive.
The main secondary efficacy endpoints included complete response, minimal residual disease, event-free survival, and overall survival.
At 1 year of follow-up, both primary endpoints were met. There was a significant reduction of allergic reactions in the eryaspase arm compared to the native L-asparaginase arm—0% (0/26) and 42.9% (12/28), respectively (P<0.001).
And there was a significant increase in the duration of circulating asparaginase activity in the eryaspase arm compared to the native L-asparaginase arm. Asparaginase levels were maintained above 100 IU/L for an average of 20.5 days with up to 2 injections during the first month of treatment with eryaspase, compared to 9.2 days in the native L-asparaginase arm, with up to 8 injections of L-asparaginase (P<0.001).
In addition, the complete response rate was higher with eryaspase. At the end of the induction phase, 71.4% of patients (n=15) in the eryaspase arm had a complete response, compared to 42.3% of patients (n=11) in the native L-asparaginase arm.
Finally, the study showed that eryaspase is well-tolerated by patients with previous allergies to L-asparaginase. Two of the 26 patients with prior allergies to L-asparaginase experienced mild allergic reactions to eryaspase.
“The results of this study are an important step forward for the treatment of ALL patients that are at risk to receive L-asparaginase, which remains an important unmet medical need,” said Yves Betrand, MD, of the Institute for Pediatric Hematology and Oncology in Lyon, France.
“The virtual absence of allergic reactions, also in patients with prior allergies to L-asparaginase, is very encouraging.”
The analysis of additional secondary and exploratory endpoints for this study is ongoing. ERYTECH said results will be available later this year and are set to be presented at an upcoming scientific conference.
Based on the results of this and earlier studies of eryaspase, ERYTECH intends to submit its application for European Marketing Authorization in the first half of 2015.
The company also plans to accelerate the product’s development in ALL in the US and to launch phase 2 clinical trials in additional oncology indications with high unmet medical need. A phase 2b study of eryaspase in acute myeloid leukemia is already underway, with more than half of the patients enrolled.
Credit: Bill Branson
Eryaspase, a product consisting of L-asparaginase encapsulated in red blood cells, may be safer and more effective than native E coli L-asparaginase, results of a phase 2/3 study suggest.
In patients with relapsed or refractory acute lymphoblastic leukemia (ALL), eryaspase given in combination with chemotherapy produced a higher complete response rate and fewer allergic reactions than native E coli L-asparaginase in combination with chemotherapy.
Eryaspase was also well-tolerated in patients who had previously experienced allergic reactions to L-asparaginase.
ERYTECH Pharma, the company developing eryaspase, recently announced these results from the GRASPIVOTALL trial.
The study included 80 children and adults with relapsed or refractory ALL, who were randomized to 1 of 3 treatment arms.
In the first 2 arms, researchers compared eryaspase to native E coli L-asparaginase, both in combination with standard chemotherapy (COOPRALL), in patients without prior allergies to L-asparaginase. In the third arm, the team evaluated eryaspase for patients who have experienced allergic reactions related to asparaginase in their first-line treatment.
The primary endpoint of the study consisted of 2 objectives: (a) superior safety, expressed as a significant reduction of the incidence of allergic reactions with eryaspase compared to native L-asparaginase, and (b) noninferior duration of asparaginase activity above the threshold of 100 IU/L during the induction phase in the nonallergic patients. Both endpoints needed to be met for the study to be considered positive.
The main secondary efficacy endpoints included complete response, minimal residual disease, event-free survival, and overall survival.
At 1 year of follow-up, both primary endpoints were met. There was a significant reduction of allergic reactions in the eryaspase arm compared to the native L-asparaginase arm—0% (0/26) and 42.9% (12/28), respectively (P<0.001).
And there was a significant increase in the duration of circulating asparaginase activity in the eryaspase arm compared to the native L-asparaginase arm. Asparaginase levels were maintained above 100 IU/L for an average of 20.5 days with up to 2 injections during the first month of treatment with eryaspase, compared to 9.2 days in the native L-asparaginase arm, with up to 8 injections of L-asparaginase (P<0.001).
In addition, the complete response rate was higher with eryaspase. At the end of the induction phase, 71.4% of patients (n=15) in the eryaspase arm had a complete response, compared to 42.3% of patients (n=11) in the native L-asparaginase arm.
Finally, the study showed that eryaspase is well-tolerated by patients with previous allergies to L-asparaginase. Two of the 26 patients with prior allergies to L-asparaginase experienced mild allergic reactions to eryaspase.
“The results of this study are an important step forward for the treatment of ALL patients that are at risk to receive L-asparaginase, which remains an important unmet medical need,” said Yves Betrand, MD, of the Institute for Pediatric Hematology and Oncology in Lyon, France.
“The virtual absence of allergic reactions, also in patients with prior allergies to L-asparaginase, is very encouraging.”
The analysis of additional secondary and exploratory endpoints for this study is ongoing. ERYTECH said results will be available later this year and are set to be presented at an upcoming scientific conference.
Based on the results of this and earlier studies of eryaspase, ERYTECH intends to submit its application for European Marketing Authorization in the first half of 2015.
The company also plans to accelerate the product’s development in ALL in the US and to launch phase 2 clinical trials in additional oncology indications with high unmet medical need. A phase 2b study of eryaspase in acute myeloid leukemia is already underway, with more than half of the patients enrolled.
Cancer treatment during pregnancy can be safe
MADRID—Two new studies suggest that children exposed to chemotherapy or radiotherapy in the womb can be spared negative long-term effects.
At a median age of 6, most of the children exposed to radiation in utero had neuropsychological, behavioral, and general health outcomes that were within normal ranges.
And children who were exposed to chemotherapy in the womb had normal mental and cardiac health at a median age of 2.
“When chemotherapy is administered after the first trimester of pregnancy, we cannot discern any problems in the children,” said Frederic Amant, MD, PhD, of University Hospitals Leuven in Belgium.
“Fear about the risks of chemotherapy administration should not be a reason to terminate a pregnancy, delay cancer treatment for the mother, or to deliver a baby prematurely.”
Dr Amant and his colleagues presented these findings (abstract 267PD_PR) and their findings on radiation (abstract 49LBA_PR) at the ESMO 2014 Congress.
Outcomes with chemotherapy
In the first study, the researchers recruited 38 children from the International Network for Cancer, Infertility and Pregnancy registry who were prenatally exposed to chemotherapy.
Most of the mothers had breast (61%) or hematologic (22%) cancers. Most were treated with anthracyclines (61%) and had received an average of 4 cycles (range, 1-7) of treatment.
The researchers assessed mental development and cardiac health in the children of these subjects, comparing them to 38 control children who were not exposed to chemotherapy.
At a median age of almost 2 years, mental development was in the normal range for both groups of children, and development was not significantly different between the groups. The mean Mental Development Index score was 99.13 for exposed children and 101.47 for controls.
Cardiac dimensions and functions were within normal ranges for both groups as well. Mean fractional shortening was 36% (range, 32-42) for exposed children and 39% (range, 32-51) for controls. Although the difference was signficant (P=0.004), the researchers said it was not clinically relevant.
“This paper points to the very important issue of long-term safety of prenatal exposure to chemotherapy and reinforces the notion that chemotherapy during gestation does not endanger the fetus and her or his subsequent development,” said Fedro Alessandro Peccatori, MD, PhD, of the European Institute of Oncology in Milan, Italy, who was not involved in this study.
“To further ameliorate neonatal outcome, a special effort should be made to prolong pregnancy duration, and stringent long-term follow-up should be pursued to confirm these findings. Meanwhile, specific measures to support prematurely delivered babies and their families should be implemented.”
Dr Amant said future studies will explore the effects of specific chemotherapy types in detail and include longer-term follow-up.
Outcomes with radiation
In a second study, Dr Amant and his colleagues explored the impact of radiotherapy on the children of women with cancer.
The study included 16 children, with a median age of 6 years, who had been exposed to radiotherapy in utero. The median maternal irradiation was 48 Gy (range, 12-70), and the median estimated fetal irradiation was 91 mGy (range, 0-1690).
Neuropsychological, behavioral, and general health outcomes were within normal ranges for most of the children. And the researchers found no linear relationship between the fetal dose of radiation and cognitive outcome.
However, there was a negative linear relationship between the gestational age at radiotherapy exposure and verbal intelligence, based on results in 8 children. Two of these children were exposed to radiotherapy in the third trimester and had verbal intelligence scores outside the normal range.
One of the 2 children had low scores on all variables of cognitive development, but other pregnancy-related complications are confounding factors. The child’s mother suffered from an aggressive non-Hodgkin tumor of the brain that impacted her general state, and she had a preterm delivery.
Dr Amant noted that this is based on a very small number of children, so the results should be interpreted with caution.
“We cannot exclude that there might be an impact of prenatal radiotherapy exposure,” he said, “but larger series are needed to further investigate this relationship.”
MADRID—Two new studies suggest that children exposed to chemotherapy or radiotherapy in the womb can be spared negative long-term effects.
At a median age of 6, most of the children exposed to radiation in utero had neuropsychological, behavioral, and general health outcomes that were within normal ranges.
And children who were exposed to chemotherapy in the womb had normal mental and cardiac health at a median age of 2.
“When chemotherapy is administered after the first trimester of pregnancy, we cannot discern any problems in the children,” said Frederic Amant, MD, PhD, of University Hospitals Leuven in Belgium.
“Fear about the risks of chemotherapy administration should not be a reason to terminate a pregnancy, delay cancer treatment for the mother, or to deliver a baby prematurely.”
Dr Amant and his colleagues presented these findings (abstract 267PD_PR) and their findings on radiation (abstract 49LBA_PR) at the ESMO 2014 Congress.
Outcomes with chemotherapy
In the first study, the researchers recruited 38 children from the International Network for Cancer, Infertility and Pregnancy registry who were prenatally exposed to chemotherapy.
Most of the mothers had breast (61%) or hematologic (22%) cancers. Most were treated with anthracyclines (61%) and had received an average of 4 cycles (range, 1-7) of treatment.
The researchers assessed mental development and cardiac health in the children of these subjects, comparing them to 38 control children who were not exposed to chemotherapy.
At a median age of almost 2 years, mental development was in the normal range for both groups of children, and development was not significantly different between the groups. The mean Mental Development Index score was 99.13 for exposed children and 101.47 for controls.
Cardiac dimensions and functions were within normal ranges for both groups as well. Mean fractional shortening was 36% (range, 32-42) for exposed children and 39% (range, 32-51) for controls. Although the difference was signficant (P=0.004), the researchers said it was not clinically relevant.
“This paper points to the very important issue of long-term safety of prenatal exposure to chemotherapy and reinforces the notion that chemotherapy during gestation does not endanger the fetus and her or his subsequent development,” said Fedro Alessandro Peccatori, MD, PhD, of the European Institute of Oncology in Milan, Italy, who was not involved in this study.
“To further ameliorate neonatal outcome, a special effort should be made to prolong pregnancy duration, and stringent long-term follow-up should be pursued to confirm these findings. Meanwhile, specific measures to support prematurely delivered babies and their families should be implemented.”
Dr Amant said future studies will explore the effects of specific chemotherapy types in detail and include longer-term follow-up.
Outcomes with radiation
In a second study, Dr Amant and his colleagues explored the impact of radiotherapy on the children of women with cancer.
The study included 16 children, with a median age of 6 years, who had been exposed to radiotherapy in utero. The median maternal irradiation was 48 Gy (range, 12-70), and the median estimated fetal irradiation was 91 mGy (range, 0-1690).
Neuropsychological, behavioral, and general health outcomes were within normal ranges for most of the children. And the researchers found no linear relationship between the fetal dose of radiation and cognitive outcome.
However, there was a negative linear relationship between the gestational age at radiotherapy exposure and verbal intelligence, based on results in 8 children. Two of these children were exposed to radiotherapy in the third trimester and had verbal intelligence scores outside the normal range.
One of the 2 children had low scores on all variables of cognitive development, but other pregnancy-related complications are confounding factors. The child’s mother suffered from an aggressive non-Hodgkin tumor of the brain that impacted her general state, and she had a preterm delivery.
Dr Amant noted that this is based on a very small number of children, so the results should be interpreted with caution.
“We cannot exclude that there might be an impact of prenatal radiotherapy exposure,” he said, “but larger series are needed to further investigate this relationship.”
MADRID—Two new studies suggest that children exposed to chemotherapy or radiotherapy in the womb can be spared negative long-term effects.
At a median age of 6, most of the children exposed to radiation in utero had neuropsychological, behavioral, and general health outcomes that were within normal ranges.
And children who were exposed to chemotherapy in the womb had normal mental and cardiac health at a median age of 2.
“When chemotherapy is administered after the first trimester of pregnancy, we cannot discern any problems in the children,” said Frederic Amant, MD, PhD, of University Hospitals Leuven in Belgium.
“Fear about the risks of chemotherapy administration should not be a reason to terminate a pregnancy, delay cancer treatment for the mother, or to deliver a baby prematurely.”
Dr Amant and his colleagues presented these findings (abstract 267PD_PR) and their findings on radiation (abstract 49LBA_PR) at the ESMO 2014 Congress.
Outcomes with chemotherapy
In the first study, the researchers recruited 38 children from the International Network for Cancer, Infertility and Pregnancy registry who were prenatally exposed to chemotherapy.
Most of the mothers had breast (61%) or hematologic (22%) cancers. Most were treated with anthracyclines (61%) and had received an average of 4 cycles (range, 1-7) of treatment.
The researchers assessed mental development and cardiac health in the children of these subjects, comparing them to 38 control children who were not exposed to chemotherapy.
At a median age of almost 2 years, mental development was in the normal range for both groups of children, and development was not significantly different between the groups. The mean Mental Development Index score was 99.13 for exposed children and 101.47 for controls.
Cardiac dimensions and functions were within normal ranges for both groups as well. Mean fractional shortening was 36% (range, 32-42) for exposed children and 39% (range, 32-51) for controls. Although the difference was signficant (P=0.004), the researchers said it was not clinically relevant.
“This paper points to the very important issue of long-term safety of prenatal exposure to chemotherapy and reinforces the notion that chemotherapy during gestation does not endanger the fetus and her or his subsequent development,” said Fedro Alessandro Peccatori, MD, PhD, of the European Institute of Oncology in Milan, Italy, who was not involved in this study.
“To further ameliorate neonatal outcome, a special effort should be made to prolong pregnancy duration, and stringent long-term follow-up should be pursued to confirm these findings. Meanwhile, specific measures to support prematurely delivered babies and their families should be implemented.”
Dr Amant said future studies will explore the effects of specific chemotherapy types in detail and include longer-term follow-up.
Outcomes with radiation
In a second study, Dr Amant and his colleagues explored the impact of radiotherapy on the children of women with cancer.
The study included 16 children, with a median age of 6 years, who had been exposed to radiotherapy in utero. The median maternal irradiation was 48 Gy (range, 12-70), and the median estimated fetal irradiation was 91 mGy (range, 0-1690).
Neuropsychological, behavioral, and general health outcomes were within normal ranges for most of the children. And the researchers found no linear relationship between the fetal dose of radiation and cognitive outcome.
However, there was a negative linear relationship between the gestational age at radiotherapy exposure and verbal intelligence, based on results in 8 children. Two of these children were exposed to radiotherapy in the third trimester and had verbal intelligence scores outside the normal range.
One of the 2 children had low scores on all variables of cognitive development, but other pregnancy-related complications are confounding factors. The child’s mother suffered from an aggressive non-Hodgkin tumor of the brain that impacted her general state, and she had a preterm delivery.
Dr Amant noted that this is based on a very small number of children, so the results should be interpreted with caution.
“We cannot exclude that there might be an impact of prenatal radiotherapy exposure,” he said, “but larger series are needed to further investigate this relationship.”
Consolidation can improve PFS in HL
Consolidation therapy with brentuximab vedotin can improve progression-free survival (PFS) for Hodgkin lymphoma (HL) patients who have undergone a transplant, according to a phase 3 study.
The trial, known as AETHERA, is a comparison of single-agent brentuximab vedotin to placebo in patients with HL who were at risk of relapse following autologous stem cell transplant (ASCT).
Brentuximab vedotin conferred a 75% improvement in PFS over placebo.
However, there was no significant difference in overall survival between the 2 treatment arms.
These results were recently announced by Seattle Genetics Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin (Adcetris).
The companies said more complete results from AETHERA will be presented at the 2014 ASH Annual Meeting in December.
AETHERA is a randomized, double-blind, placebo-controlled study designed to evaluate the potential of brentuximab vedotin to extend PFS post-ASCT in patients with HL who have at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included overall survival, safety, and tolerability.
Patients were eligible if they had risk factors for residual HL, defined as a history of refractory HL, those who relapse or progress within a year of receiving frontline chemotherapy, and/or those who have disease outside of the lymph nodes at the time of pre-ASCT relapse.
The study included 329 patients who received brentuximab vedotin or placebo every 3 weeks for up to a year.
The researchers assessed PFS a minimum of 2 years after the initiation of treatment for all patients. There was a significant improvement in PFS with brentuximab vedotin compared to placebo (hazard ratio=0.57; P=0.001).
However, a prespecified interim analysis of overall survival showed no significant difference between the treatment arms.
Patients in both arms who experienced progression received a variety of subsequent therapies. Most patients on the placebo arm received brentuximab vedotin after progression.
A further analysis of overall survival is planned in 2016. The safety profile of brentuximab vedotin in the AETHERA trial was generally consistent with the existing prescribing information.
“We anticipate reporting more complete AETHERA data at the ASH Annual Meeting in December and intend to submit a supplemental Biologics License Application to the FDA in 2015 for approval in this setting,” said Clay B. Siegall, PhD, President and Chief Executive Officer of Seattle Genetics.
The FDA has already granted brentuximab vedotin accelerated approval to treat HL patients after ASCT failure or after the failure of at least 2 prior multiagent chemotherapy regimens in patients who are not ASCT candidates. The FDA also granted the drug accelerated approval to treat systemic anaplastic large cell lymphoma after the failure of at least 1 prior multiagent chemotherapy regimen.
The European Commission granted brentuximab vedotin conditional marketing authorization for the same indications. In both cases, the drug can gain full, traditional approval once studies have shown it confers a clinical benefit.
Brentuximab vedotin has a boxed warning detailing the risk of progressive multifocal leukoencephalopathy associated with use of the drug. The drug has also been shown to pose a risk of pulmonary toxicity when combined with bleomycin. 
Consolidation therapy with brentuximab vedotin can improve progression-free survival (PFS) for Hodgkin lymphoma (HL) patients who have undergone a transplant, according to a phase 3 study.
The trial, known as AETHERA, is a comparison of single-agent brentuximab vedotin to placebo in patients with HL who were at risk of relapse following autologous stem cell transplant (ASCT).
Brentuximab vedotin conferred a 75% improvement in PFS over placebo.
However, there was no significant difference in overall survival between the 2 treatment arms.
These results were recently announced by Seattle Genetics Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin (Adcetris).
The companies said more complete results from AETHERA will be presented at the 2014 ASH Annual Meeting in December.
AETHERA is a randomized, double-blind, placebo-controlled study designed to evaluate the potential of brentuximab vedotin to extend PFS post-ASCT in patients with HL who have at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included overall survival, safety, and tolerability.
Patients were eligible if they had risk factors for residual HL, defined as a history of refractory HL, those who relapse or progress within a year of receiving frontline chemotherapy, and/or those who have disease outside of the lymph nodes at the time of pre-ASCT relapse.
The study included 329 patients who received brentuximab vedotin or placebo every 3 weeks for up to a year.
The researchers assessed PFS a minimum of 2 years after the initiation of treatment for all patients. There was a significant improvement in PFS with brentuximab vedotin compared to placebo (hazard ratio=0.57; P=0.001).
However, a prespecified interim analysis of overall survival showed no significant difference between the treatment arms.
Patients in both arms who experienced progression received a variety of subsequent therapies. Most patients on the placebo arm received brentuximab vedotin after progression.
A further analysis of overall survival is planned in 2016. The safety profile of brentuximab vedotin in the AETHERA trial was generally consistent with the existing prescribing information.
“We anticipate reporting more complete AETHERA data at the ASH Annual Meeting in December and intend to submit a supplemental Biologics License Application to the FDA in 2015 for approval in this setting,” said Clay B. Siegall, PhD, President and Chief Executive Officer of Seattle Genetics.
The FDA has already granted brentuximab vedotin accelerated approval to treat HL patients after ASCT failure or after the failure of at least 2 prior multiagent chemotherapy regimens in patients who are not ASCT candidates. The FDA also granted the drug accelerated approval to treat systemic anaplastic large cell lymphoma after the failure of at least 1 prior multiagent chemotherapy regimen.
The European Commission granted brentuximab vedotin conditional marketing authorization for the same indications. In both cases, the drug can gain full, traditional approval once studies have shown it confers a clinical benefit.
Brentuximab vedotin has a boxed warning detailing the risk of progressive multifocal leukoencephalopathy associated with use of the drug. The drug has also been shown to pose a risk of pulmonary toxicity when combined with bleomycin.
Consolidation therapy with brentuximab vedotin can improve progression-free survival (PFS) for Hodgkin lymphoma (HL) patients who have undergone a transplant, according to a phase 3 study.
The trial, known as AETHERA, is a comparison of single-agent brentuximab vedotin to placebo in patients with HL who were at risk of relapse following autologous stem cell transplant (ASCT).
Brentuximab vedotin conferred a 75% improvement in PFS over placebo.
However, there was no significant difference in overall survival between the 2 treatment arms.
These results were recently announced by Seattle Genetics Inc. and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin (Adcetris).
The companies said more complete results from AETHERA will be presented at the 2014 ASH Annual Meeting in December.
AETHERA is a randomized, double-blind, placebo-controlled study designed to evaluate the potential of brentuximab vedotin to extend PFS post-ASCT in patients with HL who have at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included overall survival, safety, and tolerability.
Patients were eligible if they had risk factors for residual HL, defined as a history of refractory HL, those who relapse or progress within a year of receiving frontline chemotherapy, and/or those who have disease outside of the lymph nodes at the time of pre-ASCT relapse.
The study included 329 patients who received brentuximab vedotin or placebo every 3 weeks for up to a year.
The researchers assessed PFS a minimum of 2 years after the initiation of treatment for all patients. There was a significant improvement in PFS with brentuximab vedotin compared to placebo (hazard ratio=0.57; P=0.001).
However, a prespecified interim analysis of overall survival showed no significant difference between the treatment arms.
Patients in both arms who experienced progression received a variety of subsequent therapies. Most patients on the placebo arm received brentuximab vedotin after progression.
A further analysis of overall survival is planned in 2016. The safety profile of brentuximab vedotin in the AETHERA trial was generally consistent with the existing prescribing information.
“We anticipate reporting more complete AETHERA data at the ASH Annual Meeting in December and intend to submit a supplemental Biologics License Application to the FDA in 2015 for approval in this setting,” said Clay B. Siegall, PhD, President and Chief Executive Officer of Seattle Genetics.
The FDA has already granted brentuximab vedotin accelerated approval to treat HL patients after ASCT failure or after the failure of at least 2 prior multiagent chemotherapy regimens in patients who are not ASCT candidates. The FDA also granted the drug accelerated approval to treat systemic anaplastic large cell lymphoma after the failure of at least 1 prior multiagent chemotherapy regimen.
The European Commission granted brentuximab vedotin conditional marketing authorization for the same indications. In both cases, the drug can gain full, traditional approval once studies have shown it confers a clinical benefit.
Brentuximab vedotin has a boxed warning detailing the risk of progressive multifocal leukoencephalopathy associated with use of the drug. The drug has also been shown to pose a risk of pulmonary toxicity when combined with bleomycin.
Maintenance may be unnecessary in FL
Credit: Bill Branson
New research suggests maintenance therapy may not be necessary for patients with follicular lymphoma (FL) who have a low tumor burden.
Investigators compared rituximab re-treatment with rituximab maintenance in nearly 300 FL patients, and results showed no significant difference between the treatment groups in the time to disease recurrence.
The researchers also noted that the re-treatment strategy was more cost-effective.
“For those 2 reasons, we recommend a retreatment strategy over a maintenance strategy in this patient population,” said Brad S. Kahl, MD, of the University of Wisconsin in Madison.
Dr Kahl and his colleagues described this research—the RESORT trial—in the Journal of Clinical Oncology. Early results from this trial were previously presented at the 2011 ASH Annual Meeting.
The team evaluated 289 patients with previously untreated, low-tumor-burden FL. All patients responded to initial treatment with rituximab (4 doses).
Patients were then randomized to receive maintenance therapy—a single dose of rituximab every 3 months until treatment failure—or rituximab re-treatment upon disease recurrence. Patients receiving re-treatment could receive rituximab every time they experienced progression, until treatment failure.
The median number of rituximab doses was 4 in the re-treatment arm and 18 in the maintenance arm. Three-year freedom from cytotoxic therapy was 84% in the re-treatment arm and 95% in the maintenance arm (P=0.03).
There was no significant difference between the arms in the time to disease recurrence. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years in the re-treatment arm and 4.3 years in the maintenance arm (P=0.54).
The researchers found no difference in health-related quality of life or anxiety between the treatment arms.
They also said grade 3 to 5 adverse events were infrequent in both arms. One patient developed progressive multifocal leukoencephalopathy after the 15th maintenance dose of rituximab and died.
Second malignancies were reported in 16 patients receiving re-treatment and 14 patients on maintenance therapy, but there were no obvious trends toward specific cancers.
“The study shows that a rituximab re-treatment strategy provides comparable disease control to a maintenance strategy in low-tumor-burden follicular lymphoma,” Dr Kahl said. “In addition, a re-treatment strategy is more cost-effective, as it requires about a quarter as much drug utilization.”
The study was accompanied by an editorial saying these results should change clinical practice.
Credit: Bill Branson
New research suggests maintenance therapy may not be necessary for patients with follicular lymphoma (FL) who have a low tumor burden.
Investigators compared rituximab re-treatment with rituximab maintenance in nearly 300 FL patients, and results showed no significant difference between the treatment groups in the time to disease recurrence.
The researchers also noted that the re-treatment strategy was more cost-effective.
“For those 2 reasons, we recommend a retreatment strategy over a maintenance strategy in this patient population,” said Brad S. Kahl, MD, of the University of Wisconsin in Madison.
Dr Kahl and his colleagues described this research—the RESORT trial—in the Journal of Clinical Oncology. Early results from this trial were previously presented at the 2011 ASH Annual Meeting.
The team evaluated 289 patients with previously untreated, low-tumor-burden FL. All patients responded to initial treatment with rituximab (4 doses).
Patients were then randomized to receive maintenance therapy—a single dose of rituximab every 3 months until treatment failure—or rituximab re-treatment upon disease recurrence. Patients receiving re-treatment could receive rituximab every time they experienced progression, until treatment failure.
The median number of rituximab doses was 4 in the re-treatment arm and 18 in the maintenance arm. Three-year freedom from cytotoxic therapy was 84% in the re-treatment arm and 95% in the maintenance arm (P=0.03).
There was no significant difference between the arms in the time to disease recurrence. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years in the re-treatment arm and 4.3 years in the maintenance arm (P=0.54).
The researchers found no difference in health-related quality of life or anxiety between the treatment arms.
They also said grade 3 to 5 adverse events were infrequent in both arms. One patient developed progressive multifocal leukoencephalopathy after the 15th maintenance dose of rituximab and died.
Second malignancies were reported in 16 patients receiving re-treatment and 14 patients on maintenance therapy, but there were no obvious trends toward specific cancers.
“The study shows that a rituximab re-treatment strategy provides comparable disease control to a maintenance strategy in low-tumor-burden follicular lymphoma,” Dr Kahl said. “In addition, a re-treatment strategy is more cost-effective, as it requires about a quarter as much drug utilization.”
The study was accompanied by an editorial saying these results should change clinical practice.
Credit: Bill Branson
New research suggests maintenance therapy may not be necessary for patients with follicular lymphoma (FL) who have a low tumor burden.
Investigators compared rituximab re-treatment with rituximab maintenance in nearly 300 FL patients, and results showed no significant difference between the treatment groups in the time to disease recurrence.
The researchers also noted that the re-treatment strategy was more cost-effective.
“For those 2 reasons, we recommend a retreatment strategy over a maintenance strategy in this patient population,” said Brad S. Kahl, MD, of the University of Wisconsin in Madison.
Dr Kahl and his colleagues described this research—the RESORT trial—in the Journal of Clinical Oncology. Early results from this trial were previously presented at the 2011 ASH Annual Meeting.
The team evaluated 289 patients with previously untreated, low-tumor-burden FL. All patients responded to initial treatment with rituximab (4 doses).
Patients were then randomized to receive maintenance therapy—a single dose of rituximab every 3 months until treatment failure—or rituximab re-treatment upon disease recurrence. Patients receiving re-treatment could receive rituximab every time they experienced progression, until treatment failure.
The median number of rituximab doses was 4 in the re-treatment arm and 18 in the maintenance arm. Three-year freedom from cytotoxic therapy was 84% in the re-treatment arm and 95% in the maintenance arm (P=0.03).
There was no significant difference between the arms in the time to disease recurrence. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years in the re-treatment arm and 4.3 years in the maintenance arm (P=0.54).
The researchers found no difference in health-related quality of life or anxiety between the treatment arms.
They also said grade 3 to 5 adverse events were infrequent in both arms. One patient developed progressive multifocal leukoencephalopathy after the 15th maintenance dose of rituximab and died.
Second malignancies were reported in 16 patients receiving re-treatment and 14 patients on maintenance therapy, but there were no obvious trends toward specific cancers.
“The study shows that a rituximab re-treatment strategy provides comparable disease control to a maintenance strategy in low-tumor-burden follicular lymphoma,” Dr Kahl said. “In addition, a re-treatment strategy is more cost-effective, as it requires about a quarter as much drug utilization.”
The study was accompanied by an editorial saying these results should change clinical practice.
Targeting drug resistance earlier
Credit: PNAS
PHILADELPHIA—A combination treatment strategy that takes tumor evolution into account could help us avoid drug resistance in hematologic malignancies, researchers say.
Preclinical experiments suggest we can prevent resistance by starting secondary treatment prior to relapse.
For example, a patient receiving dasatinib for acute lymphoblastic leukemia (ALL) could benefit from receiving crizotinib or foretinib during the early stages of clonal evolution.
The researchers described this strategy in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.
“Our goal is to identify vulnerabilities in cancer across stages of tumor evolution while it is developing resistance to initial treatment, to help guide the design of drug combination strategies,” said Douglas Lauffenburger, PhD, of the Koch Institute for Integrative Cancer Research at MIT in Boston.
“There may be many stages in a tumor evolution while under treatment that may make them vulnerable to already existing therapies. Rather than waiting for the tumor to become resistant to the first treatment and then thinking about a second-line drug to use, we can capitalize on opportunities that exploit vulnerabilities at different early stages, as the tumor is evolving to become resistant to the first drug.”
Dr Lauffenburger and his colleagues used a combination of computational and experimental approaches to identify drugs likely to be effective against a murine ALL cell line as the cells evolve.
To develop drug combinations based on the characteristics of evolving tumors, the researchers used escalating doses of imatinib, dasatinib, nilotinib, foretinib, and crizotinib on ALL cells.
As some cells exhibited resistance to a particular drug, the team treated the resistant cells with other drugs to check for cross-resistance. They found that resistant cells surviving at low multiples of the original drug dose actually demonstrated sensitization to certain other drugs, with the sensitization abrogated at higher doses.
Specifically, cell populations that were resistant to dasatinib at 1x and 2x IC90 became even more sensitive to crizotinib and foretinib. However, the sensitivity was lost at IC90 4x and above.
“Instead of only looking for the most resistant population of ALL cells at the end of this selection process, we monitored for drug sensitivity of the cells at each stage of the dose escalation,” Dr Lauffenburger explained.
“This led us to discover the vulnerabilities of a tumor at different stages of clonal evolution, a phenomenon we would have missed if we only analyzed for drug sensitivity at the last stage of this process, which is equivalent to when a patient has relapsed.”
Credit: PNAS
PHILADELPHIA—A combination treatment strategy that takes tumor evolution into account could help us avoid drug resistance in hematologic malignancies, researchers say.
Preclinical experiments suggest we can prevent resistance by starting secondary treatment prior to relapse.
For example, a patient receiving dasatinib for acute lymphoblastic leukemia (ALL) could benefit from receiving crizotinib or foretinib during the early stages of clonal evolution.
The researchers described this strategy in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.
“Our goal is to identify vulnerabilities in cancer across stages of tumor evolution while it is developing resistance to initial treatment, to help guide the design of drug combination strategies,” said Douglas Lauffenburger, PhD, of the Koch Institute for Integrative Cancer Research at MIT in Boston.
“There may be many stages in a tumor evolution while under treatment that may make them vulnerable to already existing therapies. Rather than waiting for the tumor to become resistant to the first treatment and then thinking about a second-line drug to use, we can capitalize on opportunities that exploit vulnerabilities at different early stages, as the tumor is evolving to become resistant to the first drug.”
Dr Lauffenburger and his colleagues used a combination of computational and experimental approaches to identify drugs likely to be effective against a murine ALL cell line as the cells evolve.
To develop drug combinations based on the characteristics of evolving tumors, the researchers used escalating doses of imatinib, dasatinib, nilotinib, foretinib, and crizotinib on ALL cells.
As some cells exhibited resistance to a particular drug, the team treated the resistant cells with other drugs to check for cross-resistance. They found that resistant cells surviving at low multiples of the original drug dose actually demonstrated sensitization to certain other drugs, with the sensitization abrogated at higher doses.
Specifically, cell populations that were resistant to dasatinib at 1x and 2x IC90 became even more sensitive to crizotinib and foretinib. However, the sensitivity was lost at IC90 4x and above.
“Instead of only looking for the most resistant population of ALL cells at the end of this selection process, we monitored for drug sensitivity of the cells at each stage of the dose escalation,” Dr Lauffenburger explained.
“This led us to discover the vulnerabilities of a tumor at different stages of clonal evolution, a phenomenon we would have missed if we only analyzed for drug sensitivity at the last stage of this process, which is equivalent to when a patient has relapsed.”
Credit: PNAS
PHILADELPHIA—A combination treatment strategy that takes tumor evolution into account could help us avoid drug resistance in hematologic malignancies, researchers say.
Preclinical experiments suggest we can prevent resistance by starting secondary treatment prior to relapse.
For example, a patient receiving dasatinib for acute lymphoblastic leukemia (ALL) could benefit from receiving crizotinib or foretinib during the early stages of clonal evolution.
The researchers described this strategy in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.
“Our goal is to identify vulnerabilities in cancer across stages of tumor evolution while it is developing resistance to initial treatment, to help guide the design of drug combination strategies,” said Douglas Lauffenburger, PhD, of the Koch Institute for Integrative Cancer Research at MIT in Boston.
“There may be many stages in a tumor evolution while under treatment that may make them vulnerable to already existing therapies. Rather than waiting for the tumor to become resistant to the first treatment and then thinking about a second-line drug to use, we can capitalize on opportunities that exploit vulnerabilities at different early stages, as the tumor is evolving to become resistant to the first drug.”
Dr Lauffenburger and his colleagues used a combination of computational and experimental approaches to identify drugs likely to be effective against a murine ALL cell line as the cells evolve.
To develop drug combinations based on the characteristics of evolving tumors, the researchers used escalating doses of imatinib, dasatinib, nilotinib, foretinib, and crizotinib on ALL cells.
As some cells exhibited resistance to a particular drug, the team treated the resistant cells with other drugs to check for cross-resistance. They found that resistant cells surviving at low multiples of the original drug dose actually demonstrated sensitization to certain other drugs, with the sensitization abrogated at higher doses.
Specifically, cell populations that were resistant to dasatinib at 1x and 2x IC90 became even more sensitive to crizotinib and foretinib. However, the sensitivity was lost at IC90 4x and above.
“Instead of only looking for the most resistant population of ALL cells at the end of this selection process, we monitored for drug sensitivity of the cells at each stage of the dose escalation,” Dr Lauffenburger explained.
“This led us to discover the vulnerabilities of a tumor at different stages of clonal evolution, a phenomenon we would have missed if we only analyzed for drug sensitivity at the last stage of this process, which is equivalent to when a patient has relapsed.”
Five genes linked to risk of severe malaria
Credit: Peter H. Seeberger
Investigators have identified 5 genes that appear to affect a person’s susceptibility to severe malaria.
The group’s analyses suggest that single-nucleotide polymorphisms (SNPs) in HBB, ABO, ATP2B4, G6PD, and CD40LG are associated with an increased or decreased risk of severe malaria, cerebral malaria, and severe malarial anemia.
This knowledge could lead to new therapeutics or vaccines to target severe malaria.
“[This study] has allowed for investigation of genes that influence susceptibility to malaria on a scale that has previously not been achieved,” said Sarah Dunstan, PhD, of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
“It involved a large number of severe malaria patients from multiple countries, which allows us to identify genes that truly have an effect on whether or not you develop severe malaria.”
Dr Dunstan and her colleagues detailed this research in Nature Genetics.
The team collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 control subjects across 12 locations in countries of Africa, Asia, and Oceania.
The researchers tested 55 SNPs in 27 gene regions that were associated with severe malaria in previous research: ABO, ADORA2B, ATP2B4, C6, CD36, CD40LG, CR1, ACKR1 (DARC), G6PD, GNAS, HBB, ICAM1, IL1A, IL1B, IL4, IL10, IL13, IL22, IRF1, LTA, NOS2, SPTB, TLR1, TLR4, TLR6, TLR9, and TNF.
The team found evidence of associations with the HBB, ABO, ATP2B4, G6PD, and CD40LG loci, but no association for the other 22 loci.
HBB
The HBB gene encodes β-globin, which has 3 variants associated with resistance to malaria: hemoglobin S (HbS), hemoglobin C (HbC), and hemoglobin E (HbE). The SNP responsible for HbE, rs33950507, was rare or absent in most groups, so the sample was too small to estimate association with severe malaria.
However, for HbS (SNP rs334), heterozygotes had a reduced risk of severe malaria (odds ratio [OR]=0.14; P=1.6×10−225), cerebral malaria (OR=0.11; P=4.7×10−88), and severe malarial anemia (OR=0.11; P=9.3×10−65).
For HbC (SNP rs33930165), each copy of the derived allele reduced the risk of severe malaria by 29% (OR=0.71; P=6.9×10−9), cerebral malaria by 28% (OR=0.72; P=0.01), and severe malarial anemia by 26% (OR=0.74; P=2.1×10−3).
ABO
The ABO gene encodes the glycosyltransferase enzyme that determines ABO blood group. Blood group O was associated with a lower risk of severe malaria (OR=0.74; P=5.0×10−32), cerebral malaria (OR=0.73; P=8.9×10−16), and severe malarial anemia (OR=0.68; P=7.9×10−14).
The researchers also found that rs8176746, an SNP in ABO that determines the production of B antigens, was associated with an increased risk of severe malaria (OR=1.25; P=2.0×10−17).
G6PD
G6PD is an X-linked gene encoding glucose-6-phosphate dehydrogenase. The investigators found that deficiency in G6PD (rs1050828 [G6PD c.202C>T]) can reduce the risk of cerebral malaria but increase the risk of severe malarial anemia.
There was an increased risk of severe malarial anemia in male hemizygotes (OR=1.49; P=3.6×10−5) and in female homozygotes (OR=1.94; P=1.9×10−3), as well as a decreased risk of cerebral malaria in female heterozygotes (OR=0.87; P=0.06) and male hemizygotes (OR=0.81; P=0.01).
ATP2B4
ATP2B4 encodes a calcium transporter found in the plasma membrane of erythrocytes. The derived alleles of rs10900585 and rs55868763 were associated with an increased risk of severe malaria, and the derived alleles of rs4951074 and rs1541255 were associated with a decreased risk.
Subjects with at least one copy of the derived allele at rs10900585 had an OR of 1.32 for severe malaria (P=1.7×10−9), and those homozygous for the derived allele at rs4951074 had an OR of 0.77 (P=7.6×10−7). Findings were similar for cerebral malaria and severe malarial anemia.
CD40LG
CD40LG is a gene on the X chromosome that has previously been associated with severe malaria. Homozygotes for the derived allele of rs3092945 had a decreased risk of severe malaria (OR=0.85; P=1.1×10−6) when the researchers analyzed data from the study sites together.
However, the results differed when they analyzed sites individually. For instance, homozygotes had a reduced risk of severe malaria in The Gambia (OR=0.54; P=2.3×10−22) and an increased risk in Kenya (OR=1.42; P=7.8×10−6).
These findings suggest the role of common human genetic disorders in severe malaria is more complex than we thought, Dr Dunstan said. But the results should enable a better understanding of the mechanisms and processes at work during progression to severe disease.
Credit: Peter H. Seeberger
Investigators have identified 5 genes that appear to affect a person’s susceptibility to severe malaria.
The group’s analyses suggest that single-nucleotide polymorphisms (SNPs) in HBB, ABO, ATP2B4, G6PD, and CD40LG are associated with an increased or decreased risk of severe malaria, cerebral malaria, and severe malarial anemia.
This knowledge could lead to new therapeutics or vaccines to target severe malaria.
“[This study] has allowed for investigation of genes that influence susceptibility to malaria on a scale that has previously not been achieved,” said Sarah Dunstan, PhD, of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
“It involved a large number of severe malaria patients from multiple countries, which allows us to identify genes that truly have an effect on whether or not you develop severe malaria.”
Dr Dunstan and her colleagues detailed this research in Nature Genetics.
The team collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 control subjects across 12 locations in countries of Africa, Asia, and Oceania.
The researchers tested 55 SNPs in 27 gene regions that were associated with severe malaria in previous research: ABO, ADORA2B, ATP2B4, C6, CD36, CD40LG, CR1, ACKR1 (DARC), G6PD, GNAS, HBB, ICAM1, IL1A, IL1B, IL4, IL10, IL13, IL22, IRF1, LTA, NOS2, SPTB, TLR1, TLR4, TLR6, TLR9, and TNF.
The team found evidence of associations with the HBB, ABO, ATP2B4, G6PD, and CD40LG loci, but no association for the other 22 loci.
HBB
The HBB gene encodes β-globin, which has 3 variants associated with resistance to malaria: hemoglobin S (HbS), hemoglobin C (HbC), and hemoglobin E (HbE). The SNP responsible for HbE, rs33950507, was rare or absent in most groups, so the sample was too small to estimate association with severe malaria.
However, for HbS (SNP rs334), heterozygotes had a reduced risk of severe malaria (odds ratio [OR]=0.14; P=1.6×10−225), cerebral malaria (OR=0.11; P=4.7×10−88), and severe malarial anemia (OR=0.11; P=9.3×10−65).
For HbC (SNP rs33930165), each copy of the derived allele reduced the risk of severe malaria by 29% (OR=0.71; P=6.9×10−9), cerebral malaria by 28% (OR=0.72; P=0.01), and severe malarial anemia by 26% (OR=0.74; P=2.1×10−3).
ABO
The ABO gene encodes the glycosyltransferase enzyme that determines ABO blood group. Blood group O was associated with a lower risk of severe malaria (OR=0.74; P=5.0×10−32), cerebral malaria (OR=0.73; P=8.9×10−16), and severe malarial anemia (OR=0.68; P=7.9×10−14).
The researchers also found that rs8176746, an SNP in ABO that determines the production of B antigens, was associated with an increased risk of severe malaria (OR=1.25; P=2.0×10−17).
G6PD
G6PD is an X-linked gene encoding glucose-6-phosphate dehydrogenase. The investigators found that deficiency in G6PD (rs1050828 [G6PD c.202C>T]) can reduce the risk of cerebral malaria but increase the risk of severe malarial anemia.
There was an increased risk of severe malarial anemia in male hemizygotes (OR=1.49; P=3.6×10−5) and in female homozygotes (OR=1.94; P=1.9×10−3), as well as a decreased risk of cerebral malaria in female heterozygotes (OR=0.87; P=0.06) and male hemizygotes (OR=0.81; P=0.01).
ATP2B4
ATP2B4 encodes a calcium transporter found in the plasma membrane of erythrocytes. The derived alleles of rs10900585 and rs55868763 were associated with an increased risk of severe malaria, and the derived alleles of rs4951074 and rs1541255 were associated with a decreased risk.
Subjects with at least one copy of the derived allele at rs10900585 had an OR of 1.32 for severe malaria (P=1.7×10−9), and those homozygous for the derived allele at rs4951074 had an OR of 0.77 (P=7.6×10−7). Findings were similar for cerebral malaria and severe malarial anemia.
CD40LG
CD40LG is a gene on the X chromosome that has previously been associated with severe malaria. Homozygotes for the derived allele of rs3092945 had a decreased risk of severe malaria (OR=0.85; P=1.1×10−6) when the researchers analyzed data from the study sites together.
However, the results differed when they analyzed sites individually. For instance, homozygotes had a reduced risk of severe malaria in The Gambia (OR=0.54; P=2.3×10−22) and an increased risk in Kenya (OR=1.42; P=7.8×10−6).
These findings suggest the role of common human genetic disorders in severe malaria is more complex than we thought, Dr Dunstan said. But the results should enable a better understanding of the mechanisms and processes at work during progression to severe disease.
Credit: Peter H. Seeberger
Investigators have identified 5 genes that appear to affect a person’s susceptibility to severe malaria.
The group’s analyses suggest that single-nucleotide polymorphisms (SNPs) in HBB, ABO, ATP2B4, G6PD, and CD40LG are associated with an increased or decreased risk of severe malaria, cerebral malaria, and severe malarial anemia.
This knowledge could lead to new therapeutics or vaccines to target severe malaria.
“[This study] has allowed for investigation of genes that influence susceptibility to malaria on a scale that has previously not been achieved,” said Sarah Dunstan, PhD, of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
“It involved a large number of severe malaria patients from multiple countries, which allows us to identify genes that truly have an effect on whether or not you develop severe malaria.”
Dr Dunstan and her colleagues detailed this research in Nature Genetics.
The team collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 control subjects across 12 locations in countries of Africa, Asia, and Oceania.
The researchers tested 55 SNPs in 27 gene regions that were associated with severe malaria in previous research: ABO, ADORA2B, ATP2B4, C6, CD36, CD40LG, CR1, ACKR1 (DARC), G6PD, GNAS, HBB, ICAM1, IL1A, IL1B, IL4, IL10, IL13, IL22, IRF1, LTA, NOS2, SPTB, TLR1, TLR4, TLR6, TLR9, and TNF.
The team found evidence of associations with the HBB, ABO, ATP2B4, G6PD, and CD40LG loci, but no association for the other 22 loci.
HBB
The HBB gene encodes β-globin, which has 3 variants associated with resistance to malaria: hemoglobin S (HbS), hemoglobin C (HbC), and hemoglobin E (HbE). The SNP responsible for HbE, rs33950507, was rare or absent in most groups, so the sample was too small to estimate association with severe malaria.
However, for HbS (SNP rs334), heterozygotes had a reduced risk of severe malaria (odds ratio [OR]=0.14; P=1.6×10−225), cerebral malaria (OR=0.11; P=4.7×10−88), and severe malarial anemia (OR=0.11; P=9.3×10−65).
For HbC (SNP rs33930165), each copy of the derived allele reduced the risk of severe malaria by 29% (OR=0.71; P=6.9×10−9), cerebral malaria by 28% (OR=0.72; P=0.01), and severe malarial anemia by 26% (OR=0.74; P=2.1×10−3).
ABO
The ABO gene encodes the glycosyltransferase enzyme that determines ABO blood group. Blood group O was associated with a lower risk of severe malaria (OR=0.74; P=5.0×10−32), cerebral malaria (OR=0.73; P=8.9×10−16), and severe malarial anemia (OR=0.68; P=7.9×10−14).
The researchers also found that rs8176746, an SNP in ABO that determines the production of B antigens, was associated with an increased risk of severe malaria (OR=1.25; P=2.0×10−17).
G6PD
G6PD is an X-linked gene encoding glucose-6-phosphate dehydrogenase. The investigators found that deficiency in G6PD (rs1050828 [G6PD c.202C>T]) can reduce the risk of cerebral malaria but increase the risk of severe malarial anemia.
There was an increased risk of severe malarial anemia in male hemizygotes (OR=1.49; P=3.6×10−5) and in female homozygotes (OR=1.94; P=1.9×10−3), as well as a decreased risk of cerebral malaria in female heterozygotes (OR=0.87; P=0.06) and male hemizygotes (OR=0.81; P=0.01).
ATP2B4
ATP2B4 encodes a calcium transporter found in the plasma membrane of erythrocytes. The derived alleles of rs10900585 and rs55868763 were associated with an increased risk of severe malaria, and the derived alleles of rs4951074 and rs1541255 were associated with a decreased risk.
Subjects with at least one copy of the derived allele at rs10900585 had an OR of 1.32 for severe malaria (P=1.7×10−9), and those homozygous for the derived allele at rs4951074 had an OR of 0.77 (P=7.6×10−7). Findings were similar for cerebral malaria and severe malarial anemia.
CD40LG
CD40LG is a gene on the X chromosome that has previously been associated with severe malaria. Homozygotes for the derived allele of rs3092945 had a decreased risk of severe malaria (OR=0.85; P=1.1×10−6) when the researchers analyzed data from the study sites together.
However, the results differed when they analyzed sites individually. For instance, homozygotes had a reduced risk of severe malaria in The Gambia (OR=0.54; P=2.3×10−22) and an increased risk in Kenya (OR=1.42; P=7.8×10−6).
These findings suggest the role of common human genetic disorders in severe malaria is more complex than we thought, Dr Dunstan said. But the results should enable a better understanding of the mechanisms and processes at work during progression to severe disease.
Study points to potential anemia treatment
Credit: Georges Seguin
Acetate, the major component of vinegar, can stimulate erythropoiesis in anemic mice, according to research published in Nature Medicine.
The study suggests acetate supplements could eventually be a suitable addition or even an alternative to erythropoietin (EPO) therapy.
“[W]e may be able to treat acutely or chronically anemic patients with acetate supplements and thereby reduce the need for blood transfusions or erythropoietin therapy,” said Joseph Garcia, MD, PhD, of the UT Southwestern Medical Center in Dallas, Texas.
He and his colleagues began this study by identifying a pathway that controls erythropoiesis in conditions of stress, such as hypoxia.
Studying genetically modified mice, the researchers discovered that hypoxia stimulates the production of acetate. Acetate, in turn, activates a molecular pathway that ultimately results in erythropoiesis by triggering EPO production.
EPO is regulated by the stress-responsive transcription factor hypoxia-inducible factor-2 (HIF-2). And the researchers had previously shown that the lysine acetyltransferase CREB-binding protein (CBP) is required for HIF-2a acetylation and efficient HIF-2-dependent EPO induction during hypoxia.
With this study, the team found that these processes require acetate-dependent acetyl CoA synthetase 2 (ACSS2) as well.
Experiments showed that ACSS2 is required for HIF-2a acetylation, CBP-HIF-2a complex formation, CBP-HIF-2a recruitment to the EPO enhancer, and efficient induction of EPO gene expression.
The researchers administered acetate to acutely anemic mice and found the treatment augments stress erythropoiesis in an ACSS2-dependent manner.
When they administered acetate to mice with acquired and inherited chronic anemia, the team observed increases in EPO expression and resting hematocrit.
“Our study shows that acetate functions as a biochemical ‘flare,’” Dr Garcia said, “linking changes in cell metabolism that occur during hypoxia with the activation of a selective stress signaling pathway.”
Credit: Georges Seguin
Acetate, the major component of vinegar, can stimulate erythropoiesis in anemic mice, according to research published in Nature Medicine.
The study suggests acetate supplements could eventually be a suitable addition or even an alternative to erythropoietin (EPO) therapy.
“[W]e may be able to treat acutely or chronically anemic patients with acetate supplements and thereby reduce the need for blood transfusions or erythropoietin therapy,” said Joseph Garcia, MD, PhD, of the UT Southwestern Medical Center in Dallas, Texas.
He and his colleagues began this study by identifying a pathway that controls erythropoiesis in conditions of stress, such as hypoxia.
Studying genetically modified mice, the researchers discovered that hypoxia stimulates the production of acetate. Acetate, in turn, activates a molecular pathway that ultimately results in erythropoiesis by triggering EPO production.
EPO is regulated by the stress-responsive transcription factor hypoxia-inducible factor-2 (HIF-2). And the researchers had previously shown that the lysine acetyltransferase CREB-binding protein (CBP) is required for HIF-2a acetylation and efficient HIF-2-dependent EPO induction during hypoxia.
With this study, the team found that these processes require acetate-dependent acetyl CoA synthetase 2 (ACSS2) as well.
Experiments showed that ACSS2 is required for HIF-2a acetylation, CBP-HIF-2a complex formation, CBP-HIF-2a recruitment to the EPO enhancer, and efficient induction of EPO gene expression.
The researchers administered acetate to acutely anemic mice and found the treatment augments stress erythropoiesis in an ACSS2-dependent manner.
When they administered acetate to mice with acquired and inherited chronic anemia, the team observed increases in EPO expression and resting hematocrit.
“Our study shows that acetate functions as a biochemical ‘flare,’” Dr Garcia said, “linking changes in cell metabolism that occur during hypoxia with the activation of a selective stress signaling pathway.”
Credit: Georges Seguin
Acetate, the major component of vinegar, can stimulate erythropoiesis in anemic mice, according to research published in Nature Medicine.
The study suggests acetate supplements could eventually be a suitable addition or even an alternative to erythropoietin (EPO) therapy.
“[W]e may be able to treat acutely or chronically anemic patients with acetate supplements and thereby reduce the need for blood transfusions or erythropoietin therapy,” said Joseph Garcia, MD, PhD, of the UT Southwestern Medical Center in Dallas, Texas.
He and his colleagues began this study by identifying a pathway that controls erythropoiesis in conditions of stress, such as hypoxia.
Studying genetically modified mice, the researchers discovered that hypoxia stimulates the production of acetate. Acetate, in turn, activates a molecular pathway that ultimately results in erythropoiesis by triggering EPO production.
EPO is regulated by the stress-responsive transcription factor hypoxia-inducible factor-2 (HIF-2). And the researchers had previously shown that the lysine acetyltransferase CREB-binding protein (CBP) is required for HIF-2a acetylation and efficient HIF-2-dependent EPO induction during hypoxia.
With this study, the team found that these processes require acetate-dependent acetyl CoA synthetase 2 (ACSS2) as well.
Experiments showed that ACSS2 is required for HIF-2a acetylation, CBP-HIF-2a complex formation, CBP-HIF-2a recruitment to the EPO enhancer, and efficient induction of EPO gene expression.
The researchers administered acetate to acutely anemic mice and found the treatment augments stress erythropoiesis in an ACSS2-dependent manner.
When they administered acetate to mice with acquired and inherited chronic anemia, the team observed increases in EPO expression and resting hematocrit.
“Our study shows that acetate functions as a biochemical ‘flare,’” Dr Garcia said, “linking changes in cell metabolism that occur during hypoxia with the activation of a selective stress signaling pathway.”
Combo shows potential as frontline therapy in PTCL
Credit: NIH
MADRID—Follow-up data from a phase 1 trial suggest brentuximab vedotin plus chemotherapy may be a feasible frontline option for patients with peripheral T-cell lymphoma (PTCL).
At the ESMO 2014 Congress, investigators presented a 2-year durability analysis from a trial of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV+CHP) in patients newly diagnosed with PTCL.
The estimated 2-year overall survival rate was 80% in these patients. And the median progression-free survival was not reached.
Michelle Fanale, MD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these results as abstract 944O.
The research was sponsored by Seattle Genetics Inc. and Takeda Pharmaceuticals International, the companies co-developing brentuximab vedotin (Adcetris).
In this trial, patients received 1 of 2 treatment regimens. The first was sequential treatment (once every 3 weeks) with brentuximab vedotin at 1.8 mg/kg for 2 cycles, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for 6 cycles.
The second was combination BV+CHP every 3 weeks for 6 cycles. Patients who achieved at least a partial response after 6 cycles of treatment were eligible to receive continued single-agent brentuximab vedotin for up to 10 additional 3-week cycles.
Earlier results with both treatment regimens were published in the Journal of Clinical Oncology. At ESMO, Dr Fanale presented 2-year results among the 26 patients who received BV+CHP.
The median patient age was 56 years. Nineteen patients had systemic anaplastic large-cell lymphoma (sALCL), including 16 patients (62%) with ALK-negative disease.
Two patients had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma. The majority of patients had advanced-stage disease and/or were considered high risk.
All 26 patients had an objective response to BV+CHP, including 23 patients (88%) with a complete response. All 23 patients who achieved a complete remission demonstrated normalized glucose uptake by PET.
The median observation time was 27.1 months from the first dose of therapy. The estimated 2-year progression-free survival rate was 54%, with no patients receiving a consolidative stem cell transplant. And the estimated 2-year overall survival rate was 80%.
The most common treatment-emergent adverse events of any grade occurring in more than 40% of patients were peripheral sensory neuropathy, nausea, fatigue, hair loss, diarrhea, and shortness of breath.
Based on the results of this study, Seattle Genetics and Takeda initiated a global phase 3 study called ECHELON-2. This randomized, double-blind, placebo-controlled, multicenter trial was designed to investigate BV+CHP vs CHOP as frontline therapy in patients with CD30-positive PTCL.
The study is currently enrolling patients. It is expected to enroll 300 patients, who will be randomized to receive either treatment every 3 weeks for 6 to 8 cycles.
Credit: NIH
MADRID—Follow-up data from a phase 1 trial suggest brentuximab vedotin plus chemotherapy may be a feasible frontline option for patients with peripheral T-cell lymphoma (PTCL).
At the ESMO 2014 Congress, investigators presented a 2-year durability analysis from a trial of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV+CHP) in patients newly diagnosed with PTCL.
The estimated 2-year overall survival rate was 80% in these patients. And the median progression-free survival was not reached.
Michelle Fanale, MD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these results as abstract 944O.
The research was sponsored by Seattle Genetics Inc. and Takeda Pharmaceuticals International, the companies co-developing brentuximab vedotin (Adcetris).
In this trial, patients received 1 of 2 treatment regimens. The first was sequential treatment (once every 3 weeks) with brentuximab vedotin at 1.8 mg/kg for 2 cycles, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for 6 cycles.
The second was combination BV+CHP every 3 weeks for 6 cycles. Patients who achieved at least a partial response after 6 cycles of treatment were eligible to receive continued single-agent brentuximab vedotin for up to 10 additional 3-week cycles.
Earlier results with both treatment regimens were published in the Journal of Clinical Oncology. At ESMO, Dr Fanale presented 2-year results among the 26 patients who received BV+CHP.
The median patient age was 56 years. Nineteen patients had systemic anaplastic large-cell lymphoma (sALCL), including 16 patients (62%) with ALK-negative disease.
Two patients had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma. The majority of patients had advanced-stage disease and/or were considered high risk.
All 26 patients had an objective response to BV+CHP, including 23 patients (88%) with a complete response. All 23 patients who achieved a complete remission demonstrated normalized glucose uptake by PET.
The median observation time was 27.1 months from the first dose of therapy. The estimated 2-year progression-free survival rate was 54%, with no patients receiving a consolidative stem cell transplant. And the estimated 2-year overall survival rate was 80%.
The most common treatment-emergent adverse events of any grade occurring in more than 40% of patients were peripheral sensory neuropathy, nausea, fatigue, hair loss, diarrhea, and shortness of breath.
Based on the results of this study, Seattle Genetics and Takeda initiated a global phase 3 study called ECHELON-2. This randomized, double-blind, placebo-controlled, multicenter trial was designed to investigate BV+CHP vs CHOP as frontline therapy in patients with CD30-positive PTCL.
The study is currently enrolling patients. It is expected to enroll 300 patients, who will be randomized to receive either treatment every 3 weeks for 6 to 8 cycles.
Credit: NIH
MADRID—Follow-up data from a phase 1 trial suggest brentuximab vedotin plus chemotherapy may be a feasible frontline option for patients with peripheral T-cell lymphoma (PTCL).
At the ESMO 2014 Congress, investigators presented a 2-year durability analysis from a trial of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV+CHP) in patients newly diagnosed with PTCL.
The estimated 2-year overall survival rate was 80% in these patients. And the median progression-free survival was not reached.
Michelle Fanale, MD, of The University of Texas MD Anderson Cancer Center in Houston, and her colleagues reported these results as abstract 944O.
The research was sponsored by Seattle Genetics Inc. and Takeda Pharmaceuticals International, the companies co-developing brentuximab vedotin (Adcetris).
In this trial, patients received 1 of 2 treatment regimens. The first was sequential treatment (once every 3 weeks) with brentuximab vedotin at 1.8 mg/kg for 2 cycles, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for 6 cycles.
The second was combination BV+CHP every 3 weeks for 6 cycles. Patients who achieved at least a partial response after 6 cycles of treatment were eligible to receive continued single-agent brentuximab vedotin for up to 10 additional 3-week cycles.
Earlier results with both treatment regimens were published in the Journal of Clinical Oncology. At ESMO, Dr Fanale presented 2-year results among the 26 patients who received BV+CHP.
The median patient age was 56 years. Nineteen patients had systemic anaplastic large-cell lymphoma (sALCL), including 16 patients (62%) with ALK-negative disease.
Two patients had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma. The majority of patients had advanced-stage disease and/or were considered high risk.
All 26 patients had an objective response to BV+CHP, including 23 patients (88%) with a complete response. All 23 patients who achieved a complete remission demonstrated normalized glucose uptake by PET.
The median observation time was 27.1 months from the first dose of therapy. The estimated 2-year progression-free survival rate was 54%, with no patients receiving a consolidative stem cell transplant. And the estimated 2-year overall survival rate was 80%.
The most common treatment-emergent adverse events of any grade occurring in more than 40% of patients were peripheral sensory neuropathy, nausea, fatigue, hair loss, diarrhea, and shortness of breath.
Based on the results of this study, Seattle Genetics and Takeda initiated a global phase 3 study called ECHELON-2. This randomized, double-blind, placebo-controlled, multicenter trial was designed to investigate BV+CHP vs CHOP as frontline therapy in patients with CD30-positive PTCL.
The study is currently enrolling patients. It is expected to enroll 300 patients, who will be randomized to receive either treatment every 3 weeks for 6 to 8 cycles.
Drug can prevent chemo-induced nausea, vomiting
Credit: Rhoda Baer
MADRID—A small molecule called rolapitant can prevent nausea and vomiting in patients receiving cisplatin-based chemotherapy, results of a phase 3 trial suggest.
When given prior to chemotherapy, rolapitant induced a complete response in about 70% of patients.
These patients had no emesis after chemotherapy and did not require any rescue medication.
“This agent makes a significant difference in the way people tolerate their chemotherapy,” said Martin Chasen, MD, of Ottawa Hospital Cancer Centre in Canada.
“Patients experienced no loss in quality of life, and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he had just finished 18 holes of golf one week after receiving chemotherapy. This is in sharp contrast to many patients on current standard anti-emetics that are too ill to get out of bed within a week after each cycle of cisplatin.”
Dr Chasen and his colleagues reported these results at the ESMO 2014 Congress (abstract LBA47_PR).
The team had set out to evaluate rolapitant, a novel antagonist of the NK-1 receptor, for the prevention of severe nausea and vomiting often experienced by patients receiving cisplatin-based chemotherapy, which may cause dose reductions and treatment discontinuation.
The trial included 532 patients who were randomized 1:1 to receive rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to chemotherapy.
The primary endpoint was complete response (defined as the patient having no emesis and not requiring any rescue medication) in the delayed phase (>24-120 hours) post-chemotherapy. Key secondary endpoints included complete response during the acute phase (0-24 hours) and overall (0-120 hours).
The trial met its primary endpoint, with 72.7% of patients receiving rolapitant achieving a complete response in the delayed phase, compared to 58.4% of those receiving placebo (P<0.001).
Rolapitant also improved the complete response rate compared to placebo in the acute phase—83.7% and 73.7%, respectively (P=0.005).
Overall, the complete response rates were 70.1% and 56.5%, respectively (P=0.001).
Patients receiving rolapitant tended to report that chemotherapy had less of an impact on their daily quality of life, although the difference between the treatment arms was not significant—72.8% vs 67.8% (P=0.231).
“Rolapitant demonstrated a significant effect in both the acute and delayed phases,” Dr Chasen noted. “Our primary endpoint was achieved in the delayed phase—an incredible result.”
“We know that the NK-1 receptor in the brain must be blocked to control nausea and vomiting. Rolapitant is an exceptionally long-term receptor blocker that binds to the receptor and remains in place for up to 120 hours, therefore not allowing the chemotherapy to induce nausea and vomiting.”
Dr Chasen added that rolapitant may prove effective in patients receiving less emetogenic cancer treatments as well.
Credit: Rhoda Baer
MADRID—A small molecule called rolapitant can prevent nausea and vomiting in patients receiving cisplatin-based chemotherapy, results of a phase 3 trial suggest.
When given prior to chemotherapy, rolapitant induced a complete response in about 70% of patients.
These patients had no emesis after chemotherapy and did not require any rescue medication.
“This agent makes a significant difference in the way people tolerate their chemotherapy,” said Martin Chasen, MD, of Ottawa Hospital Cancer Centre in Canada.
“Patients experienced no loss in quality of life, and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he had just finished 18 holes of golf one week after receiving chemotherapy. This is in sharp contrast to many patients on current standard anti-emetics that are too ill to get out of bed within a week after each cycle of cisplatin.”
Dr Chasen and his colleagues reported these results at the ESMO 2014 Congress (abstract LBA47_PR).
The team had set out to evaluate rolapitant, a novel antagonist of the NK-1 receptor, for the prevention of severe nausea and vomiting often experienced by patients receiving cisplatin-based chemotherapy, which may cause dose reductions and treatment discontinuation.
The trial included 532 patients who were randomized 1:1 to receive rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to chemotherapy.
The primary endpoint was complete response (defined as the patient having no emesis and not requiring any rescue medication) in the delayed phase (>24-120 hours) post-chemotherapy. Key secondary endpoints included complete response during the acute phase (0-24 hours) and overall (0-120 hours).
The trial met its primary endpoint, with 72.7% of patients receiving rolapitant achieving a complete response in the delayed phase, compared to 58.4% of those receiving placebo (P<0.001).
Rolapitant also improved the complete response rate compared to placebo in the acute phase—83.7% and 73.7%, respectively (P=0.005).
Overall, the complete response rates were 70.1% and 56.5%, respectively (P=0.001).
Patients receiving rolapitant tended to report that chemotherapy had less of an impact on their daily quality of life, although the difference between the treatment arms was not significant—72.8% vs 67.8% (P=0.231).
“Rolapitant demonstrated a significant effect in both the acute and delayed phases,” Dr Chasen noted. “Our primary endpoint was achieved in the delayed phase—an incredible result.”
“We know that the NK-1 receptor in the brain must be blocked to control nausea and vomiting. Rolapitant is an exceptionally long-term receptor blocker that binds to the receptor and remains in place for up to 120 hours, therefore not allowing the chemotherapy to induce nausea and vomiting.”
Dr Chasen added that rolapitant may prove effective in patients receiving less emetogenic cancer treatments as well.
Credit: Rhoda Baer
MADRID—A small molecule called rolapitant can prevent nausea and vomiting in patients receiving cisplatin-based chemotherapy, results of a phase 3 trial suggest.
When given prior to chemotherapy, rolapitant induced a complete response in about 70% of patients.
These patients had no emesis after chemotherapy and did not require any rescue medication.
“This agent makes a significant difference in the way people tolerate their chemotherapy,” said Martin Chasen, MD, of Ottawa Hospital Cancer Centre in Canada.
“Patients experienced no loss in quality of life, and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he had just finished 18 holes of golf one week after receiving chemotherapy. This is in sharp contrast to many patients on current standard anti-emetics that are too ill to get out of bed within a week after each cycle of cisplatin.”
Dr Chasen and his colleagues reported these results at the ESMO 2014 Congress (abstract LBA47_PR).
The team had set out to evaluate rolapitant, a novel antagonist of the NK-1 receptor, for the prevention of severe nausea and vomiting often experienced by patients receiving cisplatin-based chemotherapy, which may cause dose reductions and treatment discontinuation.
The trial included 532 patients who were randomized 1:1 to receive rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to chemotherapy.
The primary endpoint was complete response (defined as the patient having no emesis and not requiring any rescue medication) in the delayed phase (>24-120 hours) post-chemotherapy. Key secondary endpoints included complete response during the acute phase (0-24 hours) and overall (0-120 hours).
The trial met its primary endpoint, with 72.7% of patients receiving rolapitant achieving a complete response in the delayed phase, compared to 58.4% of those receiving placebo (P<0.001).
Rolapitant also improved the complete response rate compared to placebo in the acute phase—83.7% and 73.7%, respectively (P=0.005).
Overall, the complete response rates were 70.1% and 56.5%, respectively (P=0.001).
Patients receiving rolapitant tended to report that chemotherapy had less of an impact on their daily quality of life, although the difference between the treatment arms was not significant—72.8% vs 67.8% (P=0.231).
“Rolapitant demonstrated a significant effect in both the acute and delayed phases,” Dr Chasen noted. “Our primary endpoint was achieved in the delayed phase—an incredible result.”
“We know that the NK-1 receptor in the brain must be blocked to control nausea and vomiting. Rolapitant is an exceptionally long-term receptor blocker that binds to the receptor and remains in place for up to 120 hours, therefore not allowing the chemotherapy to induce nausea and vomiting.”
Dr Chasen added that rolapitant may prove effective in patients receiving less emetogenic cancer treatments as well.
Research could aid platelet production
in the bone marrow
Scientists say they’ve shed new light on the mechanism of platelet formation, paving the way to accelerating and enhancing platelet production using stem cells.
The group uncovered their findings by studying the effects of shear stress on megakaryocyte maturation and the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
“Until recently, these microparticles were viewed as inconsequential cell debris,” said Terry Papoutsakis, PhD, of the University of Delaware in Newark.
“We now know that they play a significant biological role in platelet formation. The enhanced generation of preplatelets and platelet-like particles under shear stress correlates with physiological observations—in healthy adults, both acute and prolonged exercise leads to elevated platelet counts.”
“Now, these findings can be used to develop better bioreactor technologies for producing platelets, preplatelets, platelet-like particles, and megakaryocyte microparticles for transfusion medicine, using stem cells as starting material.”
Dr Papoutsakis and his colleagues described these findings in Blood.
The researchers discovered that shear stress accelerated DNA synthesis of immature megakaryocytes, and this was dependent upon exposure time and the shear stress level.
Physiological shear stress increased the formation of preplatelets and platelet-like particles up to 10.8-fold. And it increased megakaryocyte microparticle production up to 47-fold. Platelet-like particles generated under shear flow showed improved function.
Experiments also revealed that phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. But inhibiting caspase-3 reduced the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
Finally, the researchers found that coculturing megakaryocyte microparticles with hematopoietic stem and progenitor cells promoted differentiation to mature megakaryocytes that synthesized α- and dense-granules, and formed preplatelets without exogenous thrombopoietin.
The team noted that, unlike platelets themselves, these microparticles can be frozen, which will enable them to be stored and used for platelet production on an as-needed basis.
“Knowing that these microparticles have a biological function opens the door to other applications, including genetic therapies,” Dr Papoutsakis said. “We’re hopeful that our discovery can break the vicious cycle of [immune thrombocytopenia] as well as other conditions that cause reduced platelet count and cause life-threatening bleeding.”
in the bone marrow
Scientists say they’ve shed new light on the mechanism of platelet formation, paving the way to accelerating and enhancing platelet production using stem cells.
The group uncovered their findings by studying the effects of shear stress on megakaryocyte maturation and the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
“Until recently, these microparticles were viewed as inconsequential cell debris,” said Terry Papoutsakis, PhD, of the University of Delaware in Newark.
“We now know that they play a significant biological role in platelet formation. The enhanced generation of preplatelets and platelet-like particles under shear stress correlates with physiological observations—in healthy adults, both acute and prolonged exercise leads to elevated platelet counts.”
“Now, these findings can be used to develop better bioreactor technologies for producing platelets, preplatelets, platelet-like particles, and megakaryocyte microparticles for transfusion medicine, using stem cells as starting material.”
Dr Papoutsakis and his colleagues described these findings in Blood.
The researchers discovered that shear stress accelerated DNA synthesis of immature megakaryocytes, and this was dependent upon exposure time and the shear stress level.
Physiological shear stress increased the formation of preplatelets and platelet-like particles up to 10.8-fold. And it increased megakaryocyte microparticle production up to 47-fold. Platelet-like particles generated under shear flow showed improved function.
Experiments also revealed that phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. But inhibiting caspase-3 reduced the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
Finally, the researchers found that coculturing megakaryocyte microparticles with hematopoietic stem and progenitor cells promoted differentiation to mature megakaryocytes that synthesized α- and dense-granules, and formed preplatelets without exogenous thrombopoietin.
The team noted that, unlike platelets themselves, these microparticles can be frozen, which will enable them to be stored and used for platelet production on an as-needed basis.
“Knowing that these microparticles have a biological function opens the door to other applications, including genetic therapies,” Dr Papoutsakis said. “We’re hopeful that our discovery can break the vicious cycle of [immune thrombocytopenia] as well as other conditions that cause reduced platelet count and cause life-threatening bleeding.”
in the bone marrow
Scientists say they’ve shed new light on the mechanism of platelet formation, paving the way to accelerating and enhancing platelet production using stem cells.
The group uncovered their findings by studying the effects of shear stress on megakaryocyte maturation and the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
“Until recently, these microparticles were viewed as inconsequential cell debris,” said Terry Papoutsakis, PhD, of the University of Delaware in Newark.
“We now know that they play a significant biological role in platelet formation. The enhanced generation of preplatelets and platelet-like particles under shear stress correlates with physiological observations—in healthy adults, both acute and prolonged exercise leads to elevated platelet counts.”
“Now, these findings can be used to develop better bioreactor technologies for producing platelets, preplatelets, platelet-like particles, and megakaryocyte microparticles for transfusion medicine, using stem cells as starting material.”
Dr Papoutsakis and his colleagues described these findings in Blood.
The researchers discovered that shear stress accelerated DNA synthesis of immature megakaryocytes, and this was dependent upon exposure time and the shear stress level.
Physiological shear stress increased the formation of preplatelets and platelet-like particles up to 10.8-fold. And it increased megakaryocyte microparticle production up to 47-fold. Platelet-like particles generated under shear flow showed improved function.
Experiments also revealed that phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. But inhibiting caspase-3 reduced the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
Finally, the researchers found that coculturing megakaryocyte microparticles with hematopoietic stem and progenitor cells promoted differentiation to mature megakaryocytes that synthesized α- and dense-granules, and formed preplatelets without exogenous thrombopoietin.
The team noted that, unlike platelets themselves, these microparticles can be frozen, which will enable them to be stored and used for platelet production on an as-needed basis.
“Knowing that these microparticles have a biological function opens the door to other applications, including genetic therapies,” Dr Papoutsakis said. “We’re hopeful that our discovery can break the vicious cycle of [immune thrombocytopenia] as well as other conditions that cause reduced platelet count and cause life-threatening bleeding.”