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EC expands indication for ofatumumab
Credit: Linda Bartlett
The European Commission (EC) has expanded the indication for the anti-CD20 monoclonal antibody ofatumumab (Arzerra).
The EC granted conditional approval for ofatumumab in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.
In 2010, the EC granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. Ofatumumab will not receive full approval until the drug’s developers, GlaxoSmithKline and GenMab, submit results of additional research to the EC.
Trial results
The EC’s new approval of ofatumumab, for previously untreated CLL patients, is based on results from 2 trials, COMPLEMENT 1 and OMB115991.
The phase 3 COMPLEMENT 1 trial was a comparison of ofatumumab plus chlorambucil (n=221) with chlorambucil alone (n=226) in CLL patients for whom fludarabine-based treatment was considered inappropriate.
In this study, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).
In the phase 2 trial known as OMB115991, researchers evaluated ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL for whom fludarabine-based treatment was considered inappropriate.
The combination elicited an overall response rate of 95% and a complete response rate of 43%.
The overall safety profile of ofatumumab in CLL (previously untreated and relapsed/refractory) is based on data from 511 patients in clinical trials.
This includes 250 patients with relapsed/refractory CLL who were treated with ofatumumab alone and 261 patients with previously untreated CLL who were treated in combination with an alkylating agent.
The most common adverse effects associated with ofatumumab were infusion reactions, neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia, lower respiratory tract infection (including pneumonia), upper respiratory tract infection, sepsis (including neutropenic sepsis and septic shock), herpes virus infection, and urinary tract infection. 
Credit: Linda Bartlett
The European Commission (EC) has expanded the indication for the anti-CD20 monoclonal antibody ofatumumab (Arzerra).
The EC granted conditional approval for ofatumumab in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.
In 2010, the EC granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. Ofatumumab will not receive full approval until the drug’s developers, GlaxoSmithKline and GenMab, submit results of additional research to the EC.
Trial results
The EC’s new approval of ofatumumab, for previously untreated CLL patients, is based on results from 2 trials, COMPLEMENT 1 and OMB115991.
The phase 3 COMPLEMENT 1 trial was a comparison of ofatumumab plus chlorambucil (n=221) with chlorambucil alone (n=226) in CLL patients for whom fludarabine-based treatment was considered inappropriate.
In this study, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).
In the phase 2 trial known as OMB115991, researchers evaluated ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL for whom fludarabine-based treatment was considered inappropriate.
The combination elicited an overall response rate of 95% and a complete response rate of 43%.
The overall safety profile of ofatumumab in CLL (previously untreated and relapsed/refractory) is based on data from 511 patients in clinical trials.
This includes 250 patients with relapsed/refractory CLL who were treated with ofatumumab alone and 261 patients with previously untreated CLL who were treated in combination with an alkylating agent.
The most common adverse effects associated with ofatumumab were infusion reactions, neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia, lower respiratory tract infection (including pneumonia), upper respiratory tract infection, sepsis (including neutropenic sepsis and septic shock), herpes virus infection, and urinary tract infection.
Credit: Linda Bartlett
The European Commission (EC) has expanded the indication for the anti-CD20 monoclonal antibody ofatumumab (Arzerra).
The EC granted conditional approval for ofatumumab in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.
In 2010, the EC granted ofatumumab conditional approval to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. Ofatumumab will not receive full approval until the drug’s developers, GlaxoSmithKline and GenMab, submit results of additional research to the EC.
Trial results
The EC’s new approval of ofatumumab, for previously untreated CLL patients, is based on results from 2 trials, COMPLEMENT 1 and OMB115991.
The phase 3 COMPLEMENT 1 trial was a comparison of ofatumumab plus chlorambucil (n=221) with chlorambucil alone (n=226) in CLL patients for whom fludarabine-based treatment was considered inappropriate.
In this study, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).
In the phase 2 trial known as OMB115991, researchers evaluated ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL for whom fludarabine-based treatment was considered inappropriate.
The combination elicited an overall response rate of 95% and a complete response rate of 43%.
The overall safety profile of ofatumumab in CLL (previously untreated and relapsed/refractory) is based on data from 511 patients in clinical trials.
This includes 250 patients with relapsed/refractory CLL who were treated with ofatumumab alone and 261 patients with previously untreated CLL who were treated in combination with an alkylating agent.
The most common adverse effects associated with ofatumumab were infusion reactions, neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia, lower respiratory tract infection (including pneumonia), upper respiratory tract infection, sepsis (including neutropenic sepsis and septic shock), herpes virus infection, and urinary tract infection.
Circadian disruption negatively affects RBCs
Credit: NHLBI
MANCHESTER—Preclinical research indicates that circadian disruption has severe adverse effects on red blood cells (RBCs), a finding that might possibly explain the high incidence of heart disease observed in shift workers.
The study also showed the negative effects could be reduced under hypoxic conditions. Hypoxia in combination with circadian disruption produced fresh RBCs.
And this, according to researchers, suggests blood donations might help decrease the risk of cardiovascular disease in shift workers.
This research was presented at the 2014 Annual Main Meeting of the Society for Experimental Biology (SEB). It was also published in Chronobiology International.
The researchers, led by Margit Egg, PhD, of the University of Innsbruck in Austria, set out to investigate the impact of circadian disruption on hypoxic signaling and the cardiovascular system.
The team used zebrafish, a model organism that, like humans, is active during the day. To disrupt circadian rhythms, the researchers subjected the fish to alternate short days (7 hours) and long days (21 hours), resembling shift patterns common in industry.
Results showed that circadian disruption increased the number of aged RBCs that accumulated in the blood vessels.
“Normally, there is a balance between newly produced red blood cells and old ones which are removed from the blood,” Dr Egg noted.
Old cells are less flexible and become stuck in the spleen and liver, where they are engulfed by white blood cells. Circadian disruption appears to inhibit this removal process, but the researchers are unsure why this is the case.
They do know that having large aggregates of old RBCs in the vessels increases the chance of a clot that could lead to a heart attack. This may explain why shift workers have a 30% higher risk of cardiovascular disease. In addition, the decreased functionality of the aged cells reduces the oxygen-carrying capacity of the blood.
However, the researchers also found that zebrafish were less affected by circadian disruption if they were simultaneously exposed to hypoxic conditions. This is because hypoxia stimulates the production of fresh RBCs.
The team noted that the cell signaling pathways that regulate circadian rhythms and the hypoxic response are intrinsically linked. This is based on the observation that genes activated by hypoxia, such as erythropoietin, normally show a daily rhythm of activity that becomes disturbed under hypoxic conditions.
“In zebrafish, hypoxia in combination with jetlag led to the production of fresh red blood cells, counteracting the harmful consequences of jetlag and reducing mortality by 10%,” Dr Egg noted.
“Blood donations in humans also stimulate the generation of new fresh erythrocytes. Therefore, blood donations on a regular basis might be a very simple measure to help decrease the cardiovascular risk in human shift workers.”
Dr Egg and her colleagues are currently investigating whether circadian disruption affects any other physiological processes, apart from the cardiovascular system.
Credit: NHLBI
MANCHESTER—Preclinical research indicates that circadian disruption has severe adverse effects on red blood cells (RBCs), a finding that might possibly explain the high incidence of heart disease observed in shift workers.
The study also showed the negative effects could be reduced under hypoxic conditions. Hypoxia in combination with circadian disruption produced fresh RBCs.
And this, according to researchers, suggests blood donations might help decrease the risk of cardiovascular disease in shift workers.
This research was presented at the 2014 Annual Main Meeting of the Society for Experimental Biology (SEB). It was also published in Chronobiology International.
The researchers, led by Margit Egg, PhD, of the University of Innsbruck in Austria, set out to investigate the impact of circadian disruption on hypoxic signaling and the cardiovascular system.
The team used zebrafish, a model organism that, like humans, is active during the day. To disrupt circadian rhythms, the researchers subjected the fish to alternate short days (7 hours) and long days (21 hours), resembling shift patterns common in industry.
Results showed that circadian disruption increased the number of aged RBCs that accumulated in the blood vessels.
“Normally, there is a balance between newly produced red blood cells and old ones which are removed from the blood,” Dr Egg noted.
Old cells are less flexible and become stuck in the spleen and liver, where they are engulfed by white blood cells. Circadian disruption appears to inhibit this removal process, but the researchers are unsure why this is the case.
They do know that having large aggregates of old RBCs in the vessels increases the chance of a clot that could lead to a heart attack. This may explain why shift workers have a 30% higher risk of cardiovascular disease. In addition, the decreased functionality of the aged cells reduces the oxygen-carrying capacity of the blood.
However, the researchers also found that zebrafish were less affected by circadian disruption if they were simultaneously exposed to hypoxic conditions. This is because hypoxia stimulates the production of fresh RBCs.
The team noted that the cell signaling pathways that regulate circadian rhythms and the hypoxic response are intrinsically linked. This is based on the observation that genes activated by hypoxia, such as erythropoietin, normally show a daily rhythm of activity that becomes disturbed under hypoxic conditions.
“In zebrafish, hypoxia in combination with jetlag led to the production of fresh red blood cells, counteracting the harmful consequences of jetlag and reducing mortality by 10%,” Dr Egg noted.
“Blood donations in humans also stimulate the generation of new fresh erythrocytes. Therefore, blood donations on a regular basis might be a very simple measure to help decrease the cardiovascular risk in human shift workers.”
Dr Egg and her colleagues are currently investigating whether circadian disruption affects any other physiological processes, apart from the cardiovascular system.
Credit: NHLBI
MANCHESTER—Preclinical research indicates that circadian disruption has severe adverse effects on red blood cells (RBCs), a finding that might possibly explain the high incidence of heart disease observed in shift workers.
The study also showed the negative effects could be reduced under hypoxic conditions. Hypoxia in combination with circadian disruption produced fresh RBCs.
And this, according to researchers, suggests blood donations might help decrease the risk of cardiovascular disease in shift workers.
This research was presented at the 2014 Annual Main Meeting of the Society for Experimental Biology (SEB). It was also published in Chronobiology International.
The researchers, led by Margit Egg, PhD, of the University of Innsbruck in Austria, set out to investigate the impact of circadian disruption on hypoxic signaling and the cardiovascular system.
The team used zebrafish, a model organism that, like humans, is active during the day. To disrupt circadian rhythms, the researchers subjected the fish to alternate short days (7 hours) and long days (21 hours), resembling shift patterns common in industry.
Results showed that circadian disruption increased the number of aged RBCs that accumulated in the blood vessels.
“Normally, there is a balance between newly produced red blood cells and old ones which are removed from the blood,” Dr Egg noted.
Old cells are less flexible and become stuck in the spleen and liver, where they are engulfed by white blood cells. Circadian disruption appears to inhibit this removal process, but the researchers are unsure why this is the case.
They do know that having large aggregates of old RBCs in the vessels increases the chance of a clot that could lead to a heart attack. This may explain why shift workers have a 30% higher risk of cardiovascular disease. In addition, the decreased functionality of the aged cells reduces the oxygen-carrying capacity of the blood.
However, the researchers also found that zebrafish were less affected by circadian disruption if they were simultaneously exposed to hypoxic conditions. This is because hypoxia stimulates the production of fresh RBCs.
The team noted that the cell signaling pathways that regulate circadian rhythms and the hypoxic response are intrinsically linked. This is based on the observation that genes activated by hypoxia, such as erythropoietin, normally show a daily rhythm of activity that becomes disturbed under hypoxic conditions.
“In zebrafish, hypoxia in combination with jetlag led to the production of fresh red blood cells, counteracting the harmful consequences of jetlag and reducing mortality by 10%,” Dr Egg noted.
“Blood donations in humans also stimulate the generation of new fresh erythrocytes. Therefore, blood donations on a regular basis might be a very simple measure to help decrease the cardiovascular risk in human shift workers.”
Dr Egg and her colleagues are currently investigating whether circadian disruption affects any other physiological processes, apart from the cardiovascular system.
Inhibitor gets accelerated approval for PTCL
The US Food and Drug Administration (FDA) has granted accelerated approval for belinostat (Beleodaq) to treat relapsed or refractory peripheral T-cell lymphoma (PTCL).
Belinostat is a histone deacetylase inhibitor with antineoplastic activity. The drug works by inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis.
The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs.
Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit.
The FDA granted belinostat accelerated approval based on results of a phase 2 trial, which included 129 patients with relapsed or refractory PTCL. All patients received belinostat until disease progression or unacceptable toxicity.
About 26% of patients achieved a complete or partial response. The most common side effects were nausea, fatigue, pyrexia, anemia, and vomiting.
“[Belinostat] is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
The FDA granted accelerated approval to pralatrexate (Folotyn) in 2009 for use in patients with relapsed or refractory PTCL and romidepsin (Istodax) in 2011 for PTCL patients who had received at least 1 prior therapy.
Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.
The US Food and Drug Administration (FDA) has granted accelerated approval for belinostat (Beleodaq) to treat relapsed or refractory peripheral T-cell lymphoma (PTCL).
Belinostat is a histone deacetylase inhibitor with antineoplastic activity. The drug works by inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis.
The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs.
Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit.
The FDA granted belinostat accelerated approval based on results of a phase 2 trial, which included 129 patients with relapsed or refractory PTCL. All patients received belinostat until disease progression or unacceptable toxicity.
About 26% of patients achieved a complete or partial response. The most common side effects were nausea, fatigue, pyrexia, anemia, and vomiting.
“[Belinostat] is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
The FDA granted accelerated approval to pralatrexate (Folotyn) in 2009 for use in patients with relapsed or refractory PTCL and romidepsin (Istodax) in 2011 for PTCL patients who had received at least 1 prior therapy.
Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.
The US Food and Drug Administration (FDA) has granted accelerated approval for belinostat (Beleodaq) to treat relapsed or refractory peripheral T-cell lymphoma (PTCL).
Belinostat is a histone deacetylase inhibitor with antineoplastic activity. The drug works by inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis.
The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs.
Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit.
The FDA granted belinostat accelerated approval based on results of a phase 2 trial, which included 129 patients with relapsed or refractory PTCL. All patients received belinostat until disease progression or unacceptable toxicity.
About 26% of patients achieved a complete or partial response. The most common side effects were nausea, fatigue, pyrexia, anemia, and vomiting.
“[Belinostat] is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
The FDA granted accelerated approval to pralatrexate (Folotyn) in 2009 for use in patients with relapsed or refractory PTCL and romidepsin (Istodax) in 2011 for PTCL patients who had received at least 1 prior therapy.
Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.
New compound blocks essential enzyme
Credit: Peter H. Seeberger
A novel compound can inhibit an enzyme that is essential for malaria parasite survival, according to research published in PLOS Biology.
Researchers believe that creating this compound, WEHI-916, is the first step toward developing a new class of antimalarial drugs that could cure and prevent malaria infections caused by all species of the parasite, including those resistant to existing drugs.
The group developed WEHI-916 to block the enzyme Plasmepsin V. They previously showed Plasmepsin V is responsible for controlling the transport of proteins in and out of the malaria parasite.
Now, they’ve used WEHI-916 to prove the importance of Plasmepsin V to the survival of both Plasmodium vivax and Plasmodium falciparum.
“Researchers, including us, had been trying, without success, to learn more about Plasmepsin V using standard genetic techniques,” said study author Just Boddey, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“Our idea was to create a drug-like compound that would block Plasmepsin V so we could investigate its importance. We found that blocking Plasmepsin V kills malaria parasites and delivered a new and effective potential drug at the same time.”
Plasmepsin V was an ideal drug target because its inhibition effectively halted the transport of hundreds of malaria proteins, Dr Boddey noted.
“The Plasmodium parasite needs to produce and deliver over 300 different proteins to the red blood cell to survive in the body and hide from the host’s immune system,” he said. “Instead of targeting individual proteins, we can block Plasmepsin V and prevent all of those proteins from leaving the parasite.”
The researchers believe these findings could aid the development of drugs that are effective in curing malaria caused by all 5 species of Plasmodium parasite.
“Our study has shown that Plasmepsin V is a key enzyme in [P vivax and P falciparum], and WEHI-916 can inhibit Plasmepsin V isolated from both of them,” said study author Brad Sleebs, PhD, also of The Walter and Eliza Hall Institute.
“Not only does this compound enable us to prove Plasmepsin V is an excellent drug target, it is a starting point for a research program that could lead to a new class of antimalarial drugs.”
Now, the researchers have turned their attention to developing WEHI-916 and related compounds for human use.
“We are now examining in our insectary whether Plasmepsin V could be a target during other stages of the malaria lifecycle,” Dr Boddey said. “The enzyme is present in the parasites that first infect humans in the liver, as well as in parasite forms that exit humans and infect mosquitoes.”
“If WEHI-916 kills the parasite during these stages as well, it will mean any drugs that target Plasmepsin V can be used as a preventative as well as a cure.”
Credit: Peter H. Seeberger
A novel compound can inhibit an enzyme that is essential for malaria parasite survival, according to research published in PLOS Biology.
Researchers believe that creating this compound, WEHI-916, is the first step toward developing a new class of antimalarial drugs that could cure and prevent malaria infections caused by all species of the parasite, including those resistant to existing drugs.
The group developed WEHI-916 to block the enzyme Plasmepsin V. They previously showed Plasmepsin V is responsible for controlling the transport of proteins in and out of the malaria parasite.
Now, they’ve used WEHI-916 to prove the importance of Plasmepsin V to the survival of both Plasmodium vivax and Plasmodium falciparum.
“Researchers, including us, had been trying, without success, to learn more about Plasmepsin V using standard genetic techniques,” said study author Just Boddey, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“Our idea was to create a drug-like compound that would block Plasmepsin V so we could investigate its importance. We found that blocking Plasmepsin V kills malaria parasites and delivered a new and effective potential drug at the same time.”
Plasmepsin V was an ideal drug target because its inhibition effectively halted the transport of hundreds of malaria proteins, Dr Boddey noted.
“The Plasmodium parasite needs to produce and deliver over 300 different proteins to the red blood cell to survive in the body and hide from the host’s immune system,” he said. “Instead of targeting individual proteins, we can block Plasmepsin V and prevent all of those proteins from leaving the parasite.”
The researchers believe these findings could aid the development of drugs that are effective in curing malaria caused by all 5 species of Plasmodium parasite.
“Our study has shown that Plasmepsin V is a key enzyme in [P vivax and P falciparum], and WEHI-916 can inhibit Plasmepsin V isolated from both of them,” said study author Brad Sleebs, PhD, also of The Walter and Eliza Hall Institute.
“Not only does this compound enable us to prove Plasmepsin V is an excellent drug target, it is a starting point for a research program that could lead to a new class of antimalarial drugs.”
Now, the researchers have turned their attention to developing WEHI-916 and related compounds for human use.
“We are now examining in our insectary whether Plasmepsin V could be a target during other stages of the malaria lifecycle,” Dr Boddey said. “The enzyme is present in the parasites that first infect humans in the liver, as well as in parasite forms that exit humans and infect mosquitoes.”
“If WEHI-916 kills the parasite during these stages as well, it will mean any drugs that target Plasmepsin V can be used as a preventative as well as a cure.”
Credit: Peter H. Seeberger
A novel compound can inhibit an enzyme that is essential for malaria parasite survival, according to research published in PLOS Biology.
Researchers believe that creating this compound, WEHI-916, is the first step toward developing a new class of antimalarial drugs that could cure and prevent malaria infections caused by all species of the parasite, including those resistant to existing drugs.
The group developed WEHI-916 to block the enzyme Plasmepsin V. They previously showed Plasmepsin V is responsible for controlling the transport of proteins in and out of the malaria parasite.
Now, they’ve used WEHI-916 to prove the importance of Plasmepsin V to the survival of both Plasmodium vivax and Plasmodium falciparum.
“Researchers, including us, had been trying, without success, to learn more about Plasmepsin V using standard genetic techniques,” said study author Just Boddey, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“Our idea was to create a drug-like compound that would block Plasmepsin V so we could investigate its importance. We found that blocking Plasmepsin V kills malaria parasites and delivered a new and effective potential drug at the same time.”
Plasmepsin V was an ideal drug target because its inhibition effectively halted the transport of hundreds of malaria proteins, Dr Boddey noted.
“The Plasmodium parasite needs to produce and deliver over 300 different proteins to the red blood cell to survive in the body and hide from the host’s immune system,” he said. “Instead of targeting individual proteins, we can block Plasmepsin V and prevent all of those proteins from leaving the parasite.”
The researchers believe these findings could aid the development of drugs that are effective in curing malaria caused by all 5 species of Plasmodium parasite.
“Our study has shown that Plasmepsin V is a key enzyme in [P vivax and P falciparum], and WEHI-916 can inhibit Plasmepsin V isolated from both of them,” said study author Brad Sleebs, PhD, also of The Walter and Eliza Hall Institute.
“Not only does this compound enable us to prove Plasmepsin V is an excellent drug target, it is a starting point for a research program that could lead to a new class of antimalarial drugs.”
Now, the researchers have turned their attention to developing WEHI-916 and related compounds for human use.
“We are now examining in our insectary whether Plasmepsin V could be a target during other stages of the malaria lifecycle,” Dr Boddey said. “The enzyme is present in the parasites that first infect humans in the liver, as well as in parasite forms that exit humans and infect mosquitoes.”
“If WEHI-916 kills the parasite during these stages as well, it will mean any drugs that target Plasmepsin V can be used as a preventative as well as a cure.”
Unsuspected aspect of immune regulation revealed
Immunologists may have discovered an additional role for B cells. Their research suggests the cells participate in the development of regulatory T cells (Tregs).
Until now, the only non-thymic cells known to aid Treg production were dendritic cells, which travel to the thymus to deliver antigens.
The new research, published in the Journal of Immunology, suggests B cells can do the same thing.
B cells were previously thought to specialize only in antibody production. With their newly discovered role, the cells become much more interesting and complex characters, according to the researchers.
The findings mean B cells could have useful applications for treating transplant patients and those with autoimmune disorders.
“Regulatory T cells are critical in the outcome of an immune response, so anything that regulates them becomes very interesting to immunologists,” said study author Shane Grey, PhD, of the Garvan Institute of Medical Research in Darlinghurst, New South Wales, Australia.
“Right now, there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory—to infuse into patients as therapy. Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells.”
Dr Grey and his colleagues worked with mice genetically modified to express high levels of BAFF, which increases B-cell survival. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.
“It has been known for years that some B cells travel to the thymus, but no one has understood why,” said study author Stacey Walters, also of the Garvan Institute of Medical Research.
“Our experiments showed clearly that B cells participated in the creation of regulatory T cells. The more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities. One possibility is using BAFF, a non-toxic substance, to ramp up the B-cell count of patients before transplant procedures.”
Research has suggested that Tregs can reduce the risk of graft-vs-host disease, promote enhanced immune reconstitution, and decrease the incidence of infectious complications in stem cell transplant recipients. And several studies have shown that high levels of Tregs can prevent graft rejection after solid organ transplant.
Immunologists may have discovered an additional role for B cells. Their research suggests the cells participate in the development of regulatory T cells (Tregs).
Until now, the only non-thymic cells known to aid Treg production were dendritic cells, which travel to the thymus to deliver antigens.
The new research, published in the Journal of Immunology, suggests B cells can do the same thing.
B cells were previously thought to specialize only in antibody production. With their newly discovered role, the cells become much more interesting and complex characters, according to the researchers.
The findings mean B cells could have useful applications for treating transplant patients and those with autoimmune disorders.
“Regulatory T cells are critical in the outcome of an immune response, so anything that regulates them becomes very interesting to immunologists,” said study author Shane Grey, PhD, of the Garvan Institute of Medical Research in Darlinghurst, New South Wales, Australia.
“Right now, there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory—to infuse into patients as therapy. Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells.”
Dr Grey and his colleagues worked with mice genetically modified to express high levels of BAFF, which increases B-cell survival. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.
“It has been known for years that some B cells travel to the thymus, but no one has understood why,” said study author Stacey Walters, also of the Garvan Institute of Medical Research.
“Our experiments showed clearly that B cells participated in the creation of regulatory T cells. The more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities. One possibility is using BAFF, a non-toxic substance, to ramp up the B-cell count of patients before transplant procedures.”
Research has suggested that Tregs can reduce the risk of graft-vs-host disease, promote enhanced immune reconstitution, and decrease the incidence of infectious complications in stem cell transplant recipients. And several studies have shown that high levels of Tregs can prevent graft rejection after solid organ transplant.
Immunologists may have discovered an additional role for B cells. Their research suggests the cells participate in the development of regulatory T cells (Tregs).
Until now, the only non-thymic cells known to aid Treg production were dendritic cells, which travel to the thymus to deliver antigens.
The new research, published in the Journal of Immunology, suggests B cells can do the same thing.
B cells were previously thought to specialize only in antibody production. With their newly discovered role, the cells become much more interesting and complex characters, according to the researchers.
The findings mean B cells could have useful applications for treating transplant patients and those with autoimmune disorders.
“Regulatory T cells are critical in the outcome of an immune response, so anything that regulates them becomes very interesting to immunologists,” said study author Shane Grey, PhD, of the Garvan Institute of Medical Research in Darlinghurst, New South Wales, Australia.
“Right now, there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory—to infuse into patients as therapy. Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells.”
Dr Grey and his colleagues worked with mice genetically modified to express high levels of BAFF, which increases B-cell survival. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.
“It has been known for years that some B cells travel to the thymus, but no one has understood why,” said study author Stacey Walters, also of the Garvan Institute of Medical Research.
“Our experiments showed clearly that B cells participated in the creation of regulatory T cells. The more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities. One possibility is using BAFF, a non-toxic substance, to ramp up the B-cell count of patients before transplant procedures.”
Research has suggested that Tregs can reduce the risk of graft-vs-host disease, promote enhanced immune reconstitution, and decrease the incidence of infectious complications in stem cell transplant recipients. And several studies have shown that high levels of Tregs can prevent graft rejection after solid organ transplant.
Mixing meds and supplements to dangerous effect
Credit: CDC
A new study indicates that a fair share of patients may be mixing the herbal supplement St. John’s wort with prescribed medications, which can have dangerous results.
St. John’s wort can reduce the concentration of numerous drugs in the body, including anticoagulants and chemotherapeutic agents. And this can result in impaired effectiveness and treatment failure.
But the supplement can also interact with medications to produce serious adverse events.
“Patients may have a false sense of safety with so-called ‘natural’ treatments like St. John’s wort,” said study author Sarah Taylor, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.
“And it is crucial for physicians to know the dangers of ‘natural’ treatments and to communicate the risks to patients effectively.”
Dr Taylor and her colleagues investigated the use of St. John’s wort and reported their findings in The Journal of Alternative and Complementary Medicine.
To determine how often the supplement was being prescribed or taken with other medications, the researchers conducted a retrospective analysis of nationally representative data collected by the National Ambulatory Medical Care Survey from 1993 to 2010.
The team found the use of St. John’s wort in potentially harmful combinations in 28% of the cases reviewed. The drugs involved were warfarin, selective serotonin reuptake inhibitors, benzodiazepines, statins, verapamil, digoxin, and oral contraceptives.
Possible drug interactions include serotonin syndrome (a potentially fatal condition that causes high levels of the chemical serotonin to accumulate in the body), heart disease due to impaired efficacy of blood pressure medications, or unplanned pregnancy due to contraceptive failure, Dr Taylor said.
A key limitation of this study is that only medications recorded by the physician were analyzed. And Dr Taylor said the rate of St. John’s wort interactions may actually be underestimated because the database did not include patients who were using St. John’s wort but did not tell their doctor.
“Labeling requirements for helpful supplements such as St. John’s wort need to provide appropriate cautions and risk information,” Dr Taylor said, adding that France has banned the use of St. John’s wort products, and several other countries, including Japan, the UK, and Canada, are in the process of including drug-herb interaction warnings on St. John’s wort products.
“Doctors also need to be trained to always ask if the patient is taking any supplements, vitamins, minerals or herbs, especially before prescribing any of the common drugs that might interact with St. John’s wort.”
Credit: CDC
A new study indicates that a fair share of patients may be mixing the herbal supplement St. John’s wort with prescribed medications, which can have dangerous results.
St. John’s wort can reduce the concentration of numerous drugs in the body, including anticoagulants and chemotherapeutic agents. And this can result in impaired effectiveness and treatment failure.
But the supplement can also interact with medications to produce serious adverse events.
“Patients may have a false sense of safety with so-called ‘natural’ treatments like St. John’s wort,” said study author Sarah Taylor, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.
“And it is crucial for physicians to know the dangers of ‘natural’ treatments and to communicate the risks to patients effectively.”
Dr Taylor and her colleagues investigated the use of St. John’s wort and reported their findings in The Journal of Alternative and Complementary Medicine.
To determine how often the supplement was being prescribed or taken with other medications, the researchers conducted a retrospective analysis of nationally representative data collected by the National Ambulatory Medical Care Survey from 1993 to 2010.
The team found the use of St. John’s wort in potentially harmful combinations in 28% of the cases reviewed. The drugs involved were warfarin, selective serotonin reuptake inhibitors, benzodiazepines, statins, verapamil, digoxin, and oral contraceptives.
Possible drug interactions include serotonin syndrome (a potentially fatal condition that causes high levels of the chemical serotonin to accumulate in the body), heart disease due to impaired efficacy of blood pressure medications, or unplanned pregnancy due to contraceptive failure, Dr Taylor said.
A key limitation of this study is that only medications recorded by the physician were analyzed. And Dr Taylor said the rate of St. John’s wort interactions may actually be underestimated because the database did not include patients who were using St. John’s wort but did not tell their doctor.
“Labeling requirements for helpful supplements such as St. John’s wort need to provide appropriate cautions and risk information,” Dr Taylor said, adding that France has banned the use of St. John’s wort products, and several other countries, including Japan, the UK, and Canada, are in the process of including drug-herb interaction warnings on St. John’s wort products.
“Doctors also need to be trained to always ask if the patient is taking any supplements, vitamins, minerals or herbs, especially before prescribing any of the common drugs that might interact with St. John’s wort.”
Credit: CDC
A new study indicates that a fair share of patients may be mixing the herbal supplement St. John’s wort with prescribed medications, which can have dangerous results.
St. John’s wort can reduce the concentration of numerous drugs in the body, including anticoagulants and chemotherapeutic agents. And this can result in impaired effectiveness and treatment failure.
But the supplement can also interact with medications to produce serious adverse events.
“Patients may have a false sense of safety with so-called ‘natural’ treatments like St. John’s wort,” said study author Sarah Taylor, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.
“And it is crucial for physicians to know the dangers of ‘natural’ treatments and to communicate the risks to patients effectively.”
Dr Taylor and her colleagues investigated the use of St. John’s wort and reported their findings in The Journal of Alternative and Complementary Medicine.
To determine how often the supplement was being prescribed or taken with other medications, the researchers conducted a retrospective analysis of nationally representative data collected by the National Ambulatory Medical Care Survey from 1993 to 2010.
The team found the use of St. John’s wort in potentially harmful combinations in 28% of the cases reviewed. The drugs involved were warfarin, selective serotonin reuptake inhibitors, benzodiazepines, statins, verapamil, digoxin, and oral contraceptives.
Possible drug interactions include serotonin syndrome (a potentially fatal condition that causes high levels of the chemical serotonin to accumulate in the body), heart disease due to impaired efficacy of blood pressure medications, or unplanned pregnancy due to contraceptive failure, Dr Taylor said.
A key limitation of this study is that only medications recorded by the physician were analyzed. And Dr Taylor said the rate of St. John’s wort interactions may actually be underestimated because the database did not include patients who were using St. John’s wort but did not tell their doctor.
“Labeling requirements for helpful supplements such as St. John’s wort need to provide appropriate cautions and risk information,” Dr Taylor said, adding that France has banned the use of St. John’s wort products, and several other countries, including Japan, the UK, and Canada, are in the process of including drug-herb interaction warnings on St. John’s wort products.
“Doctors also need to be trained to always ask if the patient is taking any supplements, vitamins, minerals or herbs, especially before prescribing any of the common drugs that might interact with St. John’s wort.”
FISH may help predict survival in ALCL
Researchers have discovered 3 subgroups of ALK-negative anaplastic large-cell lymphoma (ALCL) that have markedly different survival rates, according to a paper published in Blood.
They found that ALCL patients with TP63 rearrangements had a 17% chance of living 5 years beyond diagnosis, compared to 90% of patients who had DUSP22 rearrangements.
A third group of patients, those with neither rearrangement, had a 42% survival rate.
The researchers noted that these subgroups cannot be differentiated by routine pathology but can be identified via fluorescence in situ hybridization (FISH).
“This is the first study to demonstrate unequivocal genetic and clinical heterogeneity among systemic ALK-negative anaplastic large-cell lymphomas,” said study author Andrew L. Feldman, MD, of the Mayo Clinic in Rochester, Minnesota.
“Most strikingly, patients with DUSP22-rearranged ALCL had excellent overall survival rates, while patients with TP63-rearranged ALCL had dismal outcomes and nearly always failed standard therapy.”
Currently, all ALK-negative ALCLs are treated the same, using chemotherapy and, in some institutions, stem cell transplantation. But these new findings make a case for additional testing and possible changes to the standard of care.
“This is a great example of where individualized medicine can make a difference,” Dr Feldman said. “Patients whose chance of surviving is 1 in 6 are receiving the same therapy as patients whose odds are 9 in 10. Developing tests that identify how tumors are different is a critical step toward being able to tailor therapy to each individual patient.”
Therefore, Dr Feldman and his colleagues recommend performing FISH in all patients with ALK-negative ALCL.
To learn more about testing for DUSP22 and TP63:
- 6p25.3 FISH (DUSP22/IRF4): http://www.mayomedicallaboratories.com/test-catalog/Overview/60506
- 3q28 FISH (TP63): http://www.mayomedicallaboratories.com/test-catalog/Overview/70014.
Researchers have discovered 3 subgroups of ALK-negative anaplastic large-cell lymphoma (ALCL) that have markedly different survival rates, according to a paper published in Blood.
They found that ALCL patients with TP63 rearrangements had a 17% chance of living 5 years beyond diagnosis, compared to 90% of patients who had DUSP22 rearrangements.
A third group of patients, those with neither rearrangement, had a 42% survival rate.
The researchers noted that these subgroups cannot be differentiated by routine pathology but can be identified via fluorescence in situ hybridization (FISH).
“This is the first study to demonstrate unequivocal genetic and clinical heterogeneity among systemic ALK-negative anaplastic large-cell lymphomas,” said study author Andrew L. Feldman, MD, of the Mayo Clinic in Rochester, Minnesota.
“Most strikingly, patients with DUSP22-rearranged ALCL had excellent overall survival rates, while patients with TP63-rearranged ALCL had dismal outcomes and nearly always failed standard therapy.”
Currently, all ALK-negative ALCLs are treated the same, using chemotherapy and, in some institutions, stem cell transplantation. But these new findings make a case for additional testing and possible changes to the standard of care.
“This is a great example of where individualized medicine can make a difference,” Dr Feldman said. “Patients whose chance of surviving is 1 in 6 are receiving the same therapy as patients whose odds are 9 in 10. Developing tests that identify how tumors are different is a critical step toward being able to tailor therapy to each individual patient.”
Therefore, Dr Feldman and his colleagues recommend performing FISH in all patients with ALK-negative ALCL.
To learn more about testing for DUSP22 and TP63:
- 6p25.3 FISH (DUSP22/IRF4): http://www.mayomedicallaboratories.com/test-catalog/Overview/60506
- 3q28 FISH (TP63): http://www.mayomedicallaboratories.com/test-catalog/Overview/70014.
Researchers have discovered 3 subgroups of ALK-negative anaplastic large-cell lymphoma (ALCL) that have markedly different survival rates, according to a paper published in Blood.
They found that ALCL patients with TP63 rearrangements had a 17% chance of living 5 years beyond diagnosis, compared to 90% of patients who had DUSP22 rearrangements.
A third group of patients, those with neither rearrangement, had a 42% survival rate.
The researchers noted that these subgroups cannot be differentiated by routine pathology but can be identified via fluorescence in situ hybridization (FISH).
“This is the first study to demonstrate unequivocal genetic and clinical heterogeneity among systemic ALK-negative anaplastic large-cell lymphomas,” said study author Andrew L. Feldman, MD, of the Mayo Clinic in Rochester, Minnesota.
“Most strikingly, patients with DUSP22-rearranged ALCL had excellent overall survival rates, while patients with TP63-rearranged ALCL had dismal outcomes and nearly always failed standard therapy.”
Currently, all ALK-negative ALCLs are treated the same, using chemotherapy and, in some institutions, stem cell transplantation. But these new findings make a case for additional testing and possible changes to the standard of care.
“This is a great example of where individualized medicine can make a difference,” Dr Feldman said. “Patients whose chance of surviving is 1 in 6 are receiving the same therapy as patients whose odds are 9 in 10. Developing tests that identify how tumors are different is a critical step toward being able to tailor therapy to each individual patient.”
Therefore, Dr Feldman and his colleagues recommend performing FISH in all patients with ALK-negative ALCL.
To learn more about testing for DUSP22 and TP63:
- 6p25.3 FISH (DUSP22/IRF4): http://www.mayomedicallaboratories.com/test-catalog/Overview/60506
- 3q28 FISH (TP63): http://www.mayomedicallaboratories.com/test-catalog/Overview/70014.
Mosquitos can sniff out malaria-infected mice
Credit: James Gathany
Scientists have found evidence to suggest that malaria parasites change the body odor of their host to attract hungry mosquitos.
The team observed an increase in mosquito attraction to malaria-infected mice, compared to healthy controls.
And the infected mice exhibited elevations in certain components of their natural scent, which suggests the malaria parasite changes the characteristics of its host’s body odor to make the host more attractive to mosquitos.
These findings appear in Proceedings of the National Academy of Sciences.
The researchers found that mice infected with Plasmodium chabaudii were more attractive to Anopheles stephensi mosquitos than uninfected control mice. And the attraction corresponded to an overall elevation in scent emissions from the infected mice.
However, malaria infection did not appear to trigger the expression of unique scent components. Instead, it seems the malaria pathogens alter the levels of compounds already present in the scent of uninfected mice.
“There appears to be an overall elevation of several compounds that are attractive to mosquitos,” said study author Consuelo De Moraes, PhD, of the Swiss Federal Institute of Technology in Zürich (ETH Zürich).
“Since mosquitos probably don’t benefit from feeding on infected people, it may make sense for the pathogen to exaggerate existing odor cues that the insects are already using for host location,” added study author Mark Mescher, PhD, also of ETH Zürich.
What the researchers found most surprising is the fact that the malaria infection leaves its mark on body odor long-term. Even when infected mice no longer had symptoms, their body odor showed they were carriers of the pathogen.
However, not all stages of disease smelled the same. The team found the scent profile of the acutely ill differed from the profile in mice exhibiting later stages of malaria infection.
Although the findings from this study cannot be directly translated to human malaria, they suggest similar effects might be involved in the attraction of mosquitos to infected people. Drs Mescher and De Moraes are currently investigating this possibility through additional research involving human subjects in Africa.
Credit: James Gathany
Scientists have found evidence to suggest that malaria parasites change the body odor of their host to attract hungry mosquitos.
The team observed an increase in mosquito attraction to malaria-infected mice, compared to healthy controls.
And the infected mice exhibited elevations in certain components of their natural scent, which suggests the malaria parasite changes the characteristics of its host’s body odor to make the host more attractive to mosquitos.
These findings appear in Proceedings of the National Academy of Sciences.
The researchers found that mice infected with Plasmodium chabaudii were more attractive to Anopheles stephensi mosquitos than uninfected control mice. And the attraction corresponded to an overall elevation in scent emissions from the infected mice.
However, malaria infection did not appear to trigger the expression of unique scent components. Instead, it seems the malaria pathogens alter the levels of compounds already present in the scent of uninfected mice.
“There appears to be an overall elevation of several compounds that are attractive to mosquitos,” said study author Consuelo De Moraes, PhD, of the Swiss Federal Institute of Technology in Zürich (ETH Zürich).
“Since mosquitos probably don’t benefit from feeding on infected people, it may make sense for the pathogen to exaggerate existing odor cues that the insects are already using for host location,” added study author Mark Mescher, PhD, also of ETH Zürich.
What the researchers found most surprising is the fact that the malaria infection leaves its mark on body odor long-term. Even when infected mice no longer had symptoms, their body odor showed they were carriers of the pathogen.
However, not all stages of disease smelled the same. The team found the scent profile of the acutely ill differed from the profile in mice exhibiting later stages of malaria infection.
Although the findings from this study cannot be directly translated to human malaria, they suggest similar effects might be involved in the attraction of mosquitos to infected people. Drs Mescher and De Moraes are currently investigating this possibility through additional research involving human subjects in Africa.
Credit: James Gathany
Scientists have found evidence to suggest that malaria parasites change the body odor of their host to attract hungry mosquitos.
The team observed an increase in mosquito attraction to malaria-infected mice, compared to healthy controls.
And the infected mice exhibited elevations in certain components of their natural scent, which suggests the malaria parasite changes the characteristics of its host’s body odor to make the host more attractive to mosquitos.
These findings appear in Proceedings of the National Academy of Sciences.
The researchers found that mice infected with Plasmodium chabaudii were more attractive to Anopheles stephensi mosquitos than uninfected control mice. And the attraction corresponded to an overall elevation in scent emissions from the infected mice.
However, malaria infection did not appear to trigger the expression of unique scent components. Instead, it seems the malaria pathogens alter the levels of compounds already present in the scent of uninfected mice.
“There appears to be an overall elevation of several compounds that are attractive to mosquitos,” said study author Consuelo De Moraes, PhD, of the Swiss Federal Institute of Technology in Zürich (ETH Zürich).
“Since mosquitos probably don’t benefit from feeding on infected people, it may make sense for the pathogen to exaggerate existing odor cues that the insects are already using for host location,” added study author Mark Mescher, PhD, also of ETH Zürich.
What the researchers found most surprising is the fact that the malaria infection leaves its mark on body odor long-term. Even when infected mice no longer had symptoms, their body odor showed they were carriers of the pathogen.
However, not all stages of disease smelled the same. The team found the scent profile of the acutely ill differed from the profile in mice exhibiting later stages of malaria infection.
Although the findings from this study cannot be directly translated to human malaria, they suggest similar effects might be involved in the attraction of mosquitos to infected people. Drs Mescher and De Moraes are currently investigating this possibility through additional research involving human subjects in Africa.
Study validates drug’s efficacy in CLL/SLL
MILAN—Results of the phase 3 RESONATE trial suggest ibrutinib can improve response and survival rates in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), when compared to ofatumumab.
Ibrutinib conferred these benefits irrespective of baseline clinical characteristics or molecular features, including 17p deletion.
Atrial fibrillation and bleeding-related events were more common with ibrutinib. But the rate of serious adverse events was similar between the treatment arms.
About 86% of patients remained on ibrutinib at last analysis, and roughly 29% of patients initially randomized to ofatumumab crossed over to the ibrutinib arm after disease progression.
“This study undoubtedly confirms that ibrutinib is a very effective agent—as a single-agent—in relapsed CLL patients,” said investigator Peter Hillmen, MD, PhD, of The Leeds Teaching Hospitals in the UK.
Dr Hillmen presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S693. The RESONATE trial was sponsored by Pharmacyclics and Janssen, the companies developing ibrutinib.
The trial included 391 patients with relapsed or refractory CLL/SLL. They were randomized to receive oral ibrutinib at 420 mg once daily until progression or unacceptable toxicity (n=195) or intravenous ofatumumab at an initial dose of 300 mg, followed by 11 doses of 2000 mg (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57).
The median age in both treatment arms was 67. Overall, roughly 50% of patients had received 3 or more prior therapies, including purine analogs, alkylating agents, and anti-CD20 antibodies. The proportion of patients with del17p was similar between the treatment arms—32% in the ibrutinib arm and 33% in the ofatumumab arm.
Response and survival
At the time of interim analysis, patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm, according to an independent review committee.
In addition, ibrutinib significantly prolonged progression-free survival (PFS). The median PFS was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The improvement in PFS represents a 78% reduction in the risk of progression or death.
Dr Hillmen noted that PFS favored ibrutinib regardless of baseline characteristics such as refractoriness to purine analogs, del17p, age, gender, Rai stage, bulky disease, number of prior treatments, del11q, B2 microglobulin, and IgVH mutation status.
Ibrutinib significantly prolonged overall survival (OS) as well. The median OS was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049). The improvement in OS represents a 56% reduction in the risk of death in patients treated with ibrutinib.
Adverse events
Dr Hillmen pointed out that the median treatment duration was 8.6 months for ibrutinib and 5.3 months for ofatumumab, and this difference confounds the assessment of side effects.
Nevertheless, nearly all patients in both treatment arms experienced adverse events—99% in the ibrutinib arm and 98% in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.
Atrial fibrillation of any grade was more common in the ibrutinib arm (n=10) than in the ofatumumab arm (n=1), but 5 of the ibrutinib-treated patients had a prior history of atrial fibrillation. Bleeding-related events were also more common with ibrutinib (44% vs 12%), as were diarrhea (48% vs 18%) and arthralgia (17% vs 7%).
Events more common in the ofatumumab arm included infusion-related reactions (28% vs 0%), peripheral sensory neuropathy (13% vs 4%), urticaria (6% vs 1%), night sweats (13% vs 5%), and pruritus (9% vs 4%).
MILAN—Results of the phase 3 RESONATE trial suggest ibrutinib can improve response and survival rates in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), when compared to ofatumumab.
Ibrutinib conferred these benefits irrespective of baseline clinical characteristics or molecular features, including 17p deletion.
Atrial fibrillation and bleeding-related events were more common with ibrutinib. But the rate of serious adverse events was similar between the treatment arms.
About 86% of patients remained on ibrutinib at last analysis, and roughly 29% of patients initially randomized to ofatumumab crossed over to the ibrutinib arm after disease progression.
“This study undoubtedly confirms that ibrutinib is a very effective agent—as a single-agent—in relapsed CLL patients,” said investigator Peter Hillmen, MD, PhD, of The Leeds Teaching Hospitals in the UK.
Dr Hillmen presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S693. The RESONATE trial was sponsored by Pharmacyclics and Janssen, the companies developing ibrutinib.
The trial included 391 patients with relapsed or refractory CLL/SLL. They were randomized to receive oral ibrutinib at 420 mg once daily until progression or unacceptable toxicity (n=195) or intravenous ofatumumab at an initial dose of 300 mg, followed by 11 doses of 2000 mg (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57).
The median age in both treatment arms was 67. Overall, roughly 50% of patients had received 3 or more prior therapies, including purine analogs, alkylating agents, and anti-CD20 antibodies. The proportion of patients with del17p was similar between the treatment arms—32% in the ibrutinib arm and 33% in the ofatumumab arm.
Response and survival
At the time of interim analysis, patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm, according to an independent review committee.
In addition, ibrutinib significantly prolonged progression-free survival (PFS). The median PFS was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The improvement in PFS represents a 78% reduction in the risk of progression or death.
Dr Hillmen noted that PFS favored ibrutinib regardless of baseline characteristics such as refractoriness to purine analogs, del17p, age, gender, Rai stage, bulky disease, number of prior treatments, del11q, B2 microglobulin, and IgVH mutation status.
Ibrutinib significantly prolonged overall survival (OS) as well. The median OS was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049). The improvement in OS represents a 56% reduction in the risk of death in patients treated with ibrutinib.
Adverse events
Dr Hillmen pointed out that the median treatment duration was 8.6 months for ibrutinib and 5.3 months for ofatumumab, and this difference confounds the assessment of side effects.
Nevertheless, nearly all patients in both treatment arms experienced adverse events—99% in the ibrutinib arm and 98% in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.
Atrial fibrillation of any grade was more common in the ibrutinib arm (n=10) than in the ofatumumab arm (n=1), but 5 of the ibrutinib-treated patients had a prior history of atrial fibrillation. Bleeding-related events were also more common with ibrutinib (44% vs 12%), as were diarrhea (48% vs 18%) and arthralgia (17% vs 7%).
Events more common in the ofatumumab arm included infusion-related reactions (28% vs 0%), peripheral sensory neuropathy (13% vs 4%), urticaria (6% vs 1%), night sweats (13% vs 5%), and pruritus (9% vs 4%).
MILAN—Results of the phase 3 RESONATE trial suggest ibrutinib can improve response and survival rates in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), when compared to ofatumumab.
Ibrutinib conferred these benefits irrespective of baseline clinical characteristics or molecular features, including 17p deletion.
Atrial fibrillation and bleeding-related events were more common with ibrutinib. But the rate of serious adverse events was similar between the treatment arms.
About 86% of patients remained on ibrutinib at last analysis, and roughly 29% of patients initially randomized to ofatumumab crossed over to the ibrutinib arm after disease progression.
“This study undoubtedly confirms that ibrutinib is a very effective agent—as a single-agent—in relapsed CLL patients,” said investigator Peter Hillmen, MD, PhD, of The Leeds Teaching Hospitals in the UK.
Dr Hillmen presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S693. The RESONATE trial was sponsored by Pharmacyclics and Janssen, the companies developing ibrutinib.
The trial included 391 patients with relapsed or refractory CLL/SLL. They were randomized to receive oral ibrutinib at 420 mg once daily until progression or unacceptable toxicity (n=195) or intravenous ofatumumab at an initial dose of 300 mg, followed by 11 doses of 2000 mg (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57).
The median age in both treatment arms was 67. Overall, roughly 50% of patients had received 3 or more prior therapies, including purine analogs, alkylating agents, and anti-CD20 antibodies. The proportion of patients with del17p was similar between the treatment arms—32% in the ibrutinib arm and 33% in the ofatumumab arm.
Response and survival
At the time of interim analysis, patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm, according to an independent review committee.
In addition, ibrutinib significantly prolonged progression-free survival (PFS). The median PFS was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The improvement in PFS represents a 78% reduction in the risk of progression or death.
Dr Hillmen noted that PFS favored ibrutinib regardless of baseline characteristics such as refractoriness to purine analogs, del17p, age, gender, Rai stage, bulky disease, number of prior treatments, del11q, B2 microglobulin, and IgVH mutation status.
Ibrutinib significantly prolonged overall survival (OS) as well. The median OS was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049). The improvement in OS represents a 56% reduction in the risk of death in patients treated with ibrutinib.
Adverse events
Dr Hillmen pointed out that the median treatment duration was 8.6 months for ibrutinib and 5.3 months for ofatumumab, and this difference confounds the assessment of side effects.
Nevertheless, nearly all patients in both treatment arms experienced adverse events—99% in the ibrutinib arm and 98% in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.
Atrial fibrillation of any grade was more common in the ibrutinib arm (n=10) than in the ofatumumab arm (n=1), but 5 of the ibrutinib-treated patients had a prior history of atrial fibrillation. Bleeding-related events were also more common with ibrutinib (44% vs 12%), as were diarrhea (48% vs 18%) and arthralgia (17% vs 7%).
Events more common in the ofatumumab arm included infusion-related reactions (28% vs 0%), peripheral sensory neuropathy (13% vs 4%), urticaria (6% vs 1%), night sweats (13% vs 5%), and pruritus (9% vs 4%).
HSCT regimen could be ‘transformative’ for SCD
pre-HSCT (top) and post-HSCT
Credit: NIH Molecular and
Clinical Hematology Branch
In a small study, a nonmyeloablative hematopoietic stem cell transplant (HSCT) regimen reversed sickle cell disease (SCD) phenotype in a majority of adult patients, some of whom also had thalassemia.
Half of the patients were able to stop taking immunosuppressants and did not develop graft-vs-host disease (GVHD).
There were adverse events associated with the regimen, but the researchers believe it shows promise and could be “transformative” for patients with severe SCD.
The team described the regimen and its effects in JAMA.
Matthew M. Hsieh, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and his colleagues first explored a nonmyeloablative HSCT approach in a pilot group of 10 adults with severe SCD.
The regimen had few toxic effects, but all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in patients with donor CD3 engraftment of greater than 50% and normalization of hemoglobin.
In JAMA, the team described the outcomes for 20 additional patients with severe SCD, with or without thalassemia, along with updated results from the first 10 patients.
All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013. Two patients had heterozygous hemoglobin S and C, 1 patient had HbSβ+-thalassemia, 1 patient had HbSβ0- thalassemia, and 1 had transfusion-dependent β-thalassemia intermedia. The remaining patients had homozygous hemoglobin S.
Patients received alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and an infusion of unmanipulated, filgrastim-mobilized peripheral blood stem cells (5.5-31.7 × 106 cells/kg) from HLA-matched siblings.
There were 38 serious adverse events. The most common were pain-related (n=15), transplant-related infections (n=6), abdominal events (n=6), and toxic effects associated with sirolimus (n=5).
As of October 25, 2013, 29 patients were still alive, with a median follow-up of 3.4 years. Twenty-six patients (87%) had long-term stable donor engraftment without acute or chronic GVHD.
Hemoglobin levels improved after HSCT. At 1 year, 25 patients (83%) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and did not develop GVHD.
“Typically, stem cell recipients must take immunosuppressants all their lives,” Dr Hsieh noted. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”
Hospitalization rates also decreased following HSCT. The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant.
“One of the most debilitating effects of sickle cell disease is the often relentless pain,” Dr Hsieh pointed out. “Following the transplant, we saw a significant decrease in hospitalizations and narcotics to control that pain.”
Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg at 6 months after the transplant.
“The devastating complications associated with sickle cell disease can deeply affect quality of life, ability to work, and long-term well-being,” said study author Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases.
“This study represents an important advance in our efforts to make a potentially transformative treatment available to a wider range of people, especially those who could not tolerate a standard stem cell transplant or long-term use of immunosuppressants.”
pre-HSCT (top) and post-HSCT
Credit: NIH Molecular and
Clinical Hematology Branch
In a small study, a nonmyeloablative hematopoietic stem cell transplant (HSCT) regimen reversed sickle cell disease (SCD) phenotype in a majority of adult patients, some of whom also had thalassemia.
Half of the patients were able to stop taking immunosuppressants and did not develop graft-vs-host disease (GVHD).
There were adverse events associated with the regimen, but the researchers believe it shows promise and could be “transformative” for patients with severe SCD.
The team described the regimen and its effects in JAMA.
Matthew M. Hsieh, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and his colleagues first explored a nonmyeloablative HSCT approach in a pilot group of 10 adults with severe SCD.
The regimen had few toxic effects, but all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in patients with donor CD3 engraftment of greater than 50% and normalization of hemoglobin.
In JAMA, the team described the outcomes for 20 additional patients with severe SCD, with or without thalassemia, along with updated results from the first 10 patients.
All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013. Two patients had heterozygous hemoglobin S and C, 1 patient had HbSβ+-thalassemia, 1 patient had HbSβ0- thalassemia, and 1 had transfusion-dependent β-thalassemia intermedia. The remaining patients had homozygous hemoglobin S.
Patients received alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and an infusion of unmanipulated, filgrastim-mobilized peripheral blood stem cells (5.5-31.7 × 106 cells/kg) from HLA-matched siblings.
There were 38 serious adverse events. The most common were pain-related (n=15), transplant-related infections (n=6), abdominal events (n=6), and toxic effects associated with sirolimus (n=5).
As of October 25, 2013, 29 patients were still alive, with a median follow-up of 3.4 years. Twenty-six patients (87%) had long-term stable donor engraftment without acute or chronic GVHD.
Hemoglobin levels improved after HSCT. At 1 year, 25 patients (83%) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and did not develop GVHD.
“Typically, stem cell recipients must take immunosuppressants all their lives,” Dr Hsieh noted. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”
Hospitalization rates also decreased following HSCT. The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant.
“One of the most debilitating effects of sickle cell disease is the often relentless pain,” Dr Hsieh pointed out. “Following the transplant, we saw a significant decrease in hospitalizations and narcotics to control that pain.”
Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg at 6 months after the transplant.
“The devastating complications associated with sickle cell disease can deeply affect quality of life, ability to work, and long-term well-being,” said study author Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases.
“This study represents an important advance in our efforts to make a potentially transformative treatment available to a wider range of people, especially those who could not tolerate a standard stem cell transplant or long-term use of immunosuppressants.”
pre-HSCT (top) and post-HSCT
Credit: NIH Molecular and
Clinical Hematology Branch
In a small study, a nonmyeloablative hematopoietic stem cell transplant (HSCT) regimen reversed sickle cell disease (SCD) phenotype in a majority of adult patients, some of whom also had thalassemia.
Half of the patients were able to stop taking immunosuppressants and did not develop graft-vs-host disease (GVHD).
There were adverse events associated with the regimen, but the researchers believe it shows promise and could be “transformative” for patients with severe SCD.
The team described the regimen and its effects in JAMA.
Matthew M. Hsieh, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and his colleagues first explored a nonmyeloablative HSCT approach in a pilot group of 10 adults with severe SCD.
The regimen had few toxic effects, but all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in patients with donor CD3 engraftment of greater than 50% and normalization of hemoglobin.
In JAMA, the team described the outcomes for 20 additional patients with severe SCD, with or without thalassemia, along with updated results from the first 10 patients.
All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013. Two patients had heterozygous hemoglobin S and C, 1 patient had HbSβ+-thalassemia, 1 patient had HbSβ0- thalassemia, and 1 had transfusion-dependent β-thalassemia intermedia. The remaining patients had homozygous hemoglobin S.
Patients received alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and an infusion of unmanipulated, filgrastim-mobilized peripheral blood stem cells (5.5-31.7 × 106 cells/kg) from HLA-matched siblings.
There were 38 serious adverse events. The most common were pain-related (n=15), transplant-related infections (n=6), abdominal events (n=6), and toxic effects associated with sirolimus (n=5).
As of October 25, 2013, 29 patients were still alive, with a median follow-up of 3.4 years. Twenty-six patients (87%) had long-term stable donor engraftment without acute or chronic GVHD.
Hemoglobin levels improved after HSCT. At 1 year, 25 patients (83%) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and did not develop GVHD.
“Typically, stem cell recipients must take immunosuppressants all their lives,” Dr Hsieh noted. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”
Hospitalization rates also decreased following HSCT. The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant.
“One of the most debilitating effects of sickle cell disease is the often relentless pain,” Dr Hsieh pointed out. “Following the transplant, we saw a significant decrease in hospitalizations and narcotics to control that pain.”
Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg at 6 months after the transplant.
“The devastating complications associated with sickle cell disease can deeply affect quality of life, ability to work, and long-term well-being,” said study author Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases.
“This study represents an important advance in our efforts to make a potentially transformative treatment available to a wider range of people, especially those who could not tolerate a standard stem cell transplant or long-term use of immunosuppressants.”