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Study reveals SNPs that may increase risk of MM
A large study has revealed several genetic variations that may increase a person’s risk of developing multiple myeloma (MM).
The findings, published in Nature Communications, build on existing research that suggests MM can run in families.
“Our study expands our understanding of how inherited risk factors can influence the risk of myeloma,” said Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.
“We know that the inherited risk of myeloma does not come from just one or two major risk genes, as can be the case with breast cancer, but from multiple different genetic variants, each with only a small individual effect on risk. Identifying more of these variants gives us new insights into the potential causes of the disease and open up new strategies for prevention.”
For this study, Dr Houlston and his colleagues compared DNA from 9866 MM patients and 239,188 healthy adults.
This confirmed the association between MM and 9 previously reported single nucleotide polymorphisms (SNPs):
- rs6746082 at 2p23.3
- rs1052501 at 3p22.1
- rs4487645 at 7p15.3
- rs10936599 at 3q26.2
- rs2285803 at 6p21.3
- rs4273077 at 17p11.2
- rs877529 at 22q13.1
- rs56219066 at 5q15
- rs138740 at 22q13.
It also revealed 8 new SNPs that may increase the risk of MM:
- rs34229995 at 6p22.3 (P=1.31 × 10−8)
- rs9372120 at 6q21 (P=9.09 × 10−15)
- rs7781265 at 7q36.1 (P=9.71 × 10−9)
- rs1948915 at 8q24.21 (P=4.20 × 10−11)
- rs2811710 at 9p21.3 (P=1.72 × 10−13)
- rs2790457 at 10p12.1 (P=1.77 × 10−8)
- rs7193541 at 16q23.1 (P=5.00 × 10−12)
- rs6066835 at 20q13.13 (P=1.36 × 10−13).
These SNPs are located in regions of the genome involved in regulating genes linked to cell processes known to go wrong in MM development—namely, JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3, and PREX1.
This suggests that subtle effects on the activity of key genes could mean the proper development of plasma cells breaks down, increasing the likelihood of developing MM. However, as the researchers noted, further study is needed to confirm and better understand this phenomenon. 
A large study has revealed several genetic variations that may increase a person’s risk of developing multiple myeloma (MM).
The findings, published in Nature Communications, build on existing research that suggests MM can run in families.
“Our study expands our understanding of how inherited risk factors can influence the risk of myeloma,” said Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.
“We know that the inherited risk of myeloma does not come from just one or two major risk genes, as can be the case with breast cancer, but from multiple different genetic variants, each with only a small individual effect on risk. Identifying more of these variants gives us new insights into the potential causes of the disease and open up new strategies for prevention.”
For this study, Dr Houlston and his colleagues compared DNA from 9866 MM patients and 239,188 healthy adults.
This confirmed the association between MM and 9 previously reported single nucleotide polymorphisms (SNPs):
- rs6746082 at 2p23.3
- rs1052501 at 3p22.1
- rs4487645 at 7p15.3
- rs10936599 at 3q26.2
- rs2285803 at 6p21.3
- rs4273077 at 17p11.2
- rs877529 at 22q13.1
- rs56219066 at 5q15
- rs138740 at 22q13.
It also revealed 8 new SNPs that may increase the risk of MM:
- rs34229995 at 6p22.3 (P=1.31 × 10−8)
- rs9372120 at 6q21 (P=9.09 × 10−15)
- rs7781265 at 7q36.1 (P=9.71 × 10−9)
- rs1948915 at 8q24.21 (P=4.20 × 10−11)
- rs2811710 at 9p21.3 (P=1.72 × 10−13)
- rs2790457 at 10p12.1 (P=1.77 × 10−8)
- rs7193541 at 16q23.1 (P=5.00 × 10−12)
- rs6066835 at 20q13.13 (P=1.36 × 10−13).
These SNPs are located in regions of the genome involved in regulating genes linked to cell processes known to go wrong in MM development—namely, JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3, and PREX1.
This suggests that subtle effects on the activity of key genes could mean the proper development of plasma cells breaks down, increasing the likelihood of developing MM. However, as the researchers noted, further study is needed to confirm and better understand this phenomenon.
A large study has revealed several genetic variations that may increase a person’s risk of developing multiple myeloma (MM).
The findings, published in Nature Communications, build on existing research that suggests MM can run in families.
“Our study expands our understanding of how inherited risk factors can influence the risk of myeloma,” said Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.
“We know that the inherited risk of myeloma does not come from just one or two major risk genes, as can be the case with breast cancer, but from multiple different genetic variants, each with only a small individual effect on risk. Identifying more of these variants gives us new insights into the potential causes of the disease and open up new strategies for prevention.”
For this study, Dr Houlston and his colleagues compared DNA from 9866 MM patients and 239,188 healthy adults.
This confirmed the association between MM and 9 previously reported single nucleotide polymorphisms (SNPs):
- rs6746082 at 2p23.3
- rs1052501 at 3p22.1
- rs4487645 at 7p15.3
- rs10936599 at 3q26.2
- rs2285803 at 6p21.3
- rs4273077 at 17p11.2
- rs877529 at 22q13.1
- rs56219066 at 5q15
- rs138740 at 22q13.
It also revealed 8 new SNPs that may increase the risk of MM:
- rs34229995 at 6p22.3 (P=1.31 × 10−8)
- rs9372120 at 6q21 (P=9.09 × 10−15)
- rs7781265 at 7q36.1 (P=9.71 × 10−9)
- rs1948915 at 8q24.21 (P=4.20 × 10−11)
- rs2811710 at 9p21.3 (P=1.72 × 10−13)
- rs2790457 at 10p12.1 (P=1.77 × 10−8)
- rs7193541 at 16q23.1 (P=5.00 × 10−12)
- rs6066835 at 20q13.13 (P=1.36 × 10−13).
These SNPs are located in regions of the genome involved in regulating genes linked to cell processes known to go wrong in MM development—namely, JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3, and PREX1.
This suggests that subtle effects on the activity of key genes could mean the proper development of plasma cells breaks down, increasing the likelihood of developing MM. However, as the researchers noted, further study is needed to confirm and better understand this phenomenon.
Efficacy of malaria vaccine declines over time
Photo by Caitlin Kleiboer
Results from a phase 2 study of the malaria vaccine RTS,S (also known as RTS,S/AS01 or Mosquirix) suggest its efficacy decreases over time, and this decline is fastest in children living in areas with higher-than-average rates of malaria.
Researchers say the results suggest the benefits of the vaccine are likely to vary across different populations and highlight the need for more research to
determine the most effective way of using RTS,S, which last year became the first malaria vaccine to receive a green light from the European Medicines Agency.
“We found that 3-dose vaccination with RTS,S was initially protective, but this was offset by a rebound in later years among children exposed to higher-than-average levels of malaria-carrying mosquitoes,” said Philip Bejon, PhD, of the Kenya Medical Research Institute–Wellcome Trust Programme in Kilifi, Kenya.
Dr Bejon and his colleagues reported these results in NEJM.
The researchers followed 447 children who had received 3 doses of either RTS,S or a rabies (control) vaccine when they were 5 months to 17 months old.
After 7 years, there were 312 children still involved in the study. During the first year, the risk of getting malaria in the vaccinated children was 35.9% less than in the control group. After 7 years, this protection fell to 3.6%.
And in children exposed to higher-than-average rates of malaria, there were slightly more cases of malaria in the vaccinated group than the control group—1002 and 992 cases, respectively—5 years after vaccination.
This “rebound” effect, which has been seen in previous studies, is thought to occur because children initially protected by the vaccine develop their natural immunity against malaria more slowly than unvaccinated children.
Results from a phase 3 study showed that 3 doses of RTS,S reduced the risk of malaria in young children by 28% over 4 years, but this improved to 36% when children were given a fourth dose 18 months after the first dose. Longer-term follow up of these children is ongoing.
“Overall, our study shows that RTS,S can benefit children but suggests that a fourth dose may be important for sustaining this protection over the long term and to protect against a potential rebound,” said Ally Olotu, PhD, of the Kenya Medical Research Institute–Wellcome Trust Programme.
“Results from 3 sites involved in the original phase 3 study that are continuing follow up, and the WHO’s planned pilot program, will tell us more about the vaccine’s efficacy in different settings and help determine which populations would benefit most from receiving it as part of a wider vaccination strategy.”
Photo by Caitlin Kleiboer
Results from a phase 2 study of the malaria vaccine RTS,S (also known as RTS,S/AS01 or Mosquirix) suggest its efficacy decreases over time, and this decline is fastest in children living in areas with higher-than-average rates of malaria.
Researchers say the results suggest the benefits of the vaccine are likely to vary across different populations and highlight the need for more research to
determine the most effective way of using RTS,S, which last year became the first malaria vaccine to receive a green light from the European Medicines Agency.
“We found that 3-dose vaccination with RTS,S was initially protective, but this was offset by a rebound in later years among children exposed to higher-than-average levels of malaria-carrying mosquitoes,” said Philip Bejon, PhD, of the Kenya Medical Research Institute–Wellcome Trust Programme in Kilifi, Kenya.
Dr Bejon and his colleagues reported these results in NEJM.
The researchers followed 447 children who had received 3 doses of either RTS,S or a rabies (control) vaccine when they were 5 months to 17 months old.
After 7 years, there were 312 children still involved in the study. During the first year, the risk of getting malaria in the vaccinated children was 35.9% less than in the control group. After 7 years, this protection fell to 3.6%.
And in children exposed to higher-than-average rates of malaria, there were slightly more cases of malaria in the vaccinated group than the control group—1002 and 992 cases, respectively—5 years after vaccination.
This “rebound” effect, which has been seen in previous studies, is thought to occur because children initially protected by the vaccine develop their natural immunity against malaria more slowly than unvaccinated children.
Results from a phase 3 study showed that 3 doses of RTS,S reduced the risk of malaria in young children by 28% over 4 years, but this improved to 36% when children were given a fourth dose 18 months after the first dose. Longer-term follow up of these children is ongoing.
“Overall, our study shows that RTS,S can benefit children but suggests that a fourth dose may be important for sustaining this protection over the long term and to protect against a potential rebound,” said Ally Olotu, PhD, of the Kenya Medical Research Institute–Wellcome Trust Programme.
“Results from 3 sites involved in the original phase 3 study that are continuing follow up, and the WHO’s planned pilot program, will tell us more about the vaccine’s efficacy in different settings and help determine which populations would benefit most from receiving it as part of a wider vaccination strategy.”
Photo by Caitlin Kleiboer
Results from a phase 2 study of the malaria vaccine RTS,S (also known as RTS,S/AS01 or Mosquirix) suggest its efficacy decreases over time, and this decline is fastest in children living in areas with higher-than-average rates of malaria.
Researchers say the results suggest the benefits of the vaccine are likely to vary across different populations and highlight the need for more research to
determine the most effective way of using RTS,S, which last year became the first malaria vaccine to receive a green light from the European Medicines Agency.
“We found that 3-dose vaccination with RTS,S was initially protective, but this was offset by a rebound in later years among children exposed to higher-than-average levels of malaria-carrying mosquitoes,” said Philip Bejon, PhD, of the Kenya Medical Research Institute–Wellcome Trust Programme in Kilifi, Kenya.
Dr Bejon and his colleagues reported these results in NEJM.
The researchers followed 447 children who had received 3 doses of either RTS,S or a rabies (control) vaccine when they were 5 months to 17 months old.
After 7 years, there were 312 children still involved in the study. During the first year, the risk of getting malaria in the vaccinated children was 35.9% less than in the control group. After 7 years, this protection fell to 3.6%.
And in children exposed to higher-than-average rates of malaria, there were slightly more cases of malaria in the vaccinated group than the control group—1002 and 992 cases, respectively—5 years after vaccination.
This “rebound” effect, which has been seen in previous studies, is thought to occur because children initially protected by the vaccine develop their natural immunity against malaria more slowly than unvaccinated children.
Results from a phase 3 study showed that 3 doses of RTS,S reduced the risk of malaria in young children by 28% over 4 years, but this improved to 36% when children were given a fourth dose 18 months after the first dose. Longer-term follow up of these children is ongoing.
“Overall, our study shows that RTS,S can benefit children but suggests that a fourth dose may be important for sustaining this protection over the long term and to protect against a potential rebound,” said Ally Olotu, PhD, of the Kenya Medical Research Institute–Wellcome Trust Programme.
“Results from 3 sites involved in the original phase 3 study that are continuing follow up, and the WHO’s planned pilot program, will tell us more about the vaccine’s efficacy in different settings and help determine which populations would benefit most from receiving it as part of a wider vaccination strategy.”
Telomere length linked to neutrophil recovery in AML
Image by Volker Brinkmann
Researchers say they have discovered a way to predict which children with acute myeloid leukemia (AML) are at the highest risk of delayed neutrophil recovery.
The team examined the role of telomeres in neutrophil recovery and found that the length of a patient’s telomeres can indicate the rate of recovery following chemotherapy.
The group reported their findings in the Journal of Clinical Oncology.
“We were interested in telomere length as a marker of blood count recovery because defects in telomere maintenance are known risks for bone marrow failure and aplastic anemia,” said study author Maria Monica Gramatges, MD, PhD, of Baylor College of Medicine in Houston, Texas.
“We know that up to 15% to 20% of children can take 2 months or longer to recover their blood counts after a course of AML chemotherapy. Our goal was to understand if these children had an underlying genetic predisposition associated with an impaired capacity for recovery.”
Dr Gramatges and her colleagues hypothesized that short telomere length could be associated with a delay in neutrophil recovery.
So they obtained bone marrow samples from AML patients who recovered as expected (within 30 days) after each chemotherapy course (n=62), and from AML patients who experienced significant delays in recovery after chemotherapy (n=53).
The team then measured telomere length on each subject and categorized the group by quartile, from shortest to longest.
Subjects in the quartile with the shortest telomere lengths took the longest to recover, especially during the last 2 courses of chemotherapy. In an adjusted analysis, lower telomere content was significantly associated with prolonged neutropenia after the fourth (P=0.002) and fifth courses of chemotherapy (P=0.009).
The researchers said these results support the hypothesis that telomeres are an indicator of capacity for neutrophil recovery following chemotherapy.
Dr Gramatges hopes the results of this study will be helpful in further understanding which children are at a higher risk for prolonged myelosuppression and how to target those children with modified treatments, improved supportive care, and closer monitoring in order to prevent potential complications such as severe infections.
“A significant proportion of children with AML suffer from treatment-related toxicities, with some succumbing to complications of the therapies we give, rather than from the actual cancer itself,” Dr Gramatges said.
“We hope this research will help us identify those who are at a higher risk for delayed recovery and use this knowledge to reduce the morbidity and mortality associated with AML treatment.”
Image by Volker Brinkmann
Researchers say they have discovered a way to predict which children with acute myeloid leukemia (AML) are at the highest risk of delayed neutrophil recovery.
The team examined the role of telomeres in neutrophil recovery and found that the length of a patient’s telomeres can indicate the rate of recovery following chemotherapy.
The group reported their findings in the Journal of Clinical Oncology.
“We were interested in telomere length as a marker of blood count recovery because defects in telomere maintenance are known risks for bone marrow failure and aplastic anemia,” said study author Maria Monica Gramatges, MD, PhD, of Baylor College of Medicine in Houston, Texas.
“We know that up to 15% to 20% of children can take 2 months or longer to recover their blood counts after a course of AML chemotherapy. Our goal was to understand if these children had an underlying genetic predisposition associated with an impaired capacity for recovery.”
Dr Gramatges and her colleagues hypothesized that short telomere length could be associated with a delay in neutrophil recovery.
So they obtained bone marrow samples from AML patients who recovered as expected (within 30 days) after each chemotherapy course (n=62), and from AML patients who experienced significant delays in recovery after chemotherapy (n=53).
The team then measured telomere length on each subject and categorized the group by quartile, from shortest to longest.
Subjects in the quartile with the shortest telomere lengths took the longest to recover, especially during the last 2 courses of chemotherapy. In an adjusted analysis, lower telomere content was significantly associated with prolonged neutropenia after the fourth (P=0.002) and fifth courses of chemotherapy (P=0.009).
The researchers said these results support the hypothesis that telomeres are an indicator of capacity for neutrophil recovery following chemotherapy.
Dr Gramatges hopes the results of this study will be helpful in further understanding which children are at a higher risk for prolonged myelosuppression and how to target those children with modified treatments, improved supportive care, and closer monitoring in order to prevent potential complications such as severe infections.
“A significant proportion of children with AML suffer from treatment-related toxicities, with some succumbing to complications of the therapies we give, rather than from the actual cancer itself,” Dr Gramatges said.
“We hope this research will help us identify those who are at a higher risk for delayed recovery and use this knowledge to reduce the morbidity and mortality associated with AML treatment.”
Image by Volker Brinkmann
Researchers say they have discovered a way to predict which children with acute myeloid leukemia (AML) are at the highest risk of delayed neutrophil recovery.
The team examined the role of telomeres in neutrophil recovery and found that the length of a patient’s telomeres can indicate the rate of recovery following chemotherapy.
The group reported their findings in the Journal of Clinical Oncology.
“We were interested in telomere length as a marker of blood count recovery because defects in telomere maintenance are known risks for bone marrow failure and aplastic anemia,” said study author Maria Monica Gramatges, MD, PhD, of Baylor College of Medicine in Houston, Texas.
“We know that up to 15% to 20% of children can take 2 months or longer to recover their blood counts after a course of AML chemotherapy. Our goal was to understand if these children had an underlying genetic predisposition associated with an impaired capacity for recovery.”
Dr Gramatges and her colleagues hypothesized that short telomere length could be associated with a delay in neutrophil recovery.
So they obtained bone marrow samples from AML patients who recovered as expected (within 30 days) after each chemotherapy course (n=62), and from AML patients who experienced significant delays in recovery after chemotherapy (n=53).
The team then measured telomere length on each subject and categorized the group by quartile, from shortest to longest.
Subjects in the quartile with the shortest telomere lengths took the longest to recover, especially during the last 2 courses of chemotherapy. In an adjusted analysis, lower telomere content was significantly associated with prolonged neutropenia after the fourth (P=0.002) and fifth courses of chemotherapy (P=0.009).
The researchers said these results support the hypothesis that telomeres are an indicator of capacity for neutrophil recovery following chemotherapy.
Dr Gramatges hopes the results of this study will be helpful in further understanding which children are at a higher risk for prolonged myelosuppression and how to target those children with modified treatments, improved supportive care, and closer monitoring in order to prevent potential complications such as severe infections.
“A significant proportion of children with AML suffer from treatment-related toxicities, with some succumbing to complications of the therapies we give, rather than from the actual cancer itself,” Dr Gramatges said.
“We hope this research will help us identify those who are at a higher risk for delayed recovery and use this knowledge to reduce the morbidity and mortality associated with AML treatment.”
Old drug could treat CMV
Image by Ed Uthman
Research published in PLOS Pathogens suggests that emetine, a drug once used to treat amebiasis and induce vomiting in cases of poisoning, may also halt replication of cytomegalovirus (CMV).
Although there are drugs available to treat CMV, they can cause serious toxicity.
Furthermore, resistant strains of CMV can emerge, creating “a desperate need for other ways to control this virus,” according to Ravit Boger, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr Boger and her colleagues decided to search for drugs to treat CMV by screening 1280 pharmacologically active compounds already approved by the US Food and Drug Administration.
The researchers found a “hit” with emetine, a drug that was used in the past to treat amebiasis before other drugs took its place decades ago.
Results showed that emetine can inhibit CMV at much lower doses than those used for amebiasis, and less frequent doses might be effective for CMV inhibition as well.
In vitro and in vivo tests showed that very low doses of emetine significantly reduced viral replication—75 nm in vitro and 0.1 mg/kg in mice.
Furthermore, with a half-life of 35 hours, the drug exerted its effects over a sustained period, effectively inhibiting virus replication at 14 days after 3 doses.
Additional investigation revealed that emetine’s action against CMV was due to its effects on proteins that control the cell cycle.
Dr Boger cautioned that there is a long way to go before emetine or similar agents can be considered for the treatment of CMV.
“But if further research affirms its potential value, emetine might eventually be used in patients who don’t respond to approved anti-CMV drugs, alone or in combination with these,” she said.
Dr Boger and her colleagues also believe that gaining a better understanding of emetine’s activity in cells could lead to the discovery of new drugs that take advantage of the same or similar pathways.
Image by Ed Uthman
Research published in PLOS Pathogens suggests that emetine, a drug once used to treat amebiasis and induce vomiting in cases of poisoning, may also halt replication of cytomegalovirus (CMV).
Although there are drugs available to treat CMV, they can cause serious toxicity.
Furthermore, resistant strains of CMV can emerge, creating “a desperate need for other ways to control this virus,” according to Ravit Boger, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr Boger and her colleagues decided to search for drugs to treat CMV by screening 1280 pharmacologically active compounds already approved by the US Food and Drug Administration.
The researchers found a “hit” with emetine, a drug that was used in the past to treat amebiasis before other drugs took its place decades ago.
Results showed that emetine can inhibit CMV at much lower doses than those used for amebiasis, and less frequent doses might be effective for CMV inhibition as well.
In vitro and in vivo tests showed that very low doses of emetine significantly reduced viral replication—75 nm in vitro and 0.1 mg/kg in mice.
Furthermore, with a half-life of 35 hours, the drug exerted its effects over a sustained period, effectively inhibiting virus replication at 14 days after 3 doses.
Additional investigation revealed that emetine’s action against CMV was due to its effects on proteins that control the cell cycle.
Dr Boger cautioned that there is a long way to go before emetine or similar agents can be considered for the treatment of CMV.
“But if further research affirms its potential value, emetine might eventually be used in patients who don’t respond to approved anti-CMV drugs, alone or in combination with these,” she said.
Dr Boger and her colleagues also believe that gaining a better understanding of emetine’s activity in cells could lead to the discovery of new drugs that take advantage of the same or similar pathways.
Image by Ed Uthman
Research published in PLOS Pathogens suggests that emetine, a drug once used to treat amebiasis and induce vomiting in cases of poisoning, may also halt replication of cytomegalovirus (CMV).
Although there are drugs available to treat CMV, they can cause serious toxicity.
Furthermore, resistant strains of CMV can emerge, creating “a desperate need for other ways to control this virus,” according to Ravit Boger, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr Boger and her colleagues decided to search for drugs to treat CMV by screening 1280 pharmacologically active compounds already approved by the US Food and Drug Administration.
The researchers found a “hit” with emetine, a drug that was used in the past to treat amebiasis before other drugs took its place decades ago.
Results showed that emetine can inhibit CMV at much lower doses than those used for amebiasis, and less frequent doses might be effective for CMV inhibition as well.
In vitro and in vivo tests showed that very low doses of emetine significantly reduced viral replication—75 nm in vitro and 0.1 mg/kg in mice.
Furthermore, with a half-life of 35 hours, the drug exerted its effects over a sustained period, effectively inhibiting virus replication at 14 days after 3 doses.
Additional investigation revealed that emetine’s action against CMV was due to its effects on proteins that control the cell cycle.
Dr Boger cautioned that there is a long way to go before emetine or similar agents can be considered for the treatment of CMV.
“But if further research affirms its potential value, emetine might eventually be used in patients who don’t respond to approved anti-CMV drugs, alone or in combination with these,” she said.
Dr Boger and her colleagues also believe that gaining a better understanding of emetine’s activity in cells could lead to the discovery of new drugs that take advantage of the same or similar pathways.
Computer model shows how spleen filters blood
Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.
The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.
The researchers described the model in PNAS.
Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.
More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.
In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.
Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.
“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”
In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.
A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.
The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.
Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.
The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.
The researchers described the model in PNAS.
Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.
More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.
In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.
Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.
“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”
In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.
A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.
The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.
Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.
The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.
The researchers described the model in PNAS.
Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.
More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.
In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.
Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.
“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”
In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.
A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.
The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.
New type of CAR T cells can produce responses in NHL
Image courtesy of NIAID
Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.
The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.
There was 1 adverse event considered possibly related to the treatment.
The researchers reported these results in The Journal of Clinical Investigation.
The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.
“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.
He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).
The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.
Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×108 to 2×108 κ.CAR T cells/m2).
“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.
One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.
Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.
Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.
“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.
Image courtesy of NIAID
Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.
The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.
There was 1 adverse event considered possibly related to the treatment.
The researchers reported these results in The Journal of Clinical Investigation.
The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.
“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.
He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).
The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.
Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×108 to 2×108 κ.CAR T cells/m2).
“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.
One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.
Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.
Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.
“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.
Image courtesy of NIAID
Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.
The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.
There was 1 adverse event considered possibly related to the treatment.
The researchers reported these results in The Journal of Clinical Investigation.
The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.
“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.
He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).
The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.
Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×108 to 2×108 κ.CAR T cells/m2).
“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.
One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.
Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.
Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.
“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.
Health Canada approves mAb for MM
Photo courtesy of Janssen
Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.
The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.
An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.
The NOC/c policy is designed to provide access to:
- Drugs that can treat serious, life-threatening, or severely debilitating diseases
- Drugs that can treat conditions for which no drug is currently marketed in Canada
- Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.
Studies of daratumumab
The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.
Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.
Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.
Photo courtesy of Janssen
Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.
The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.
An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.
The NOC/c policy is designed to provide access to:
- Drugs that can treat serious, life-threatening, or severely debilitating diseases
- Drugs that can treat conditions for which no drug is currently marketed in Canada
- Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.
Studies of daratumumab
The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.
Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.
Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.
Photo courtesy of Janssen
Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.
The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.
An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.
The NOC/c policy is designed to provide access to:
- Drugs that can treat serious, life-threatening, or severely debilitating diseases
- Drugs that can treat conditions for which no drug is currently marketed in Canada
- Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.
Studies of daratumumab
The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.
Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.
Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.
Inhibitor produces responses in advanced SM
Results of a phase 2 trial suggest the multikinase inhibitor midostaurin can repair organ damage in patients with advanced systemic mastocytosis (SM).
The drug produced a 60% response rate among patients with mastocytosis-related organ damage, and the median duration of response was 24.1 months.
Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose.
Jason Gotlib, MD, of the Stanford University School of Medicine in California, and his colleagues conducted this study and reported the results in NEJM.
The study was funded by Novartis Inc., which manufactures midostaurin, also known as PKC412.
The researchers noted that roughly 90% of patients with advanced SM have a mutation known as D816V in the gene that encodes the protein KIT, which controls the growth of mast cells.
Unfortunately, the only drug approved to treat advanced SM in the US is the tyrosine kinase inhibitor imatinib, and this drug is not active against the mutated KIT D816V protein. Midostaurin, on the other hand, does inhibit KIT D816V.
With this in mind, Dr Gotlib and his colleagues set out to test midostaurin (given at 100 mg twice daily until disease progression or unacceptable toxicity) in 116 patients.
Eighty-nine of the patients had mastocytosis-related organ damage, 16 had aggressive SM, 57 had SM with an associated hematologic neoplasm, and 16 had mast cell leukemia.
Response
The median follow-up was 26 months (range, 12 to 54), and the study’s primary outcome was the best overall response.
The overall response rate for the primary efficacy population (the 89 patients with mastocytosis-related organ damage) was 60%. Forty-five percent of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage.
The overall response rate was 75% for patients with aggressive SM, 58% for SM patients with an associated hematologic neoplasm, and 50% for patients with mast-cell leukemia.
Responses occurred in all subgroups, which included patients who were positive for KIT D816V.
The researchers noted that responding patients were less likely to need red blood cell or platelet transfusions, experienced improvements in liver function, and had fewer signs of malabsorption such as weight loss.
The median duration of response for all responders in the primary efficacy population (n=89) was 24.1 months.
Survival
The median overall survival was 28.7 months in the primary efficacy population (n=89) and 33.9 months in the intention-to-treat population (n=116). The median progression-free survival was 14.1 months in the primary efficacy population.
The survival benefit among patients with mast cell leukemia was particularly striking, according to Dr Gotlib. Although most people succumb to this form of the disease within 6 months of diagnosis, the median overall survival of midostaurin-treated patients with mast cell leukemia was 9.4 months.
The median overall survival was not reached among patients with aggressive SM and was 20.7 months among patients who had SM with an associated hematologic neoplasm.
Safety
The most common nonhematologic adverse events were nausea (79%), vomiting (66%), and diarrhea (54%). The most common grade 3/4 nonhematologic adverse events were fatigue (9%) and diarrhea (8%).
Grade 3/4 hematologic adverse events included new or worsening neutropenia (24%), anemia (41%), and thrombocytopenia (29%).
Researchers reduced the dose of midostaurin in 65 patients (56%), mostly due to adverse events (n=48). Twenty-one of these patients (32%) were later able to return to the initial dose.
Eighty-four patients (72%) discontinued treatment, and 32 (28%) were receiving ongoing treatment at the time of data cutoff. The most frequent reasons for treatment discontinuation were disease progression (33%) and adverse events (22%).
Compassionate use
The phase 2 study results are reinforced by a letter published in the same issue of NEJM, which describes a compassionate use program for midostaurin in advanced SM.
The letter includes results in 28 patients. After a median follow-up of 18.5 months, the overall response rate was 71%. The overall survival rate was 42.7%.
The most frequent adverse events were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% (without opportunistic infection), and photosensitivity in 25%.
Results of a phase 2 trial suggest the multikinase inhibitor midostaurin can repair organ damage in patients with advanced systemic mastocytosis (SM).
The drug produced a 60% response rate among patients with mastocytosis-related organ damage, and the median duration of response was 24.1 months.
Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose.
Jason Gotlib, MD, of the Stanford University School of Medicine in California, and his colleagues conducted this study and reported the results in NEJM.
The study was funded by Novartis Inc., which manufactures midostaurin, also known as PKC412.
The researchers noted that roughly 90% of patients with advanced SM have a mutation known as D816V in the gene that encodes the protein KIT, which controls the growth of mast cells.
Unfortunately, the only drug approved to treat advanced SM in the US is the tyrosine kinase inhibitor imatinib, and this drug is not active against the mutated KIT D816V protein. Midostaurin, on the other hand, does inhibit KIT D816V.
With this in mind, Dr Gotlib and his colleagues set out to test midostaurin (given at 100 mg twice daily until disease progression or unacceptable toxicity) in 116 patients.
Eighty-nine of the patients had mastocytosis-related organ damage, 16 had aggressive SM, 57 had SM with an associated hematologic neoplasm, and 16 had mast cell leukemia.
Response
The median follow-up was 26 months (range, 12 to 54), and the study’s primary outcome was the best overall response.
The overall response rate for the primary efficacy population (the 89 patients with mastocytosis-related organ damage) was 60%. Forty-five percent of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage.
The overall response rate was 75% for patients with aggressive SM, 58% for SM patients with an associated hematologic neoplasm, and 50% for patients with mast-cell leukemia.
Responses occurred in all subgroups, which included patients who were positive for KIT D816V.
The researchers noted that responding patients were less likely to need red blood cell or platelet transfusions, experienced improvements in liver function, and had fewer signs of malabsorption such as weight loss.
The median duration of response for all responders in the primary efficacy population (n=89) was 24.1 months.
Survival
The median overall survival was 28.7 months in the primary efficacy population (n=89) and 33.9 months in the intention-to-treat population (n=116). The median progression-free survival was 14.1 months in the primary efficacy population.
The survival benefit among patients with mast cell leukemia was particularly striking, according to Dr Gotlib. Although most people succumb to this form of the disease within 6 months of diagnosis, the median overall survival of midostaurin-treated patients with mast cell leukemia was 9.4 months.
The median overall survival was not reached among patients with aggressive SM and was 20.7 months among patients who had SM with an associated hematologic neoplasm.
Safety
The most common nonhematologic adverse events were nausea (79%), vomiting (66%), and diarrhea (54%). The most common grade 3/4 nonhematologic adverse events were fatigue (9%) and diarrhea (8%).
Grade 3/4 hematologic adverse events included new or worsening neutropenia (24%), anemia (41%), and thrombocytopenia (29%).
Researchers reduced the dose of midostaurin in 65 patients (56%), mostly due to adverse events (n=48). Twenty-one of these patients (32%) were later able to return to the initial dose.
Eighty-four patients (72%) discontinued treatment, and 32 (28%) were receiving ongoing treatment at the time of data cutoff. The most frequent reasons for treatment discontinuation were disease progression (33%) and adverse events (22%).
Compassionate use
The phase 2 study results are reinforced by a letter published in the same issue of NEJM, which describes a compassionate use program for midostaurin in advanced SM.
The letter includes results in 28 patients. After a median follow-up of 18.5 months, the overall response rate was 71%. The overall survival rate was 42.7%.
The most frequent adverse events were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% (without opportunistic infection), and photosensitivity in 25%.
Results of a phase 2 trial suggest the multikinase inhibitor midostaurin can repair organ damage in patients with advanced systemic mastocytosis (SM).
The drug produced a 60% response rate among patients with mastocytosis-related organ damage, and the median duration of response was 24.1 months.
Fifty-six percent of patients required dose reductions due to toxic effects, but 32% of these patients were able to return to the starting dose.
Jason Gotlib, MD, of the Stanford University School of Medicine in California, and his colleagues conducted this study and reported the results in NEJM.
The study was funded by Novartis Inc., which manufactures midostaurin, also known as PKC412.
The researchers noted that roughly 90% of patients with advanced SM have a mutation known as D816V in the gene that encodes the protein KIT, which controls the growth of mast cells.
Unfortunately, the only drug approved to treat advanced SM in the US is the tyrosine kinase inhibitor imatinib, and this drug is not active against the mutated KIT D816V protein. Midostaurin, on the other hand, does inhibit KIT D816V.
With this in mind, Dr Gotlib and his colleagues set out to test midostaurin (given at 100 mg twice daily until disease progression or unacceptable toxicity) in 116 patients.
Eighty-nine of the patients had mastocytosis-related organ damage, 16 had aggressive SM, 57 had SM with an associated hematologic neoplasm, and 16 had mast cell leukemia.
Response
The median follow-up was 26 months (range, 12 to 54), and the study’s primary outcome was the best overall response.
The overall response rate for the primary efficacy population (the 89 patients with mastocytosis-related organ damage) was 60%. Forty-five percent of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage.
The overall response rate was 75% for patients with aggressive SM, 58% for SM patients with an associated hematologic neoplasm, and 50% for patients with mast-cell leukemia.
Responses occurred in all subgroups, which included patients who were positive for KIT D816V.
The researchers noted that responding patients were less likely to need red blood cell or platelet transfusions, experienced improvements in liver function, and had fewer signs of malabsorption such as weight loss.
The median duration of response for all responders in the primary efficacy population (n=89) was 24.1 months.
Survival
The median overall survival was 28.7 months in the primary efficacy population (n=89) and 33.9 months in the intention-to-treat population (n=116). The median progression-free survival was 14.1 months in the primary efficacy population.
The survival benefit among patients with mast cell leukemia was particularly striking, according to Dr Gotlib. Although most people succumb to this form of the disease within 6 months of diagnosis, the median overall survival of midostaurin-treated patients with mast cell leukemia was 9.4 months.
The median overall survival was not reached among patients with aggressive SM and was 20.7 months among patients who had SM with an associated hematologic neoplasm.
Safety
The most common nonhematologic adverse events were nausea (79%), vomiting (66%), and diarrhea (54%). The most common grade 3/4 nonhematologic adverse events were fatigue (9%) and diarrhea (8%).
Grade 3/4 hematologic adverse events included new or worsening neutropenia (24%), anemia (41%), and thrombocytopenia (29%).
Researchers reduced the dose of midostaurin in 65 patients (56%), mostly due to adverse events (n=48). Twenty-one of these patients (32%) were later able to return to the initial dose.
Eighty-four patients (72%) discontinued treatment, and 32 (28%) were receiving ongoing treatment at the time of data cutoff. The most frequent reasons for treatment discontinuation were disease progression (33%) and adverse events (22%).
Compassionate use
The phase 2 study results are reinforced by a letter published in the same issue of NEJM, which describes a compassionate use program for midostaurin in advanced SM.
The letter includes results in 28 patients. After a median follow-up of 18.5 months, the overall response rate was 71%. The overall survival rate was 42.7%.
The most frequent adverse events were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% (without opportunistic infection), and photosensitivity in 25%.
Risk of AML death varies by region
Photo by Rhoda Baer
The risk of death from acute myeloid leukemia (AML) may be influenced by where a patient lives, according to a study published in Cancer.
Three regions in North Carolina were found to be associated with a higher risk of death, when compared to the rest of the state.
Patients had a significantly higher risk of death if they lived in northeastern North Carolina (from Wilson to Roanoke Rapids), in a region around Greenville, and a region around Wake County, including Durham County.
The increased risk remained even when the researchers controlled for other factors.
“The geographic survival disparities we found could not be explained by other sociodemographic variables or proximity to experienced treating facilities,” said study author Ashley Freeman, MD, of the University of North Carolina (UNC) in Chapel Hill.
“This raises the possibility that more complex features of the local healthcare infrastructure, including provider referral and practice patterns, are affecting patient outcomes.”
To study death rates from AML across North Carolina, Dr Freeman and her colleagues analyzed data on 553 adults who were diagnosed with AML between 2003 and 2009 and received inpatient chemotherapy within 30 days of diagnosis.
The team used the UNC Lineberger Integrated Cancer Information and Surveillance System, a database that links insurance claims information to a state information database called the NC Cancer Registry.
The researchers assessed the risk of death in 9 regions defined by the North Carolina Area Health Education Centers (AHEC) Program, a program established in 1972 to address physician shortages and the uneven distribution of healthcare services in North Carolina.
“We looked at geographic disparities because we are trying to improve outcomes for all citizens in North Carolina, consistent with the mission of our cancer center,” said William A. Wood, MD, of UNC.
“We are also trying to find situations in which disparities shouldn’t exist but do for arbitrary reasons—such as where a patient happens to live—so that we can figure out how to improve equity across the state.”
The researchers determined that a region around Greensboro had the lowest risk of death for AML.
Compared to the Greensboro region, the risk of death was 4 times higher in an area of northeastern North Carolina that included Roanoke Rapids, Rocky Mount, and Wilson—the highest in the state.
Compared to the Greensboro region, the risk of death was more than 2 times greater in the eastern region of the state around Greenville, and it was nearly twice as high in the region around Wake County.
“There are areas of the state where there is an elevated mortality, and we need to better understand the factors that are driving that—whether they’re environmental, patient, or provider-related,” said Anne-Marie Meyer, PhD, of UNC.
Nearly half of patients in the study received their care at hospitals not affiliated with one of the state’s 3 National Cancer Institute (NCI) comprehensive cancer centers.
The researchers did not find a significant link between the risk of death and the distance from patients’ homes to their treating facility or the nearest NCI-designated center.
And there was no significant difference in the risk of death at 1 year between patients who received treatment at an NCI-designated cancer center and those who did not. However, patients with a more serious prognosis were more likely to be treated at an NCI-designated cancer center.
The researchers did identify regional differences in healthcare resources. “Area L,” which is the name for the region in northeastern North Carolina that spans from Wilson to Roanoke Rapids, for example, has some of the lowest proportion of general practitioner physicians and radiation oncologists, as well as the highest burden of disease.
However, it is not clear why the disparities continued even after the researchers controlled for regional factors like poverty and education. The team believes other factors could be involved, such as the providers’ experience with treating rare or complex diseases or how supportive care is delivered.
Although there was not a significant association between survival and treatment at an NCI-designated center, there may be other features of treatment facilities, such as patient volume and academic affiliation, that are important for patient outcomes.
The researchers said their next step is to identify those factors and develop programs to try to close the gaps.
“The message here is that acute myeloid leukemia is representative of diseases that are uncommon, involve high-complexity care, and have high risk for morbidity and mortality,” Dr Wood said.
“If we can figure out how to coordinate and improve delivery of effective interventions for this disease throughout the state of North Carolina, then we may be able to develop a model for improving outcomes in many other diseases throughout the state as well.”
Photo by Rhoda Baer
The risk of death from acute myeloid leukemia (AML) may be influenced by where a patient lives, according to a study published in Cancer.
Three regions in North Carolina were found to be associated with a higher risk of death, when compared to the rest of the state.
Patients had a significantly higher risk of death if they lived in northeastern North Carolina (from Wilson to Roanoke Rapids), in a region around Greenville, and a region around Wake County, including Durham County.
The increased risk remained even when the researchers controlled for other factors.
“The geographic survival disparities we found could not be explained by other sociodemographic variables or proximity to experienced treating facilities,” said study author Ashley Freeman, MD, of the University of North Carolina (UNC) in Chapel Hill.
“This raises the possibility that more complex features of the local healthcare infrastructure, including provider referral and practice patterns, are affecting patient outcomes.”
To study death rates from AML across North Carolina, Dr Freeman and her colleagues analyzed data on 553 adults who were diagnosed with AML between 2003 and 2009 and received inpatient chemotherapy within 30 days of diagnosis.
The team used the UNC Lineberger Integrated Cancer Information and Surveillance System, a database that links insurance claims information to a state information database called the NC Cancer Registry.
The researchers assessed the risk of death in 9 regions defined by the North Carolina Area Health Education Centers (AHEC) Program, a program established in 1972 to address physician shortages and the uneven distribution of healthcare services in North Carolina.
“We looked at geographic disparities because we are trying to improve outcomes for all citizens in North Carolina, consistent with the mission of our cancer center,” said William A. Wood, MD, of UNC.
“We are also trying to find situations in which disparities shouldn’t exist but do for arbitrary reasons—such as where a patient happens to live—so that we can figure out how to improve equity across the state.”
The researchers determined that a region around Greensboro had the lowest risk of death for AML.
Compared to the Greensboro region, the risk of death was 4 times higher in an area of northeastern North Carolina that included Roanoke Rapids, Rocky Mount, and Wilson—the highest in the state.
Compared to the Greensboro region, the risk of death was more than 2 times greater in the eastern region of the state around Greenville, and it was nearly twice as high in the region around Wake County.
“There are areas of the state where there is an elevated mortality, and we need to better understand the factors that are driving that—whether they’re environmental, patient, or provider-related,” said Anne-Marie Meyer, PhD, of UNC.
Nearly half of patients in the study received their care at hospitals not affiliated with one of the state’s 3 National Cancer Institute (NCI) comprehensive cancer centers.
The researchers did not find a significant link between the risk of death and the distance from patients’ homes to their treating facility or the nearest NCI-designated center.
And there was no significant difference in the risk of death at 1 year between patients who received treatment at an NCI-designated cancer center and those who did not. However, patients with a more serious prognosis were more likely to be treated at an NCI-designated cancer center.
The researchers did identify regional differences in healthcare resources. “Area L,” which is the name for the region in northeastern North Carolina that spans from Wilson to Roanoke Rapids, for example, has some of the lowest proportion of general practitioner physicians and radiation oncologists, as well as the highest burden of disease.
However, it is not clear why the disparities continued even after the researchers controlled for regional factors like poverty and education. The team believes other factors could be involved, such as the providers’ experience with treating rare or complex diseases or how supportive care is delivered.
Although there was not a significant association between survival and treatment at an NCI-designated center, there may be other features of treatment facilities, such as patient volume and academic affiliation, that are important for patient outcomes.
The researchers said their next step is to identify those factors and develop programs to try to close the gaps.
“The message here is that acute myeloid leukemia is representative of diseases that are uncommon, involve high-complexity care, and have high risk for morbidity and mortality,” Dr Wood said.
“If we can figure out how to coordinate and improve delivery of effective interventions for this disease throughout the state of North Carolina, then we may be able to develop a model for improving outcomes in many other diseases throughout the state as well.”
Photo by Rhoda Baer
The risk of death from acute myeloid leukemia (AML) may be influenced by where a patient lives, according to a study published in Cancer.
Three regions in North Carolina were found to be associated with a higher risk of death, when compared to the rest of the state.
Patients had a significantly higher risk of death if they lived in northeastern North Carolina (from Wilson to Roanoke Rapids), in a region around Greenville, and a region around Wake County, including Durham County.
The increased risk remained even when the researchers controlled for other factors.
“The geographic survival disparities we found could not be explained by other sociodemographic variables or proximity to experienced treating facilities,” said study author Ashley Freeman, MD, of the University of North Carolina (UNC) in Chapel Hill.
“This raises the possibility that more complex features of the local healthcare infrastructure, including provider referral and practice patterns, are affecting patient outcomes.”
To study death rates from AML across North Carolina, Dr Freeman and her colleagues analyzed data on 553 adults who were diagnosed with AML between 2003 and 2009 and received inpatient chemotherapy within 30 days of diagnosis.
The team used the UNC Lineberger Integrated Cancer Information and Surveillance System, a database that links insurance claims information to a state information database called the NC Cancer Registry.
The researchers assessed the risk of death in 9 regions defined by the North Carolina Area Health Education Centers (AHEC) Program, a program established in 1972 to address physician shortages and the uneven distribution of healthcare services in North Carolina.
“We looked at geographic disparities because we are trying to improve outcomes for all citizens in North Carolina, consistent with the mission of our cancer center,” said William A. Wood, MD, of UNC.
“We are also trying to find situations in which disparities shouldn’t exist but do for arbitrary reasons—such as where a patient happens to live—so that we can figure out how to improve equity across the state.”
The researchers determined that a region around Greensboro had the lowest risk of death for AML.
Compared to the Greensboro region, the risk of death was 4 times higher in an area of northeastern North Carolina that included Roanoke Rapids, Rocky Mount, and Wilson—the highest in the state.
Compared to the Greensboro region, the risk of death was more than 2 times greater in the eastern region of the state around Greenville, and it was nearly twice as high in the region around Wake County.
“There are areas of the state where there is an elevated mortality, and we need to better understand the factors that are driving that—whether they’re environmental, patient, or provider-related,” said Anne-Marie Meyer, PhD, of UNC.
Nearly half of patients in the study received their care at hospitals not affiliated with one of the state’s 3 National Cancer Institute (NCI) comprehensive cancer centers.
The researchers did not find a significant link between the risk of death and the distance from patients’ homes to their treating facility or the nearest NCI-designated center.
And there was no significant difference in the risk of death at 1 year between patients who received treatment at an NCI-designated cancer center and those who did not. However, patients with a more serious prognosis were more likely to be treated at an NCI-designated cancer center.
The researchers did identify regional differences in healthcare resources. “Area L,” which is the name for the region in northeastern North Carolina that spans from Wilson to Roanoke Rapids, for example, has some of the lowest proportion of general practitioner physicians and radiation oncologists, as well as the highest burden of disease.
However, it is not clear why the disparities continued even after the researchers controlled for regional factors like poverty and education. The team believes other factors could be involved, such as the providers’ experience with treating rare or complex diseases or how supportive care is delivered.
Although there was not a significant association between survival and treatment at an NCI-designated center, there may be other features of treatment facilities, such as patient volume and academic affiliation, that are important for patient outcomes.
The researchers said their next step is to identify those factors and develop programs to try to close the gaps.
“The message here is that acute myeloid leukemia is representative of diseases that are uncommon, involve high-complexity care, and have high risk for morbidity and mortality,” Dr Wood said.
“If we can figure out how to coordinate and improve delivery of effective interventions for this disease throughout the state of North Carolina, then we may be able to develop a model for improving outcomes in many other diseases throughout the state as well.”
Drug granted breakthrough, orphan designation for cGVHD
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for ibrutinib (Imbruvica), a Bruton’s tyrosine kinase inhibitor, as a potential treatment for chronic graft-versus-host-disease (cGVHD) in patients who have failed 1 or more lines of systemic therapy.
The FDA has also granted ibrutinib orphan drug designation for this indication.
The request for breakthrough therapy designation and orphan designation for ibrutinib in patients with cGVHD was based on preliminary data from a phase 1b/2 study of patients with steroid-dependent or refractory cGVHD.
Results from this trial were presented at the 2015 ASCO Annual Meeting (abstract 7024) and the 2016 EBMT meeting (abstract P124).
About ibrutinib
Ibrutinib is an oral, once-daily therapy that inhibits Bruton’s tyrosine kinase, a signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.
Ibrutinib is FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including those with 17p deletion, patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia.
Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA previously granted ibrutinib breakthrough designation for the treatment of relapsed or refractory MCL, Waldenström’s macroglobulinemia, and CLL/SLL patients with 17p deletion. The FDA also granted ibrutinib orphan designation for all 3 indications.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
About breakthrough designation
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for ibrutinib (Imbruvica), a Bruton’s tyrosine kinase inhibitor, as a potential treatment for chronic graft-versus-host-disease (cGVHD) in patients who have failed 1 or more lines of systemic therapy.
The FDA has also granted ibrutinib orphan drug designation for this indication.
The request for breakthrough therapy designation and orphan designation for ibrutinib in patients with cGVHD was based on preliminary data from a phase 1b/2 study of patients with steroid-dependent or refractory cGVHD.
Results from this trial were presented at the 2015 ASCO Annual Meeting (abstract 7024) and the 2016 EBMT meeting (abstract P124).
About ibrutinib
Ibrutinib is an oral, once-daily therapy that inhibits Bruton’s tyrosine kinase, a signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.
Ibrutinib is FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including those with 17p deletion, patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia.
Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA previously granted ibrutinib breakthrough designation for the treatment of relapsed or refractory MCL, Waldenström’s macroglobulinemia, and CLL/SLL patients with 17p deletion. The FDA also granted ibrutinib orphan designation for all 3 indications.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
About breakthrough designation
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for ibrutinib (Imbruvica), a Bruton’s tyrosine kinase inhibitor, as a potential treatment for chronic graft-versus-host-disease (cGVHD) in patients who have failed 1 or more lines of systemic therapy.
The FDA has also granted ibrutinib orphan drug designation for this indication.
The request for breakthrough therapy designation and orphan designation for ibrutinib in patients with cGVHD was based on preliminary data from a phase 1b/2 study of patients with steroid-dependent or refractory cGVHD.
Results from this trial were presented at the 2015 ASCO Annual Meeting (abstract 7024) and the 2016 EBMT meeting (abstract P124).
About ibrutinib
Ibrutinib is an oral, once-daily therapy that inhibits Bruton’s tyrosine kinase, a signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.
Ibrutinib is FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including those with 17p deletion, patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia.
Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA previously granted ibrutinib breakthrough designation for the treatment of relapsed or refractory MCL, Waldenström’s macroglobulinemia, and CLL/SLL patients with 17p deletion. The FDA also granted ibrutinib orphan designation for all 3 indications.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
About breakthrough designation
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life-threatening conditions.
To earn the designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.