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Research helps explain how malaria evolved
Photo by Holly Lutz
A study published in Molecular Phylogenetics and Evolution has revealed a new hypothesis on the evolution of malaria.
Researchers tested malarial DNA found in birds, bats, and other small mammals from 5 East African countries and found evidence to suggest that malaria has its roots in bird hosts.
It then spread to bats and on to other mammals.
“We can’t begin to understand how malaria spread to humans until we understand its evolutionary history,” said Holly Lutz, a doctoral candidate at Cornell University in Ithaca, New York.
“In learning about its past, we may be better able to understand the effects it has on us.”
Lutz and her colleagues took blood samples from hundreds of East African birds, bats, and other small mammals and screened the blood for malaria parasites.
When they found malaria, the team took samples of the parasites’ DNA and sequenced it to identify mutations in the genetic code. From there, the researchers performed phylogenetic analyses to determine how different malaria species are related.
In analyzing the genetic codes of the parasites, the team was able to find places where the DNA differed from one species to the next. Then, the researchers used computing software to determine how the different species evolved and how they’re related to each other.
“[B]y looking at patterns of mutations in the DNA of the different malaria species, we’re able to see when it branched off from one host group into another,” Lutz explained. “It started out as a parasite in birds, and then it evolved to colonize bats, and from there, it’s evolved to affect other mammals.”
In addition to shedding light on the way malaria was able to evolve and spread, the study provides information about the manner in which animals and their parasites are connected.
“Each of these individual vertebrates is an ecosystem in and of itself,” Lutz said. “In learning more about how parasites live within their hosts, who is infecting who, and how these organisms coexist in these living, breathing ecosystems, we can learn more about how they are connected to and affected by the natural environments that we share with animals and plants.”
The researchers noted that this study doesn’t have direct implications for malaria treatment in humans. However, the team believes that having a better understanding of malaria’s evolutionary history could help scientists anticipate how it will change and evolve in the future. 
Photo by Holly Lutz
A study published in Molecular Phylogenetics and Evolution has revealed a new hypothesis on the evolution of malaria.
Researchers tested malarial DNA found in birds, bats, and other small mammals from 5 East African countries and found evidence to suggest that malaria has its roots in bird hosts.
It then spread to bats and on to other mammals.
“We can’t begin to understand how malaria spread to humans until we understand its evolutionary history,” said Holly Lutz, a doctoral candidate at Cornell University in Ithaca, New York.
“In learning about its past, we may be better able to understand the effects it has on us.”
Lutz and her colleagues took blood samples from hundreds of East African birds, bats, and other small mammals and screened the blood for malaria parasites.
When they found malaria, the team took samples of the parasites’ DNA and sequenced it to identify mutations in the genetic code. From there, the researchers performed phylogenetic analyses to determine how different malaria species are related.
In analyzing the genetic codes of the parasites, the team was able to find places where the DNA differed from one species to the next. Then, the researchers used computing software to determine how the different species evolved and how they’re related to each other.
“[B]y looking at patterns of mutations in the DNA of the different malaria species, we’re able to see when it branched off from one host group into another,” Lutz explained. “It started out as a parasite in birds, and then it evolved to colonize bats, and from there, it’s evolved to affect other mammals.”
In addition to shedding light on the way malaria was able to evolve and spread, the study provides information about the manner in which animals and their parasites are connected.
“Each of these individual vertebrates is an ecosystem in and of itself,” Lutz said. “In learning more about how parasites live within their hosts, who is infecting who, and how these organisms coexist in these living, breathing ecosystems, we can learn more about how they are connected to and affected by the natural environments that we share with animals and plants.”
The researchers noted that this study doesn’t have direct implications for malaria treatment in humans. However, the team believes that having a better understanding of malaria’s evolutionary history could help scientists anticipate how it will change and evolve in the future.
Photo by Holly Lutz
A study published in Molecular Phylogenetics and Evolution has revealed a new hypothesis on the evolution of malaria.
Researchers tested malarial DNA found in birds, bats, and other small mammals from 5 East African countries and found evidence to suggest that malaria has its roots in bird hosts.
It then spread to bats and on to other mammals.
“We can’t begin to understand how malaria spread to humans until we understand its evolutionary history,” said Holly Lutz, a doctoral candidate at Cornell University in Ithaca, New York.
“In learning about its past, we may be better able to understand the effects it has on us.”
Lutz and her colleagues took blood samples from hundreds of East African birds, bats, and other small mammals and screened the blood for malaria parasites.
When they found malaria, the team took samples of the parasites’ DNA and sequenced it to identify mutations in the genetic code. From there, the researchers performed phylogenetic analyses to determine how different malaria species are related.
In analyzing the genetic codes of the parasites, the team was able to find places where the DNA differed from one species to the next. Then, the researchers used computing software to determine how the different species evolved and how they’re related to each other.
“[B]y looking at patterns of mutations in the DNA of the different malaria species, we’re able to see when it branched off from one host group into another,” Lutz explained. “It started out as a parasite in birds, and then it evolved to colonize bats, and from there, it’s evolved to affect other mammals.”
In addition to shedding light on the way malaria was able to evolve and spread, the study provides information about the manner in which animals and their parasites are connected.
“Each of these individual vertebrates is an ecosystem in and of itself,” Lutz said. “In learning more about how parasites live within their hosts, who is infecting who, and how these organisms coexist in these living, breathing ecosystems, we can learn more about how they are connected to and affected by the natural environments that we share with animals and plants.”
The researchers noted that this study doesn’t have direct implications for malaria treatment in humans. However, the team believes that having a better understanding of malaria’s evolutionary history could help scientists anticipate how it will change and evolve in the future.
Study: Dying at home doesn’t mean dying sooner
patient’s hand
Choosing to die at home does not hasten death for patients with terminal cancer, according to a study published in Cancer.
The research showed that cancer patients who died at home lived at least as long as patients who spent their last days in hospitals.
Investigators say these results suggest oncologists should not hesitate to refer patients for home-based palliative care simply because less medical treatment may be provided.
“The cancer patient and family tend to be concerned that the quality of medical treatment provided at home will be inferior to that given in a hospital and that survival might be shortened,” said study author Jun Hamano, MD, of the University of Tsukuba in Japan.
“However, our finding—that home death does not actually have a negative influence on the survival of cancer patients at all and, rather, may have a positive influence—could suggest that the patient and family can choose the place of death in terms of their preference and values.”
Dr Hamano and his colleagues conducted this research by prospectively studying 2069 patients—1582 receiving hospital-based palliative care and 487 receiving home-based palliative care.
In all, 1607 patients died in the hospital, and 462 died at home.
Among patients thought to have only days to live, the survival of those who died at home was significantly longer than the survival of those who died in a hospital. The estimated median survival times were 13 days and 9 days, respectively (P<0.006).
Similarly, survival was significantly longer in the home group than the hospital group among patients thought to have weeks to live. The estimated median survival times were 36 days and 29 days, respectively (P<0.007).
There was no significant difference between the home and hospital groups among patients thought to have months to live. The estimated median survival times were 59 days and 62 days, respectively (P=0.925).
Finally, analyses suggested the place of death had a significant influence on the survival time in both unadjusted and adjusted models. The hazard ratios were 0.86 (P<0.01) and 0.87 (P=0.01), respectively.
Based on these findings, Dr Hamano concluded that, “Patients, families, and clinicians should be reassured that good home hospice care does not shorten patient life and even may achieve longer survival.”
patient’s hand
Choosing to die at home does not hasten death for patients with terminal cancer, according to a study published in Cancer.
The research showed that cancer patients who died at home lived at least as long as patients who spent their last days in hospitals.
Investigators say these results suggest oncologists should not hesitate to refer patients for home-based palliative care simply because less medical treatment may be provided.
“The cancer patient and family tend to be concerned that the quality of medical treatment provided at home will be inferior to that given in a hospital and that survival might be shortened,” said study author Jun Hamano, MD, of the University of Tsukuba in Japan.
“However, our finding—that home death does not actually have a negative influence on the survival of cancer patients at all and, rather, may have a positive influence—could suggest that the patient and family can choose the place of death in terms of their preference and values.”
Dr Hamano and his colleagues conducted this research by prospectively studying 2069 patients—1582 receiving hospital-based palliative care and 487 receiving home-based palliative care.
In all, 1607 patients died in the hospital, and 462 died at home.
Among patients thought to have only days to live, the survival of those who died at home was significantly longer than the survival of those who died in a hospital. The estimated median survival times were 13 days and 9 days, respectively (P<0.006).
Similarly, survival was significantly longer in the home group than the hospital group among patients thought to have weeks to live. The estimated median survival times were 36 days and 29 days, respectively (P<0.007).
There was no significant difference between the home and hospital groups among patients thought to have months to live. The estimated median survival times were 59 days and 62 days, respectively (P=0.925).
Finally, analyses suggested the place of death had a significant influence on the survival time in both unadjusted and adjusted models. The hazard ratios were 0.86 (P<0.01) and 0.87 (P=0.01), respectively.
Based on these findings, Dr Hamano concluded that, “Patients, families, and clinicians should be reassured that good home hospice care does not shorten patient life and even may achieve longer survival.”
patient’s hand
Choosing to die at home does not hasten death for patients with terminal cancer, according to a study published in Cancer.
The research showed that cancer patients who died at home lived at least as long as patients who spent their last days in hospitals.
Investigators say these results suggest oncologists should not hesitate to refer patients for home-based palliative care simply because less medical treatment may be provided.
“The cancer patient and family tend to be concerned that the quality of medical treatment provided at home will be inferior to that given in a hospital and that survival might be shortened,” said study author Jun Hamano, MD, of the University of Tsukuba in Japan.
“However, our finding—that home death does not actually have a negative influence on the survival of cancer patients at all and, rather, may have a positive influence—could suggest that the patient and family can choose the place of death in terms of their preference and values.”
Dr Hamano and his colleagues conducted this research by prospectively studying 2069 patients—1582 receiving hospital-based palliative care and 487 receiving home-based palliative care.
In all, 1607 patients died in the hospital, and 462 died at home.
Among patients thought to have only days to live, the survival of those who died at home was significantly longer than the survival of those who died in a hospital. The estimated median survival times were 13 days and 9 days, respectively (P<0.006).
Similarly, survival was significantly longer in the home group than the hospital group among patients thought to have weeks to live. The estimated median survival times were 36 days and 29 days, respectively (P<0.007).
There was no significant difference between the home and hospital groups among patients thought to have months to live. The estimated median survival times were 59 days and 62 days, respectively (P=0.925).
Finally, analyses suggested the place of death had a significant influence on the survival time in both unadjusted and adjusted models. The hazard ratios were 0.86 (P<0.01) and 0.87 (P=0.01), respectively.
Based on these findings, Dr Hamano concluded that, “Patients, families, and clinicians should be reassured that good home hospice care does not shorten patient life and even may achieve longer survival.”
EC grants gene therapy orphan designation for hemophilia A
The European Commission (EC) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.
BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union.
The product must provide significant benefit to those affected by the condition.
Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.
BMN 270 is under development by BioMarin Pharmaceutical Inc.
BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.
Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.
The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.
Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.
BMN 270 also has orphan designation in the US.
The European Commission (EC) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.
BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union.
The product must provide significant benefit to those affected by the condition.
Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.
BMN 270 is under development by BioMarin Pharmaceutical Inc.
BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.
Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.
The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.
Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.
BMN 270 also has orphan designation in the US.
The European Commission (EC) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.
BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union.
The product must provide significant benefit to those affected by the condition.
Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.
BMN 270 is under development by BioMarin Pharmaceutical Inc.
BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.
Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.
The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.
Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.
BMN 270 also has orphan designation in the US.
Drug exhibits preclinical activity against MDS
Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).
Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).
APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.
The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.
“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.
Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.
By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.
Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.
Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.
On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.
When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.
They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.
Baseline BFU-E number affects response
The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.
Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).
However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).
The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).
The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).
Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.
“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.
Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.
Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).
Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).
APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.
The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.
“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.
Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.
By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.
Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.
Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.
On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.
When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.
They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.
Baseline BFU-E number affects response
The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.
Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).
However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).
The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).
The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).
Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.
“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.
Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.
Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).
Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).
APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.
The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.
“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.
Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.
By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.
Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.
Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.
On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.
When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.
They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.
Baseline BFU-E number affects response
The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.
Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).
However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).
The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).
The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).
Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.
“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.
Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.
Lenalidomide prolongs PFS, not OS, in rel/ref MCL
Photo by Esther Dyson
Results of the phase 2 SPRINT trial suggest lenalidomide compares favorably to other single-agent therapies for patients with relapsed/refractory mantle cell lymphoma (MCL).
Patients who received lenalidomide had a significantly higher overall response rate and significantly longer progression-free survival (PFS) compared to patients who received single-agent therapy chosen by investigators.
However, there was no significant difference between the treatment arms with regard to overall survival (OS).
In addition, there were more treatment-related adverse events (AEs) in the lenalidomide arm than the investigator’s choice arm.
These results were published in The Lancet Oncology. The study was funded by Celgene Corporation, the company developing lenalidomide.
“The SPRINT study provided the first head-to-head, randomized, controlled study of single-agent lenalidomide compared with a range of single-agent comparators in previously treated MCL,” said study author Marek Trneny, MD, of Charles University Hospital in Prague, Czech Republic.
“The study demonstrated a statistically significant reduction in the risk of disease progression or death for lenalidomide over investigator’s choice in patients with relapsed/refractory MCL.”
The study enrolled 254 patients with relapsed/refractory MCL who were ineligible for intensive chemotherapy or hematopoietic stem cell transplant. The patients’ median age was 68.5 (range, 44-88), and they had received a median of 2 previous treatment regimens (range, 1-≥4).
Treatment
The patients were randomized (2:1) to receive lenalidomide orally at 25 mg on days 1-21 every 28 days until progressive disease or intolerability (n=170) or single-agent investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
In all, 167 patients in the lenalidomide arm and 83 patients in the investigator’s choice arm received at least 1 dose of treatment. In the investigator’s choice arm, 33% of patients received rituximab, 24% got gemcitabine, 22% fludarabine, 13% chlorambucil, and 8% cytarabine.
After disease progression on investigator’s choice, 46% of patients crossed over to the lenalidomide arm.
Before cycle 6, half of the patients in the lenalidomide arm and two-thirds of those in the investigator’s choice arm had discontinued treatment. After discontinuation, 46% of patients in the lenalidomide arm and 50% in the investigator’s choice arm received 1 or more new antilymphoma therapies (excluding crossover patients).
The investigators said the proportion of patients who responded to subsequent therapies or had progressive disease did not substantially differ whether they had previously been randomized to lenalidomide or investigator’s choice.
Efficacy
As of the data cutoff point (March 7, 2014), the median follow-up was 15.9 months (range, 7.6 to 31.7).
The overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001). The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged PFS. The median PFS was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm. The hazard ratio was 0.61 (P=0.004).
There was no significant difference in OS between the treatment arms. The median OS was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm. The hazard ratio was 0.89 (P=0.45)
A total of 128 patients (50%) died. Most deaths occurred during follow-up, and the most frequent cause of death was underlying lymphoma.
Safety
The incidence of treatment-related AEs was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
The most common grade 3 or higher AEs—in the lenalidomide and investigator’s choice arms, respectively—were neutropenia (44% vs 34%) without increased risk of infection, thrombocytopenia (18% vs 28%), leukopenia (8% vs 11%), and anemia (8% vs 7%).
The incidence of any-grade nasopharyngitis was 15% in the lenalidomide arm and 6% in the investigator’s choice arm. The incidence of upper respiratory tract infection was 12% and 6%, respectively. Febrile neutropenia was reported in 6% and 2% of patients, respectively.
Growth factors were used more often in the lenalidomide arm than the investigator’s choice arm—30% and 23%, respectively. But platelet transfusions were used less often in the lenalidomide arm—4% and 11%, respectively.
Photo by Esther Dyson
Results of the phase 2 SPRINT trial suggest lenalidomide compares favorably to other single-agent therapies for patients with relapsed/refractory mantle cell lymphoma (MCL).
Patients who received lenalidomide had a significantly higher overall response rate and significantly longer progression-free survival (PFS) compared to patients who received single-agent therapy chosen by investigators.
However, there was no significant difference between the treatment arms with regard to overall survival (OS).
In addition, there were more treatment-related adverse events (AEs) in the lenalidomide arm than the investigator’s choice arm.
These results were published in The Lancet Oncology. The study was funded by Celgene Corporation, the company developing lenalidomide.
“The SPRINT study provided the first head-to-head, randomized, controlled study of single-agent lenalidomide compared with a range of single-agent comparators in previously treated MCL,” said study author Marek Trneny, MD, of Charles University Hospital in Prague, Czech Republic.
“The study demonstrated a statistically significant reduction in the risk of disease progression or death for lenalidomide over investigator’s choice in patients with relapsed/refractory MCL.”
The study enrolled 254 patients with relapsed/refractory MCL who were ineligible for intensive chemotherapy or hematopoietic stem cell transplant. The patients’ median age was 68.5 (range, 44-88), and they had received a median of 2 previous treatment regimens (range, 1-≥4).
Treatment
The patients were randomized (2:1) to receive lenalidomide orally at 25 mg on days 1-21 every 28 days until progressive disease or intolerability (n=170) or single-agent investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
In all, 167 patients in the lenalidomide arm and 83 patients in the investigator’s choice arm received at least 1 dose of treatment. In the investigator’s choice arm, 33% of patients received rituximab, 24% got gemcitabine, 22% fludarabine, 13% chlorambucil, and 8% cytarabine.
After disease progression on investigator’s choice, 46% of patients crossed over to the lenalidomide arm.
Before cycle 6, half of the patients in the lenalidomide arm and two-thirds of those in the investigator’s choice arm had discontinued treatment. After discontinuation, 46% of patients in the lenalidomide arm and 50% in the investigator’s choice arm received 1 or more new antilymphoma therapies (excluding crossover patients).
The investigators said the proportion of patients who responded to subsequent therapies or had progressive disease did not substantially differ whether they had previously been randomized to lenalidomide or investigator’s choice.
Efficacy
As of the data cutoff point (March 7, 2014), the median follow-up was 15.9 months (range, 7.6 to 31.7).
The overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001). The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged PFS. The median PFS was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm. The hazard ratio was 0.61 (P=0.004).
There was no significant difference in OS between the treatment arms. The median OS was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm. The hazard ratio was 0.89 (P=0.45)
A total of 128 patients (50%) died. Most deaths occurred during follow-up, and the most frequent cause of death was underlying lymphoma.
Safety
The incidence of treatment-related AEs was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
The most common grade 3 or higher AEs—in the lenalidomide and investigator’s choice arms, respectively—were neutropenia (44% vs 34%) without increased risk of infection, thrombocytopenia (18% vs 28%), leukopenia (8% vs 11%), and anemia (8% vs 7%).
The incidence of any-grade nasopharyngitis was 15% in the lenalidomide arm and 6% in the investigator’s choice arm. The incidence of upper respiratory tract infection was 12% and 6%, respectively. Febrile neutropenia was reported in 6% and 2% of patients, respectively.
Growth factors were used more often in the lenalidomide arm than the investigator’s choice arm—30% and 23%, respectively. But platelet transfusions were used less often in the lenalidomide arm—4% and 11%, respectively.
Photo by Esther Dyson
Results of the phase 2 SPRINT trial suggest lenalidomide compares favorably to other single-agent therapies for patients with relapsed/refractory mantle cell lymphoma (MCL).
Patients who received lenalidomide had a significantly higher overall response rate and significantly longer progression-free survival (PFS) compared to patients who received single-agent therapy chosen by investigators.
However, there was no significant difference between the treatment arms with regard to overall survival (OS).
In addition, there were more treatment-related adverse events (AEs) in the lenalidomide arm than the investigator’s choice arm.
These results were published in The Lancet Oncology. The study was funded by Celgene Corporation, the company developing lenalidomide.
“The SPRINT study provided the first head-to-head, randomized, controlled study of single-agent lenalidomide compared with a range of single-agent comparators in previously treated MCL,” said study author Marek Trneny, MD, of Charles University Hospital in Prague, Czech Republic.
“The study demonstrated a statistically significant reduction in the risk of disease progression or death for lenalidomide over investigator’s choice in patients with relapsed/refractory MCL.”
The study enrolled 254 patients with relapsed/refractory MCL who were ineligible for intensive chemotherapy or hematopoietic stem cell transplant. The patients’ median age was 68.5 (range, 44-88), and they had received a median of 2 previous treatment regimens (range, 1-≥4).
Treatment
The patients were randomized (2:1) to receive lenalidomide orally at 25 mg on days 1-21 every 28 days until progressive disease or intolerability (n=170) or single-agent investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
In all, 167 patients in the lenalidomide arm and 83 patients in the investigator’s choice arm received at least 1 dose of treatment. In the investigator’s choice arm, 33% of patients received rituximab, 24% got gemcitabine, 22% fludarabine, 13% chlorambucil, and 8% cytarabine.
After disease progression on investigator’s choice, 46% of patients crossed over to the lenalidomide arm.
Before cycle 6, half of the patients in the lenalidomide arm and two-thirds of those in the investigator’s choice arm had discontinued treatment. After discontinuation, 46% of patients in the lenalidomide arm and 50% in the investigator’s choice arm received 1 or more new antilymphoma therapies (excluding crossover patients).
The investigators said the proportion of patients who responded to subsequent therapies or had progressive disease did not substantially differ whether they had previously been randomized to lenalidomide or investigator’s choice.
Efficacy
As of the data cutoff point (March 7, 2014), the median follow-up was 15.9 months (range, 7.6 to 31.7).
The overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001). The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged PFS. The median PFS was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm. The hazard ratio was 0.61 (P=0.004).
There was no significant difference in OS between the treatment arms. The median OS was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm. The hazard ratio was 0.89 (P=0.45)
A total of 128 patients (50%) died. Most deaths occurred during follow-up, and the most frequent cause of death was underlying lymphoma.
Safety
The incidence of treatment-related AEs was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
The most common grade 3 or higher AEs—in the lenalidomide and investigator’s choice arms, respectively—were neutropenia (44% vs 34%) without increased risk of infection, thrombocytopenia (18% vs 28%), leukopenia (8% vs 11%), and anemia (8% vs 7%).
The incidence of any-grade nasopharyngitis was 15% in the lenalidomide arm and 6% in the investigator’s choice arm. The incidence of upper respiratory tract infection was 12% and 6%, respectively. Febrile neutropenia was reported in 6% and 2% of patients, respectively.
Growth factors were used more often in the lenalidomide arm than the investigator’s choice arm—30% and 23%, respectively. But platelet transfusions were used less often in the lenalidomide arm—4% and 11%, respectively.
Team traces evolution of malaria
Photo courtesy of
Sesh Sundararaman,
University of Pennsylvania
By studying malaria parasites found in chimpanzees, researchers believe they have gained new insights regarding a malaria parasite that infects humans.
The team used a selective amplification technique to sequence the genomes of 2 divergent Plasmodium species, P reichenowi and P gaboni, from chimpanzee blood.
This revealed clues about the evolution and pathogenicity of P falciparum, the deadliest malaria parasite that affects humans.
The researchers described this work in Nature Communications.
They noted that African apes harbor at least 6 Plasmodium species that have been classified into a separate subgenus, called Laverania. Three of these Laverania species, including P reichenowi and P gaboni, reside in chimps.
Three others—including P praefalciparum, which gave rise to P falciparum—reside in gorillas. The gorilla origin of P falciparum was discovered several years ago by this same group of investigators.
“We want to know why Plasmodium falciparum is so deadly,” said Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.
“The answer must lie in the blueprint—the genome—of its chimpanzee and gorilla cousins. We also want to know how and when the gorilla precursor of Plasmodium falciparum jumped into humans and why this happened only once.”
In an attempt to answer these questions, Dr Hahn and her colleagues used their selective amplification method to sequence Laverania genomes.
They used small amounts of unprocessed blood collected during routine health screens of chimpanzees living in sanctuaries. With their technique, the team found they could generate “high-quality” Laverania genome sequences.
The researchers said the chimpanzee parasite genomes contain information about the evolutionary origins of the malaria parasites infecting humans. One of the first things to emerge from genome-wide analyses was that the parasites represent distinct, non-interbreeding species.
In addition, members of each chimpanzee parasite species display about 10 times more genetic diversity than human parasites.
“The chimpanzee parasites really highlight the lack of diversity in Plasmodium falciparum,” said Paul Sharp, PhD, of the University of Edinburgh in the UK.
“This is most likely because these parasites went through a severe bottleneck when first transmitted to humans, perhaps within the past 10,000 years.”
By comparing the different parasite genomes, the researchers found an expansion of a multi-gene family, which governs red blood cell remodeling and therefore helps the parasite to evade host immune cells and clearance by the spleen.
“The remodeling process is a key part of severe malaria pathology in human Plasmodium falciparum infections,” said Julian Rayner, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“The expansion of this gene family from a single gene in all other Plasmodium parasites to up to 21 genes in Laverania suggests that remodeling evolved early in the radiation of this group of primate parasites and contributed not only to their unique biology but perhaps also to their successful expansion.”
“We also found a short region of the genome, including 2 essential invasion genes, where Plasmodium falciparum was much more different from its close relatives than we expected,” said Lindsey Plenderleith, PhD, of the University of Edinburgh.
Further analysis yielded the surprising finding that this fragment of DNA was horizontally transferred—from one species to another—into the gorilla ancestor of P falciparum.
“It is tempting to speculate that this unusual event somehow predisposed the precursor of Plasmodium falciparum to colonize humans,” Dr Hahn said. “However, this gene transfer clearly is not the entire story.”
Although the origin of P falciparum is considered well-established, nothing is known about the circumstances that led to its emergence.
“Coaxing entire parasite genome sequences out of small quantities of unprocessed ape blood will help us to better understand what happened and whether it can happen again,” said Sesh Sundararaman, an MD/PhD student at the University of Pennsylvania.
The team plans, as a next step, to use their select genome amplification technique to sequence additional ape parasite genomes to identify host-specific interactions and transmission requirements. They believe this would reveal vulnerabilities that might be exploited to combat malaria in humans.
Photo courtesy of
Sesh Sundararaman,
University of Pennsylvania
By studying malaria parasites found in chimpanzees, researchers believe they have gained new insights regarding a malaria parasite that infects humans.
The team used a selective amplification technique to sequence the genomes of 2 divergent Plasmodium species, P reichenowi and P gaboni, from chimpanzee blood.
This revealed clues about the evolution and pathogenicity of P falciparum, the deadliest malaria parasite that affects humans.
The researchers described this work in Nature Communications.
They noted that African apes harbor at least 6 Plasmodium species that have been classified into a separate subgenus, called Laverania. Three of these Laverania species, including P reichenowi and P gaboni, reside in chimps.
Three others—including P praefalciparum, which gave rise to P falciparum—reside in gorillas. The gorilla origin of P falciparum was discovered several years ago by this same group of investigators.
“We want to know why Plasmodium falciparum is so deadly,” said Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.
“The answer must lie in the blueprint—the genome—of its chimpanzee and gorilla cousins. We also want to know how and when the gorilla precursor of Plasmodium falciparum jumped into humans and why this happened only once.”
In an attempt to answer these questions, Dr Hahn and her colleagues used their selective amplification method to sequence Laverania genomes.
They used small amounts of unprocessed blood collected during routine health screens of chimpanzees living in sanctuaries. With their technique, the team found they could generate “high-quality” Laverania genome sequences.
The researchers said the chimpanzee parasite genomes contain information about the evolutionary origins of the malaria parasites infecting humans. One of the first things to emerge from genome-wide analyses was that the parasites represent distinct, non-interbreeding species.
In addition, members of each chimpanzee parasite species display about 10 times more genetic diversity than human parasites.
“The chimpanzee parasites really highlight the lack of diversity in Plasmodium falciparum,” said Paul Sharp, PhD, of the University of Edinburgh in the UK.
“This is most likely because these parasites went through a severe bottleneck when first transmitted to humans, perhaps within the past 10,000 years.”
By comparing the different parasite genomes, the researchers found an expansion of a multi-gene family, which governs red blood cell remodeling and therefore helps the parasite to evade host immune cells and clearance by the spleen.
“The remodeling process is a key part of severe malaria pathology in human Plasmodium falciparum infections,” said Julian Rayner, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“The expansion of this gene family from a single gene in all other Plasmodium parasites to up to 21 genes in Laverania suggests that remodeling evolved early in the radiation of this group of primate parasites and contributed not only to their unique biology but perhaps also to their successful expansion.”
“We also found a short region of the genome, including 2 essential invasion genes, where Plasmodium falciparum was much more different from its close relatives than we expected,” said Lindsey Plenderleith, PhD, of the University of Edinburgh.
Further analysis yielded the surprising finding that this fragment of DNA was horizontally transferred—from one species to another—into the gorilla ancestor of P falciparum.
“It is tempting to speculate that this unusual event somehow predisposed the precursor of Plasmodium falciparum to colonize humans,” Dr Hahn said. “However, this gene transfer clearly is not the entire story.”
Although the origin of P falciparum is considered well-established, nothing is known about the circumstances that led to its emergence.
“Coaxing entire parasite genome sequences out of small quantities of unprocessed ape blood will help us to better understand what happened and whether it can happen again,” said Sesh Sundararaman, an MD/PhD student at the University of Pennsylvania.
The team plans, as a next step, to use their select genome amplification technique to sequence additional ape parasite genomes to identify host-specific interactions and transmission requirements. They believe this would reveal vulnerabilities that might be exploited to combat malaria in humans.
Photo courtesy of
Sesh Sundararaman,
University of Pennsylvania
By studying malaria parasites found in chimpanzees, researchers believe they have gained new insights regarding a malaria parasite that infects humans.
The team used a selective amplification technique to sequence the genomes of 2 divergent Plasmodium species, P reichenowi and P gaboni, from chimpanzee blood.
This revealed clues about the evolution and pathogenicity of P falciparum, the deadliest malaria parasite that affects humans.
The researchers described this work in Nature Communications.
They noted that African apes harbor at least 6 Plasmodium species that have been classified into a separate subgenus, called Laverania. Three of these Laverania species, including P reichenowi and P gaboni, reside in chimps.
Three others—including P praefalciparum, which gave rise to P falciparum—reside in gorillas. The gorilla origin of P falciparum was discovered several years ago by this same group of investigators.
“We want to know why Plasmodium falciparum is so deadly,” said Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.
“The answer must lie in the blueprint—the genome—of its chimpanzee and gorilla cousins. We also want to know how and when the gorilla precursor of Plasmodium falciparum jumped into humans and why this happened only once.”
In an attempt to answer these questions, Dr Hahn and her colleagues used their selective amplification method to sequence Laverania genomes.
They used small amounts of unprocessed blood collected during routine health screens of chimpanzees living in sanctuaries. With their technique, the team found they could generate “high-quality” Laverania genome sequences.
The researchers said the chimpanzee parasite genomes contain information about the evolutionary origins of the malaria parasites infecting humans. One of the first things to emerge from genome-wide analyses was that the parasites represent distinct, non-interbreeding species.
In addition, members of each chimpanzee parasite species display about 10 times more genetic diversity than human parasites.
“The chimpanzee parasites really highlight the lack of diversity in Plasmodium falciparum,” said Paul Sharp, PhD, of the University of Edinburgh in the UK.
“This is most likely because these parasites went through a severe bottleneck when first transmitted to humans, perhaps within the past 10,000 years.”
By comparing the different parasite genomes, the researchers found an expansion of a multi-gene family, which governs red blood cell remodeling and therefore helps the parasite to evade host immune cells and clearance by the spleen.
“The remodeling process is a key part of severe malaria pathology in human Plasmodium falciparum infections,” said Julian Rayner, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“The expansion of this gene family from a single gene in all other Plasmodium parasites to up to 21 genes in Laverania suggests that remodeling evolved early in the radiation of this group of primate parasites and contributed not only to their unique biology but perhaps also to their successful expansion.”
“We also found a short region of the genome, including 2 essential invasion genes, where Plasmodium falciparum was much more different from its close relatives than we expected,” said Lindsey Plenderleith, PhD, of the University of Edinburgh.
Further analysis yielded the surprising finding that this fragment of DNA was horizontally transferred—from one species to another—into the gorilla ancestor of P falciparum.
“It is tempting to speculate that this unusual event somehow predisposed the precursor of Plasmodium falciparum to colonize humans,” Dr Hahn said. “However, this gene transfer clearly is not the entire story.”
Although the origin of P falciparum is considered well-established, nothing is known about the circumstances that led to its emergence.
“Coaxing entire parasite genome sequences out of small quantities of unprocessed ape blood will help us to better understand what happened and whether it can happen again,” said Sesh Sundararaman, an MD/PhD student at the University of Pennsylvania.
The team plans, as a next step, to use their select genome amplification technique to sequence additional ape parasite genomes to identify host-specific interactions and transmission requirements. They believe this would reveal vulnerabilities that might be exploited to combat malaria in humans.
EMA recommends orphan designation for EBV-CTLs
among uninfected cells (blue)
Image courtesy of Benjamin
Chaigne-Delalande
The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).
The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.
Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.
About EBV-CTLs
The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.
The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.
In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.
Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.
Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.
Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.
among uninfected cells (blue)
Image courtesy of Benjamin
Chaigne-Delalande
The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).
The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.
Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.
About EBV-CTLs
The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.
The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.
In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.
Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.
Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.
Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.
among uninfected cells (blue)
Image courtesy of Benjamin
Chaigne-Delalande
The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).
The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.
The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.
Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.
About EBV-CTLs
The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.
The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.
In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.
Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.
Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.
Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.
Drug shows early promise for rel/ref NHL
Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.
Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.
However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.
Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.
The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.
The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).
The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).
The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).
Dosing, toxicity, and discontinuation
This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m2/day to 90 μg/m2/day.
The researchers found that neurologic events were dose-limiting, and 60 μg/m2/day was the MTD.
Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m2/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m2/day), 2 cases of grade 3 encephalopathy (90 μg/m2/day), and 1 case of grade 3 seizure and aphasia (90 μg/m2/day).
Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.
The researchers found that stepwise dosing (5 μg/m2/day to 60 μg/m2/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.
However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.
The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.
Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.
Response
Among patients treated at the MTD (60 μg/m2/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m2/day (2/4), 20% at 15 μg/m2/day (3/15), and 17% at 30 μg/m2/day (1/6).
Complete responses (CRs) occurred in 1 patient at the 15 μg/m2/day dose, 1 at the 30 μg/m2/day dose, 1 at the 90 μg/m2/day dose, and 8 at the 60 μg/m2/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m2/day dose.
Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.
The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).
Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.
“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”
Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.
Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.
However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.
Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.
The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.
The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).
The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).
The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).
Dosing, toxicity, and discontinuation
This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m2/day to 90 μg/m2/day.
The researchers found that neurologic events were dose-limiting, and 60 μg/m2/day was the MTD.
Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m2/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m2/day), 2 cases of grade 3 encephalopathy (90 μg/m2/day), and 1 case of grade 3 seizure and aphasia (90 μg/m2/day).
Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.
The researchers found that stepwise dosing (5 μg/m2/day to 60 μg/m2/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.
However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.
The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.
Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.
Response
Among patients treated at the MTD (60 μg/m2/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m2/day (2/4), 20% at 15 μg/m2/day (3/15), and 17% at 30 μg/m2/day (1/6).
Complete responses (CRs) occurred in 1 patient at the 15 μg/m2/day dose, 1 at the 30 μg/m2/day dose, 1 at the 90 μg/m2/day dose, and 8 at the 60 μg/m2/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m2/day dose.
Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.
The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).
Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.
“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”
Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.
Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.
However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.
Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.
The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.
The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).
The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).
The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).
Dosing, toxicity, and discontinuation
This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m2/day to 90 μg/m2/day.
The researchers found that neurologic events were dose-limiting, and 60 μg/m2/day was the MTD.
Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m2/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m2/day), 2 cases of grade 3 encephalopathy (90 μg/m2/day), and 1 case of grade 3 seizure and aphasia (90 μg/m2/day).
Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.
The researchers found that stepwise dosing (5 μg/m2/day to 60 μg/m2/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.
However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.
The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.
Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.
Response
Among patients treated at the MTD (60 μg/m2/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m2/day (2/4), 20% at 15 μg/m2/day (3/15), and 17% at 30 μg/m2/day (1/6).
Complete responses (CRs) occurred in 1 patient at the 15 μg/m2/day dose, 1 at the 30 μg/m2/day dose, 1 at the 90 μg/m2/day dose, and 8 at the 60 μg/m2/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m2/day dose.
Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.
The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).
Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.
“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”
mAb gets breakthrough designation for HLH
Photo by Linda Bartlett
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.
NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.
The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.
“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.
The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.
The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Efficacy
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.
Safety
No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.
There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.
The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Photo by Linda Bartlett
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.
NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.
The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.
“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.
The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.
The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Efficacy
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.
Safety
No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.
There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.
The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Photo by Linda Bartlett
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.
NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.
The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.
“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.
The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.
The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Efficacy
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.
Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.
Safety
No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.
There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.
The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.
Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.
Chemo has greater impact on male fertility
Photo by Nina Matthews
Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.
Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.
However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.
Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.
Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.
With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.
Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.
The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.
The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.
The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.
Outcomes
Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).
CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).
The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.
In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.
Impact of specific drugs
In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).
Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m2 increments (HR=0.82, P<0.0001).
In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m2 (HR=0.22, P=0.020) and at doses of 450 mg/m2 or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m2 or greater (HR=0.41, P=0.046).
Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).
Limitations and implications
The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.
And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.
The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.
“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”
“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”
Photo by Nina Matthews
Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.
Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.
However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.
Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.
Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.
With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.
Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.
The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.
The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.
The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.
Outcomes
Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).
CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).
The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.
In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.
Impact of specific drugs
In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).
Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m2 increments (HR=0.82, P<0.0001).
In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m2 (HR=0.22, P=0.020) and at doses of 450 mg/m2 or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m2 or greater (HR=0.41, P=0.046).
Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).
Limitations and implications
The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.
And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.
The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.
“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”
“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”
Photo by Nina Matthews
Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.
Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.
However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.
Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.
Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.
With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.
Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.
The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.
The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.
The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.
Outcomes
Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).
CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).
The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.
In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.
Impact of specific drugs
In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).
Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m2 increments (HR=0.82, P<0.0001).
In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m2 (HR=0.22, P=0.020) and at doses of 450 mg/m2 or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m2 or greater (HR=0.41, P=0.046).
Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).
Limitations and implications
The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.
And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.
The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.
“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”
“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”