Hematology Times

Researchers in the lab

Credit: Rhoda Baer

Investigators have identified drug combinations that may overcome resistance to ibrutinib in patients with mantle cell lymphoma (MCL).

The group discovered a mutation in Bruton’s tyrosine kinase (BTK) that confers resistance to the drug.

They also found that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib, so combining a CDK4 inhibitor and a PI3K inhibitor might be effective in patients who don’t respond to ibrutinib.

Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, and her colleagues detailed these findings in Cancer Discovery. Some of Dr Chen-Kiang’s colleagues reported relationships with Janssen and Pharmacyclics, the companies developing ibrutinib.

“[Ibrutinib] doesn’t work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib,” Dr Chen-Kiang noted. “We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug.”

“The knowledge that we gained from longitudinal RNA and genomic sequencing of mantle cell lymphomas with primary and acquired resistance to ibrutinib allowed us to identify rational drug combinations that may overcome resistance in these 2 settings.”

Dr Chen-Kiang and her colleagues conducted whole-exome and whole-transcriptome analyses of 5 serial biopsies from a patient with MCL who initially responded to ibrutinib before progressing.

After comparing these data with results from an analysis of healthy tissues from the same patient, the investigators found that a mutation in BTK, the C481S mutation, appeared at relapse.

The researchers found the same mutation at relapse in a second MCL patient with acquired resistance to ibrutinib but not in any patients with primary resistance to the drug.

Further analyses revealed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation.

Inhibiting CDK4 with the investigational anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K.

And palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K. The researchers recently opened a clinical trial to test ibrutinib and palbociclib in combination (NCT02159755).

“We are very excited to have generated data . . . that may be meaningful for patients,” Dr Chen-Kiang said. “It is also exciting because CDK4 is a new kind of drug target. It controls the cell cycle, which is a central cancer pathway. As such, it is not just important for mantle cell lymphoma but for many forms of cancer.”

Researchers in the lab

Credit: Rhoda Baer

Investigators have identified drug combinations that may overcome resistance to ibrutinib in patients with mantle cell lymphoma (MCL).

The group discovered a mutation in Bruton’s tyrosine kinase (BTK) that confers resistance to the drug.

They also found that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib, so combining a CDK4 inhibitor and a PI3K inhibitor might be effective in patients who don’t respond to ibrutinib.

Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, and her colleagues detailed these findings in Cancer Discovery. Some of Dr Chen-Kiang’s colleagues reported relationships with Janssen and Pharmacyclics, the companies developing ibrutinib.

“[Ibrutinib] doesn’t work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib,” Dr Chen-Kiang noted. “We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug.”

“The knowledge that we gained from longitudinal RNA and genomic sequencing of mantle cell lymphomas with primary and acquired resistance to ibrutinib allowed us to identify rational drug combinations that may overcome resistance in these 2 settings.”

Dr Chen-Kiang and her colleagues conducted whole-exome and whole-transcriptome analyses of 5 serial biopsies from a patient with MCL who initially responded to ibrutinib before progressing.

After comparing these data with results from an analysis of healthy tissues from the same patient, the investigators found that a mutation in BTK, the C481S mutation, appeared at relapse.

The researchers found the same mutation at relapse in a second MCL patient with acquired resistance to ibrutinib but not in any patients with primary resistance to the drug.

Further analyses revealed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation.

Inhibiting CDK4 with the investigational anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K.

And palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K. The researchers recently opened a clinical trial to test ibrutinib and palbociclib in combination (NCT02159755).

“We are very excited to have generated data . . . that may be meaningful for patients,” Dr Chen-Kiang said. “It is also exciting because CDK4 is a new kind of drug target. It controls the cell cycle, which is a central cancer pathway. As such, it is not just important for mantle cell lymphoma but for many forms of cancer.”

Researchers in the lab

Credit: Rhoda Baer

Investigators have identified drug combinations that may overcome resistance to ibrutinib in patients with mantle cell lymphoma (MCL).

The group discovered a mutation in Bruton’s tyrosine kinase (BTK) that confers resistance to the drug.

They also found that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib, so combining a CDK4 inhibitor and a PI3K inhibitor might be effective in patients who don’t respond to ibrutinib.

Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, and her colleagues detailed these findings in Cancer Discovery. Some of Dr Chen-Kiang’s colleagues reported relationships with Janssen and Pharmacyclics, the companies developing ibrutinib.

“[Ibrutinib] doesn’t work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib,” Dr Chen-Kiang noted. “We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug.”

“The knowledge that we gained from longitudinal RNA and genomic sequencing of mantle cell lymphomas with primary and acquired resistance to ibrutinib allowed us to identify rational drug combinations that may overcome resistance in these 2 settings.”

Dr Chen-Kiang and her colleagues conducted whole-exome and whole-transcriptome analyses of 5 serial biopsies from a patient with MCL who initially responded to ibrutinib before progressing.

After comparing these data with results from an analysis of healthy tissues from the same patient, the investigators found that a mutation in BTK, the C481S mutation, appeared at relapse.

The researchers found the same mutation at relapse in a second MCL patient with acquired resistance to ibrutinib but not in any patients with primary resistance to the drug.

Further analyses revealed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation.

Inhibiting CDK4 with the investigational anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K.

And palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K. The researchers recently opened a clinical trial to test ibrutinib and palbociclib in combination (NCT02159755).

“We are very excited to have generated data . . . that may be meaningful for patients,” Dr Chen-Kiang said. “It is also exciting because CDK4 is a new kind of drug target. It controls the cell cycle, which is a central cancer pathway. As such, it is not just important for mantle cell lymphoma but for many forms of cancer.”

Sickle cells in blood

Credit: Graham Beards

Researchers have found evidence suggesting that beneficial variants of a gene controlling hematopoiesis exist in nearly all human populations.

The team analyzed genomic data from world populations, looking at HMIP-2, a human quantitative trait locus that affects the production of fetal hemoglobin in adults.

The analysis revealed 2 alleles that promote fetal hemoglobin production and can therefore reduce the severity of thalassemia and sickle cell anemia (SCA).

“Patients who have milder versions of [these] blood disorders, thanks to their ability to keep producing fetal hemoglobin, carry genetic clues that are helping us to understand the function of the genes and biological pathways involved in these diseases,” said Stephan Menzel, MD, of King’s College London in the UK.

He and his colleagues conducted this research and reported the results in Annals of Human Genetics.

The researchers noted that HMIP (HBS1L-MYB intergenic polymorphism) on chromosome 6q23.3 was first detected in a large Asian Indian family, where it was shown to be responsible for the persistence of fetal hemoglobin production in adulthood.

And HMIP-2 occupies a 24-kb stretch of DNA that acts as a distal upstream enhancer for MYB, the gene for cMYB, which is essential to hematopoiesis.

While studying 4 groups of SCA patients of diverse African descent, Dr Menzel and his colleagues discovered 2 alleles at HMIP-2 that promote fetal hemoglobin—HMIP-2A and HMIP2-B.

Subsequent analyses revealed the alleles were present, either alone or together, in major human populations and nearly all of the ethnic groups studied.

Both HMIP-2A and HMIP2-B occur in Sub-Saharan Africa, but only at low frequencies. In much of the rest of the world, the alleles have combined, forming HMIP-2A-B, and this combination is relatively common in Europe, South Asia, and China. HMIP-2B alone is common in Far-East Asian peoples and in Amerindians.

The researchers also analyzed genomic data from Neanderthals, Denisovans, and Great Apes, but detected neither HMIP-2A nor HMIP-2B.

The team said these results suggest MYB enhancer variants that modulate the severity of SCA and thalassemia have arisen twice in modern humans, in Africa, and then spread to the rest of the world.

However, this likely occurred long before inherited blood disorders became prevalent, so the environmental factors that favored such variants in these early humans are not clear.

For the next stage of this research, Dr Menzel and his colleagues plan to explore which selection pressures or benefits might have contributed to the present population distribution of the variants.

Selection pressures could include nutritional factors, such as the availability of iron in the diet, or specific demands on red blood cell production, such as adaptation to high altitudes.

Sickle cells in blood

Credit: Graham Beards

Researchers have found evidence suggesting that beneficial variants of a gene controlling hematopoiesis exist in nearly all human populations.

The team analyzed genomic data from world populations, looking at HMIP-2, a human quantitative trait locus that affects the production of fetal hemoglobin in adults.

The analysis revealed 2 alleles that promote fetal hemoglobin production and can therefore reduce the severity of thalassemia and sickle cell anemia (SCA).

“Patients who have milder versions of [these] blood disorders, thanks to their ability to keep producing fetal hemoglobin, carry genetic clues that are helping us to understand the function of the genes and biological pathways involved in these diseases,” said Stephan Menzel, MD, of King’s College London in the UK.

He and his colleagues conducted this research and reported the results in Annals of Human Genetics.

The researchers noted that HMIP (HBS1L-MYB intergenic polymorphism) on chromosome 6q23.3 was first detected in a large Asian Indian family, where it was shown to be responsible for the persistence of fetal hemoglobin production in adulthood.

And HMIP-2 occupies a 24-kb stretch of DNA that acts as a distal upstream enhancer for MYB, the gene for cMYB, which is essential to hematopoiesis.

While studying 4 groups of SCA patients of diverse African descent, Dr Menzel and his colleagues discovered 2 alleles at HMIP-2 that promote fetal hemoglobin—HMIP-2A and HMIP2-B.

Subsequent analyses revealed the alleles were present, either alone or together, in major human populations and nearly all of the ethnic groups studied.

Both HMIP-2A and HMIP2-B occur in Sub-Saharan Africa, but only at low frequencies. In much of the rest of the world, the alleles have combined, forming HMIP-2A-B, and this combination is relatively common in Europe, South Asia, and China. HMIP-2B alone is common in Far-East Asian peoples and in Amerindians.

The researchers also analyzed genomic data from Neanderthals, Denisovans, and Great Apes, but detected neither HMIP-2A nor HMIP-2B.

The team said these results suggest MYB enhancer variants that modulate the severity of SCA and thalassemia have arisen twice in modern humans, in Africa, and then spread to the rest of the world.

However, this likely occurred long before inherited blood disorders became prevalent, so the environmental factors that favored such variants in these early humans are not clear.

For the next stage of this research, Dr Menzel and his colleagues plan to explore which selection pressures or benefits might have contributed to the present population distribution of the variants.

Selection pressures could include nutritional factors, such as the availability of iron in the diet, or specific demands on red blood cell production, such as adaptation to high altitudes.

Sickle cells in blood

Credit: Graham Beards

Researchers have found evidence suggesting that beneficial variants of a gene controlling hematopoiesis exist in nearly all human populations.

The team analyzed genomic data from world populations, looking at HMIP-2, a human quantitative trait locus that affects the production of fetal hemoglobin in adults.

The analysis revealed 2 alleles that promote fetal hemoglobin production and can therefore reduce the severity of thalassemia and sickle cell anemia (SCA).

“Patients who have milder versions of [these] blood disorders, thanks to their ability to keep producing fetal hemoglobin, carry genetic clues that are helping us to understand the function of the genes and biological pathways involved in these diseases,” said Stephan Menzel, MD, of King’s College London in the UK.

He and his colleagues conducted this research and reported the results in Annals of Human Genetics.

The researchers noted that HMIP (HBS1L-MYB intergenic polymorphism) on chromosome 6q23.3 was first detected in a large Asian Indian family, where it was shown to be responsible for the persistence of fetal hemoglobin production in adulthood.

And HMIP-2 occupies a 24-kb stretch of DNA that acts as a distal upstream enhancer for MYB, the gene for cMYB, which is essential to hematopoiesis.

While studying 4 groups of SCA patients of diverse African descent, Dr Menzel and his colleagues discovered 2 alleles at HMIP-2 that promote fetal hemoglobin—HMIP-2A and HMIP2-B.

Subsequent analyses revealed the alleles were present, either alone or together, in major human populations and nearly all of the ethnic groups studied.

Both HMIP-2A and HMIP2-B occur in Sub-Saharan Africa, but only at low frequencies. In much of the rest of the world, the alleles have combined, forming HMIP-2A-B, and this combination is relatively common in Europe, South Asia, and China. HMIP-2B alone is common in Far-East Asian peoples and in Amerindians.

The researchers also analyzed genomic data from Neanderthals, Denisovans, and Great Apes, but detected neither HMIP-2A nor HMIP-2B.

The team said these results suggest MYB enhancer variants that modulate the severity of SCA and thalassemia have arisen twice in modern humans, in Africa, and then spread to the rest of the world.

However, this likely occurred long before inherited blood disorders became prevalent, so the environmental factors that favored such variants in these early humans are not clear.

For the next stage of this research, Dr Menzel and his colleagues plan to explore which selection pressures or benefits might have contributed to the present population distribution of the variants.

Selection pressures could include nutritional factors, such as the availability of iron in the diet, or specific demands on red blood cell production, such as adaptation to high altitudes.

Child receiving RTS,S/AS01

Credit: Caitlin Kleiboer

A candidate malaria vaccine is more effective in children aged 5 months to 17 months than in infants 3 months of age or younger, results of a phase 3 study suggest.

Previous research indicated the vaccine— RTS,S/AS01—may prevent malaria in young children, but its efficacy wanes over time.

Now, researchers have reported that RTS,S/AS01 can sometimes prevent clinical malaria, severe malaria, and malaria hospitalization in children aged 5 to 17 months.

In the younger age group, the vaccine offered some protection against clinical malaria but did not significantly impact the rates of severe malaria or hospitalization.

The RTS,S Clinical Trials Partnership committee reported these findings in PLOS Medicine.

The study was sponsored by GSK Biologicals SA, the developer and manufacturer of RTS,S/AS01, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative.

The researchers studied 6537 infants aged 6 to 12 weeks and 8923 children aged 5 to 17 months treated at 11 sites in Africa.

Subjects were randomized to receive 3 doses of RTS,S/AS01 or a comparator vaccine—a rabies vaccine (VeroRab) for the children and a meningococcal C conjugate vaccine (Menjugate) for the infants.

The primary outcome, vaccine efficacy (VE), was the reduction in malaria incidence among subjects who received RTS,S/AS01 compared to the incidence among subjects who received a comparator vaccine.

In the 18 months following vaccination, VE was 46% in children aged 5 to 17 months and 27% in infants aged 6 to 12 weeks. In both age groups, VE was highest in the first 6 months after vaccination.

RTS,S/AS01 averted an average of 829 cases of clinical malaria per 1000 children vaccinated (range, 37 to 2365) and 449 cases per 1000 infants (range, -10 to 1402) within 18 months of vaccination.

In children aged 5 to 17 months, VE was 34% for severe malaria, 41% for malaria hospitalization, and 19% for all-cause hospitalization. In the infants, there was no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.

Serious adverse events occurred less often in children who received RTS,S/AS01 than in those who received a comparator vaccine—18.6% and 22.7%, respectively. In infants, the rate of serious adverse events was similar between the 2 vaccination groups.

Meningitis was more common in subjects who received RTS,S/AS01 than in those who received a comparator. However, the researchers have not established a causal relationship.

There were 16 cases of meningitis among the 5949 children in the RTS,S/AS01 group, 1 case among the 2974 children in the control group, 9 cases among the 4358 infants in the RTS,S/AS01 group, and 3 cases among the 2179 infants in the control group.

Despite the adverse events associated with RTS,S/AS01 and its decreased efficacy over time, the researchers believe the vaccine shows promise. They noted that, “even at modest levels of VE, the number of malaria cases averted was substantial.”

Now, the group is evaluating whether a booster immunization given 18 months after the primary vaccination can improve the efficacy of RTS,S/AS01.

Results of this study were previously reported at the Multilateral Initiative on Malaria Pan African Conference in October 2013 and published in The New England Journal of Medicine in October 2011 and November 2012. Long-term results of a phase 2 trial of RTS,S/AS01 were published in The New England Journal of Medicine in March 2013.

Child receiving RTS,S/AS01

Credit: Caitlin Kleiboer

A candidate malaria vaccine is more effective in children aged 5 months to 17 months than in infants 3 months of age or younger, results of a phase 3 study suggest.

Previous research indicated the vaccine— RTS,S/AS01—may prevent malaria in young children, but its efficacy wanes over time.

Now, researchers have reported that RTS,S/AS01 can sometimes prevent clinical malaria, severe malaria, and malaria hospitalization in children aged 5 to 17 months.

In the younger age group, the vaccine offered some protection against clinical malaria but did not significantly impact the rates of severe malaria or hospitalization.

The RTS,S Clinical Trials Partnership committee reported these findings in PLOS Medicine.

The study was sponsored by GSK Biologicals SA, the developer and manufacturer of RTS,S/AS01, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative.

The researchers studied 6537 infants aged 6 to 12 weeks and 8923 children aged 5 to 17 months treated at 11 sites in Africa.

Subjects were randomized to receive 3 doses of RTS,S/AS01 or a comparator vaccine—a rabies vaccine (VeroRab) for the children and a meningococcal C conjugate vaccine (Menjugate) for the infants.

The primary outcome, vaccine efficacy (VE), was the reduction in malaria incidence among subjects who received RTS,S/AS01 compared to the incidence among subjects who received a comparator vaccine.

In the 18 months following vaccination, VE was 46% in children aged 5 to 17 months and 27% in infants aged 6 to 12 weeks. In both age groups, VE was highest in the first 6 months after vaccination.

RTS,S/AS01 averted an average of 829 cases of clinical malaria per 1000 children vaccinated (range, 37 to 2365) and 449 cases per 1000 infants (range, -10 to 1402) within 18 months of vaccination.

In children aged 5 to 17 months, VE was 34% for severe malaria, 41% for malaria hospitalization, and 19% for all-cause hospitalization. In the infants, there was no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.

Serious adverse events occurred less often in children who received RTS,S/AS01 than in those who received a comparator vaccine—18.6% and 22.7%, respectively. In infants, the rate of serious adverse events was similar between the 2 vaccination groups.

Meningitis was more common in subjects who received RTS,S/AS01 than in those who received a comparator. However, the researchers have not established a causal relationship.

There were 16 cases of meningitis among the 5949 children in the RTS,S/AS01 group, 1 case among the 2974 children in the control group, 9 cases among the 4358 infants in the RTS,S/AS01 group, and 3 cases among the 2179 infants in the control group.

Despite the adverse events associated with RTS,S/AS01 and its decreased efficacy over time, the researchers believe the vaccine shows promise. They noted that, “even at modest levels of VE, the number of malaria cases averted was substantial.”

Now, the group is evaluating whether a booster immunization given 18 months after the primary vaccination can improve the efficacy of RTS,S/AS01.

Results of this study were previously reported at the Multilateral Initiative on Malaria Pan African Conference in October 2013 and published in The New England Journal of Medicine in October 2011 and November 2012. Long-term results of a phase 2 trial of RTS,S/AS01 were published in The New England Journal of Medicine in March 2013.

Child receiving RTS,S/AS01

Credit: Caitlin Kleiboer

A candidate malaria vaccine is more effective in children aged 5 months to 17 months than in infants 3 months of age or younger, results of a phase 3 study suggest.

Previous research indicated the vaccine— RTS,S/AS01—may prevent malaria in young children, but its efficacy wanes over time.

Now, researchers have reported that RTS,S/AS01 can sometimes prevent clinical malaria, severe malaria, and malaria hospitalization in children aged 5 to 17 months.

In the younger age group, the vaccine offered some protection against clinical malaria but did not significantly impact the rates of severe malaria or hospitalization.

The RTS,S Clinical Trials Partnership committee reported these findings in PLOS Medicine.

The study was sponsored by GSK Biologicals SA, the developer and manufacturer of RTS,S/AS01, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative.

The researchers studied 6537 infants aged 6 to 12 weeks and 8923 children aged 5 to 17 months treated at 11 sites in Africa.

Subjects were randomized to receive 3 doses of RTS,S/AS01 or a comparator vaccine—a rabies vaccine (VeroRab) for the children and a meningococcal C conjugate vaccine (Menjugate) for the infants.

The primary outcome, vaccine efficacy (VE), was the reduction in malaria incidence among subjects who received RTS,S/AS01 compared to the incidence among subjects who received a comparator vaccine.

In the 18 months following vaccination, VE was 46% in children aged 5 to 17 months and 27% in infants aged 6 to 12 weeks. In both age groups, VE was highest in the first 6 months after vaccination.

RTS,S/AS01 averted an average of 829 cases of clinical malaria per 1000 children vaccinated (range, 37 to 2365) and 449 cases per 1000 infants (range, -10 to 1402) within 18 months of vaccination.

In children aged 5 to 17 months, VE was 34% for severe malaria, 41% for malaria hospitalization, and 19% for all-cause hospitalization. In the infants, there was no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.

Serious adverse events occurred less often in children who received RTS,S/AS01 than in those who received a comparator vaccine—18.6% and 22.7%, respectively. In infants, the rate of serious adverse events was similar between the 2 vaccination groups.

Meningitis was more common in subjects who received RTS,S/AS01 than in those who received a comparator. However, the researchers have not established a causal relationship.

There were 16 cases of meningitis among the 5949 children in the RTS,S/AS01 group, 1 case among the 2974 children in the control group, 9 cases among the 4358 infants in the RTS,S/AS01 group, and 3 cases among the 2179 infants in the control group.

Despite the adverse events associated with RTS,S/AS01 and its decreased efficacy over time, the researchers believe the vaccine shows promise. They noted that, “even at modest levels of VE, the number of malaria cases averted was substantial.”

Now, the group is evaluating whether a booster immunization given 18 months after the primary vaccination can improve the efficacy of RTS,S/AS01.

Results of this study were previously reported at the Multilateral Initiative on Malaria Pan African Conference in October 2013 and published in The New England Journal of Medicine in October 2011 and November 2012. Long-term results of a phase 2 trial of RTS,S/AS01 were published in The New England Journal of Medicine in March 2013.

Malaria-carrying mosquito

Credit: James Gathany

Drug-resistant malaria parasites have spread to critical border regions of Southeast Asia, according to a study published in The New England Journal of Medicine.

The study confirms that resistance to the world’s most effective antimalarial drug, artemisinin, is now widespread in Southeast Asia.

This is not the first time malaria parasites have developed resistance to front-line drugs, and, each time, resistance has emerged from the same corner of Asia on the Cambodia-Thailand border.

To assess the extent of artemisinin resistance, researchers analyzed blood samples from 1241 malaria patients in 10 countries across Asia and Africa.

This revealed that artemisinin resistance in Plasmodium falciparum is now firmly established in western Cambodia, Thailand, Vietnam, eastern Myanmar, and northern Cambodia. There are also signs of emerging resistance in central Myanmar, southern Laos, and northeastern Cambodia.

There are no signs of resistance in the 3 African sites included in the study, located in Kenya, Nigeria, and the Democratic Republic of the Congo.

The study also suggested that extending the course of antimalarial treatment in areas with established resistance—for 6 days rather than the standard 3 days—could offer a temporary solution to this worsening problem.

“It may still be possible to prevent the spread of artemisinin-resistant malaria parasites across Asia and then to Africa by eliminating them, but that window of opportunity is closing fast,” said study author Nicholas White, FRS, of the University of Oxford in the UK.

“Conventional malaria control approaches won’t be enough. We will need to take more radical action and make this a global public health priority, without delay.”

He and his colleagues conducted this study by analyzing malaria-infected adults and children at 15 trial sites in 10 malaria-endemic countries between May 2011 and April 2013.

Patients received a 6-day antimalarial treatment—3 days of an artemisinin derivative and a 3-day course of artemisinin combination treatment (ACT). Then, the researchers analyzed patients’ blood to determine the rate at which the parasites were cleared.

The median parasite clearance half-life ranged from 1.8 hours in the Democratic Republic of the Congo to 7 hours at the Thailand-Cambodia border, where artemisinin resistance has been known to exist since 2005.

The proportion of patients with parasites in their blood 72 hours after treatment, a widely used test for artemisinin resistance, ranged from 0% in Kenya to 68% in Eastern Thailand.

Malaria infections that were slow to clear were strongly associated with a single point mutation in a P falciparum gene called kelch 13, an important validation of the recently discovered genetic marker (k13) in the DNA of the malaria parasite.

The researchers also found that patients who had slow-clearing infections were more likely to have parasite stages that can infect mosquitoes. This suggests artemisinin-resistant P falciparum parasites have a transmission advantage over parasites that are not resistant, which drives their spread.

“Frontline ACTs are still very effective at curing the majority of patients, but we need to be vigilant, as cure rates have fallen in areas where artemisinin resistance is established,” said study author Elizabeth Ashley, MBBS, PhD, also of the University of Oxford.

“Action is needed to prevent the spread of resistance from Myanmar into neighboring Bangladesh and India. The artemisinin drugs are arguably the best antimalarials we have ever had. We need to conserve them in areas where they are still working well.”

Malaria-carrying mosquito

Credit: James Gathany

Drug-resistant malaria parasites have spread to critical border regions of Southeast Asia, according to a study published in The New England Journal of Medicine.

The study confirms that resistance to the world’s most effective antimalarial drug, artemisinin, is now widespread in Southeast Asia.

This is not the first time malaria parasites have developed resistance to front-line drugs, and, each time, resistance has emerged from the same corner of Asia on the Cambodia-Thailand border.

To assess the extent of artemisinin resistance, researchers analyzed blood samples from 1241 malaria patients in 10 countries across Asia and Africa.

This revealed that artemisinin resistance in Plasmodium falciparum is now firmly established in western Cambodia, Thailand, Vietnam, eastern Myanmar, and northern Cambodia. There are also signs of emerging resistance in central Myanmar, southern Laos, and northeastern Cambodia.

There are no signs of resistance in the 3 African sites included in the study, located in Kenya, Nigeria, and the Democratic Republic of the Congo.

The study also suggested that extending the course of antimalarial treatment in areas with established resistance—for 6 days rather than the standard 3 days—could offer a temporary solution to this worsening problem.

“It may still be possible to prevent the spread of artemisinin-resistant malaria parasites across Asia and then to Africa by eliminating them, but that window of opportunity is closing fast,” said study author Nicholas White, FRS, of the University of Oxford in the UK.

“Conventional malaria control approaches won’t be enough. We will need to take more radical action and make this a global public health priority, without delay.”

He and his colleagues conducted this study by analyzing malaria-infected adults and children at 15 trial sites in 10 malaria-endemic countries between May 2011 and April 2013.

Patients received a 6-day antimalarial treatment—3 days of an artemisinin derivative and a 3-day course of artemisinin combination treatment (ACT). Then, the researchers analyzed patients’ blood to determine the rate at which the parasites were cleared.

The median parasite clearance half-life ranged from 1.8 hours in the Democratic Republic of the Congo to 7 hours at the Thailand-Cambodia border, where artemisinin resistance has been known to exist since 2005.

The proportion of patients with parasites in their blood 72 hours after treatment, a widely used test for artemisinin resistance, ranged from 0% in Kenya to 68% in Eastern Thailand.

Malaria infections that were slow to clear were strongly associated with a single point mutation in a P falciparum gene called kelch 13, an important validation of the recently discovered genetic marker (k13) in the DNA of the malaria parasite.

The researchers also found that patients who had slow-clearing infections were more likely to have parasite stages that can infect mosquitoes. This suggests artemisinin-resistant P falciparum parasites have a transmission advantage over parasites that are not resistant, which drives their spread.

“Frontline ACTs are still very effective at curing the majority of patients, but we need to be vigilant, as cure rates have fallen in areas where artemisinin resistance is established,” said study author Elizabeth Ashley, MBBS, PhD, also of the University of Oxford.

“Action is needed to prevent the spread of resistance from Myanmar into neighboring Bangladesh and India. The artemisinin drugs are arguably the best antimalarials we have ever had. We need to conserve them in areas where they are still working well.”

Malaria-carrying mosquito

Credit: James Gathany

Drug-resistant malaria parasites have spread to critical border regions of Southeast Asia, according to a study published in The New England Journal of Medicine.

The study confirms that resistance to the world’s most effective antimalarial drug, artemisinin, is now widespread in Southeast Asia.

This is not the first time malaria parasites have developed resistance to front-line drugs, and, each time, resistance has emerged from the same corner of Asia on the Cambodia-Thailand border.

To assess the extent of artemisinin resistance, researchers analyzed blood samples from 1241 malaria patients in 10 countries across Asia and Africa.

This revealed that artemisinin resistance in Plasmodium falciparum is now firmly established in western Cambodia, Thailand, Vietnam, eastern Myanmar, and northern Cambodia. There are also signs of emerging resistance in central Myanmar, southern Laos, and northeastern Cambodia.

There are no signs of resistance in the 3 African sites included in the study, located in Kenya, Nigeria, and the Democratic Republic of the Congo.

The study also suggested that extending the course of antimalarial treatment in areas with established resistance—for 6 days rather than the standard 3 days—could offer a temporary solution to this worsening problem.

“It may still be possible to prevent the spread of artemisinin-resistant malaria parasites across Asia and then to Africa by eliminating them, but that window of opportunity is closing fast,” said study author Nicholas White, FRS, of the University of Oxford in the UK.

“Conventional malaria control approaches won’t be enough. We will need to take more radical action and make this a global public health priority, without delay.”

He and his colleagues conducted this study by analyzing malaria-infected adults and children at 15 trial sites in 10 malaria-endemic countries between May 2011 and April 2013.

Patients received a 6-day antimalarial treatment—3 days of an artemisinin derivative and a 3-day course of artemisinin combination treatment (ACT). Then, the researchers analyzed patients’ blood to determine the rate at which the parasites were cleared.

The median parasite clearance half-life ranged from 1.8 hours in the Democratic Republic of the Congo to 7 hours at the Thailand-Cambodia border, where artemisinin resistance has been known to exist since 2005.

The proportion of patients with parasites in their blood 72 hours after treatment, a widely used test for artemisinin resistance, ranged from 0% in Kenya to 68% in Eastern Thailand.

Malaria infections that were slow to clear were strongly associated with a single point mutation in a P falciparum gene called kelch 13, an important validation of the recently discovered genetic marker (k13) in the DNA of the malaria parasite.

The researchers also found that patients who had slow-clearing infections were more likely to have parasite stages that can infect mosquitoes. This suggests artemisinin-resistant P falciparum parasites have a transmission advantage over parasites that are not resistant, which drives their spread.

“Frontline ACTs are still very effective at curing the majority of patients, but we need to be vigilant, as cure rates have fallen in areas where artemisinin resistance is established,” said study author Elizabeth Ashley, MBBS, PhD, also of the University of Oxford.

“Action is needed to prevent the spread of resistance from Myanmar into neighboring Bangladesh and India. The artemisinin drugs are arguably the best antimalarials we have ever had. We need to conserve them in areas where they are still working well.”

Human sperm stained

for semen quality testing

New research has shown that lymphoma and its treatment can impact a number of sperm characteristics, thereby reducing fertility in males.

Results also indicated that most patients eventually experience semen recovery, but the degree and timing of that recovery may depend on the patient’s diagnosis and treatment.

In this study, recovery was more likely among patients with Hodgkin lymphoma than those with non-Hodgkin lymphoma.

And recovery was both quicker and more likely among patients who did not receive alkylating chemotherapy.

On the other hand, multivariate analyses suggested that only a patient’s pre-treatment total sperm count was related to recovery.

Louis Bujan, MD, PhD, of Université de Toulouse in France, and colleagues reported these results in Fertility and Sterility.

The study included 75 patients—57 with Hodgkin lymphoma and 18 with non-Hodgkin lymphoma. The researchers collected sperm samples before patients began cancer treatment and again at later intervals: 3 months, 6 months, 12 months, and 24 months post-treatment.

The team compared patients’ sperm characteristics to those of a control group consisting of 257 healthy, fertile men.

Results revealed that lymphoma patients had impaired sperm quality even before they began treatment. Compared to fertile controls, patients had higher levels of sperm chromatin alterations and DNA fragmentation, with the only risk factor being their cancer diagnosis.

However, between 3 months and 6 months post-treatment, patients’ levels of sperm DNA fragmentation and chromatin structure damage improved. The damage level decreased relative to a patient’s own pre-treatment level of damage, while still remaining higher than damage levels in the control group.

After treatment, patients’ sperm density, total count, motility, and vitality decreased, with the lowest values seen at the 3- and 6-month marks.

Alkylating chemotherapy was more detrimental to spermatogenesis than non-alkylating drugs. Patients who received alkylating chemotherapy were more likely to cease sperm production entirely or take longer to resume sperm production than patients receiving non-alkylating chemotherapy.

Twelve months after treatment, mean sperm counts recovered to pre-treatment values for patients who had received doxorubicin, bleomycin, vinblastine, and darcarbacine (ABVD) or ABVD and radiotherapy.

But this was not the case for patients who received doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) or mechlorethamine, oncovin, procarbazine, and prednisone (MOPP).

At the 24-month mark, 7% of patients remained azoospermic. Kaplan Meir estimates suggested that, after 24 months, most patients would recover normal sperm counts.

Recovery was projected for 92% of patients who received ABVD and radiotherapy, 90% of patients who received ABVD alone, and 61% of CHOP-treated patients. (There was no estimate for MOPP therapy, perhaps due to a low number of patients.)

A patient’s type of lymphoma appeared to impact sperm count recovery as well. Estimates suggested that, after 24 months, 86% of Hodgkin lymphoma patients would experience recovery, compared to 73% of non-Hodgkin lymphoma patients.

“While many men can look forward to their fertility returning after treatment is over, not all will be so fortunate,” said Rebecca Sokol, MD, MPH, President of the American Society for Reproductive Medicine.

“It is imperative that, prior to the initiation of therapy, counseling and sperm preservation be made available to all lymphoma patients and their partners who may want to have children in the future.”

Human sperm stained

for semen quality testing

New research has shown that lymphoma and its treatment can impact a number of sperm characteristics, thereby reducing fertility in males.

Results also indicated that most patients eventually experience semen recovery, but the degree and timing of that recovery may depend on the patient’s diagnosis and treatment.

In this study, recovery was more likely among patients with Hodgkin lymphoma than those with non-Hodgkin lymphoma.

And recovery was both quicker and more likely among patients who did not receive alkylating chemotherapy.

On the other hand, multivariate analyses suggested that only a patient’s pre-treatment total sperm count was related to recovery.

Louis Bujan, MD, PhD, of Université de Toulouse in France, and colleagues reported these results in Fertility and Sterility.

The study included 75 patients—57 with Hodgkin lymphoma and 18 with non-Hodgkin lymphoma. The researchers collected sperm samples before patients began cancer treatment and again at later intervals: 3 months, 6 months, 12 months, and 24 months post-treatment.

The team compared patients’ sperm characteristics to those of a control group consisting of 257 healthy, fertile men.

Results revealed that lymphoma patients had impaired sperm quality even before they began treatment. Compared to fertile controls, patients had higher levels of sperm chromatin alterations and DNA fragmentation, with the only risk factor being their cancer diagnosis.

However, between 3 months and 6 months post-treatment, patients’ levels of sperm DNA fragmentation and chromatin structure damage improved. The damage level decreased relative to a patient’s own pre-treatment level of damage, while still remaining higher than damage levels in the control group.

After treatment, patients’ sperm density, total count, motility, and vitality decreased, with the lowest values seen at the 3- and 6-month marks.

Alkylating chemotherapy was more detrimental to spermatogenesis than non-alkylating drugs. Patients who received alkylating chemotherapy were more likely to cease sperm production entirely or take longer to resume sperm production than patients receiving non-alkylating chemotherapy.

Twelve months after treatment, mean sperm counts recovered to pre-treatment values for patients who had received doxorubicin, bleomycin, vinblastine, and darcarbacine (ABVD) or ABVD and radiotherapy.

But this was not the case for patients who received doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) or mechlorethamine, oncovin, procarbazine, and prednisone (MOPP).

At the 24-month mark, 7% of patients remained azoospermic. Kaplan Meir estimates suggested that, after 24 months, most patients would recover normal sperm counts.

Recovery was projected for 92% of patients who received ABVD and radiotherapy, 90% of patients who received ABVD alone, and 61% of CHOP-treated patients. (There was no estimate for MOPP therapy, perhaps due to a low number of patients.)

A patient’s type of lymphoma appeared to impact sperm count recovery as well. Estimates suggested that, after 24 months, 86% of Hodgkin lymphoma patients would experience recovery, compared to 73% of non-Hodgkin lymphoma patients.

“While many men can look forward to their fertility returning after treatment is over, not all will be so fortunate,” said Rebecca Sokol, MD, MPH, President of the American Society for Reproductive Medicine.

“It is imperative that, prior to the initiation of therapy, counseling and sperm preservation be made available to all lymphoma patients and their partners who may want to have children in the future.”

Human sperm stained

for semen quality testing

New research has shown that lymphoma and its treatment can impact a number of sperm characteristics, thereby reducing fertility in males.

Results also indicated that most patients eventually experience semen recovery, but the degree and timing of that recovery may depend on the patient’s diagnosis and treatment.

In this study, recovery was more likely among patients with Hodgkin lymphoma than those with non-Hodgkin lymphoma.

And recovery was both quicker and more likely among patients who did not receive alkylating chemotherapy.

On the other hand, multivariate analyses suggested that only a patient’s pre-treatment total sperm count was related to recovery.

Louis Bujan, MD, PhD, of Université de Toulouse in France, and colleagues reported these results in Fertility and Sterility.

The study included 75 patients—57 with Hodgkin lymphoma and 18 with non-Hodgkin lymphoma. The researchers collected sperm samples before patients began cancer treatment and again at later intervals: 3 months, 6 months, 12 months, and 24 months post-treatment.

The team compared patients’ sperm characteristics to those of a control group consisting of 257 healthy, fertile men.

Results revealed that lymphoma patients had impaired sperm quality even before they began treatment. Compared to fertile controls, patients had higher levels of sperm chromatin alterations and DNA fragmentation, with the only risk factor being their cancer diagnosis.

However, between 3 months and 6 months post-treatment, patients’ levels of sperm DNA fragmentation and chromatin structure damage improved. The damage level decreased relative to a patient’s own pre-treatment level of damage, while still remaining higher than damage levels in the control group.

After treatment, patients’ sperm density, total count, motility, and vitality decreased, with the lowest values seen at the 3- and 6-month marks.

Alkylating chemotherapy was more detrimental to spermatogenesis than non-alkylating drugs. Patients who received alkylating chemotherapy were more likely to cease sperm production entirely or take longer to resume sperm production than patients receiving non-alkylating chemotherapy.

Twelve months after treatment, mean sperm counts recovered to pre-treatment values for patients who had received doxorubicin, bleomycin, vinblastine, and darcarbacine (ABVD) or ABVD and radiotherapy.

But this was not the case for patients who received doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) or mechlorethamine, oncovin, procarbazine, and prednisone (MOPP).

At the 24-month mark, 7% of patients remained azoospermic. Kaplan Meir estimates suggested that, after 24 months, most patients would recover normal sperm counts.

Recovery was projected for 92% of patients who received ABVD and radiotherapy, 90% of patients who received ABVD alone, and 61% of CHOP-treated patients. (There was no estimate for MOPP therapy, perhaps due to a low number of patients.)

A patient’s type of lymphoma appeared to impact sperm count recovery as well. Estimates suggested that, after 24 months, 86% of Hodgkin lymphoma patients would experience recovery, compared to 73% of non-Hodgkin lymphoma patients.

“While many men can look forward to their fertility returning after treatment is over, not all will be so fortunate,” said Rebecca Sokol, MD, MPH, President of the American Society for Reproductive Medicine.

“It is imperative that, prior to the initiation of therapy, counseling and sperm preservation be made available to all lymphoma patients and their partners who may want to have children in the future.”

Thrombus

Credit: Kevin MacKenzie

The European Commission has approved apixaban (Eliquis) to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).

The approval applies to all European Union (EU) member states, as well as Iceland and Norway.

Apixaban was already approved in the EU to prevent venous thromboembolism (VTE) in adults who have undergone total hip or knee replacement surgery, and to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The new marketing authorization for apixaban follows the positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use in June and is supported by results of 2 phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT.

Results of AMPLIFY

The AMPLIFY trial included 5395 patients with confirmed, symptomatic DVT or PE requiring treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care, which was enoxaparin at 1 mg/kg twice daily for at least 5 days until INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or PE) or VTE-related death.

This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

Results of AMPLIFY-EXT

The AMPLIFY-EXT trial included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. The mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5-mg arm, 4.2% of patients in the 5-mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5-mg arm, 0.1% of patients in the 5-mg arm, and 0.5% of patients in the placebo arm.

About apixaban

Apixaban is approved to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation in the US, EU, Japan, and a number of other countries around the world.

The drug is approved to prevent VTE in adult patients who have undergone elective hip or knee replacement surgery in the US, EU, and a number of other countries.

And now, apixaban is approved for the treatment of DVT/PE and the prevention of recurrent DVT/PE in the EU. The drug is not approved for this indication in the US.

Apixaban is under joint development by Pfizer and Bristol-Myers Squibb.

Thrombus

Credit: Kevin MacKenzie

The European Commission has approved apixaban (Eliquis) to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).

The approval applies to all European Union (EU) member states, as well as Iceland and Norway.

Apixaban was already approved in the EU to prevent venous thromboembolism (VTE) in adults who have undergone total hip or knee replacement surgery, and to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The new marketing authorization for apixaban follows the positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use in June and is supported by results of 2 phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT.

Results of AMPLIFY

The AMPLIFY trial included 5395 patients with confirmed, symptomatic DVT or PE requiring treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care, which was enoxaparin at 1 mg/kg twice daily for at least 5 days until INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or PE) or VTE-related death.

This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

Results of AMPLIFY-EXT

The AMPLIFY-EXT trial included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. The mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5-mg arm, 4.2% of patients in the 5-mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5-mg arm, 0.1% of patients in the 5-mg arm, and 0.5% of patients in the placebo arm.

About apixaban

Apixaban is approved to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation in the US, EU, Japan, and a number of other countries around the world.

The drug is approved to prevent VTE in adult patients who have undergone elective hip or knee replacement surgery in the US, EU, and a number of other countries.

And now, apixaban is approved for the treatment of DVT/PE and the prevention of recurrent DVT/PE in the EU. The drug is not approved for this indication in the US.

Apixaban is under joint development by Pfizer and Bristol-Myers Squibb.

Thrombus

Credit: Kevin MacKenzie

The European Commission has approved apixaban (Eliquis) to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).

The approval applies to all European Union (EU) member states, as well as Iceland and Norway.

Apixaban was already approved in the EU to prevent venous thromboembolism (VTE) in adults who have undergone total hip or knee replacement surgery, and to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The new marketing authorization for apixaban follows the positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use in June and is supported by results of 2 phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT.

Results of AMPLIFY

The AMPLIFY trial included 5395 patients with confirmed, symptomatic DVT or PE requiring treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care, which was enoxaparin at 1 mg/kg twice daily for at least 5 days until INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or PE) or VTE-related death.

This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

Results of AMPLIFY-EXT

The AMPLIFY-EXT trial included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. The mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5-mg arm, 4.2% of patients in the 5-mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5-mg arm, 0.1% of patients in the 5-mg arm, and 0.5% of patients in the placebo arm.

About apixaban

Apixaban is approved to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation in the US, EU, Japan, and a number of other countries around the world.

The drug is approved to prevent VTE in adult patients who have undergone elective hip or knee replacement surgery in the US, EU, and a number of other countries.

And now, apixaban is approved for the treatment of DVT/PE and the prevention of recurrent DVT/PE in the EU. The drug is not approved for this indication in the US.

Apixaban is under joint development by Pfizer and Bristol-Myers Squibb.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

Two megakaryocytes (purple)

in the bone marrow

Researchers say they’ve identified a previously unknown but crucial component of the platelet production process.

And this discovery could help spare multiple myeloma (MM) patients from thrombocytopenia induced by the proteasome inhibitor bortezomib.

The researchers found that proteasome inhibition blocked platelet production in vitro and in vivo.

But fasudil, a Rho kinase inhibitor that is approved for use outside the US, restored platelet counts.

The researchers believe these findings, published in The Journal of Clinical Investigation, could translate to MM patients.

“A low platelet count is a big issue for people who receive bortezomib for this cancer,” said study author Andrew S. Weyrich, PhD, of the University of Utah in Salt Lake City.

“When platelet levels drop too low, it can mean interrupting treatment to allow the platelet count to recover. Fasudil potentially could help keep platelet counts normal while multiple myeloma patients receive bortezomib.”

Dr Weyrich and his colleagues found that bortezomib-induced proteasome inhibition prevented the production of proplatelets in both human and mouse megakaryocytes.

Megakaryocytes isolated from mice lacking PSMC1, an essential subunit of the 26S proteasome, also failed to produce proplatelets.

Further study revealed that the megakaryocytes’ inability to generate platelets was caused by the hyperactivation of RhoA, a protein that helps megakaryocytes maintain the proper shape to produce platelets.

When the researchers inhibited RhoA or its downstream target, Rho-associated protein kinase, in vitro, they were able to restore megakaryocyte proplatelet formation in the setting of proteasome inhibition.

Likewise, the Rho kinase inhibitor fasudil restored platelet counts in adult mice that had thrombocytopenia induced by proteasome inhibition.

Fasudil is approved in Japan and elsewhere to treat cerebral vasospasms, or constricted arteries that arise as a complication of brain aneurysms.

The drug is under investigation in US clinical trials for treating high blood pressure, diabetic macular edema, and other health issues.

There are no trials investigating fasudil’s effects on thrombocytopenia, but Dr Weyrich and his colleagues hope their study might change that. And if clinical trials produce favorable results, fasudil might be made available for MM patients much faster than a new drug.

“If the Food and Drug Administration did approve fasudil for use by multiple myeloma patients, it could, in principle, be moved to the clinic relatively fast in the United States,” Dr Weyrich said.

Two megakaryocytes (purple)

in the bone marrow

Researchers say they’ve identified a previously unknown but crucial component of the platelet production process.

And this discovery could help spare multiple myeloma (MM) patients from thrombocytopenia induced by the proteasome inhibitor bortezomib.

The researchers found that proteasome inhibition blocked platelet production in vitro and in vivo.

But fasudil, a Rho kinase inhibitor that is approved for use outside the US, restored platelet counts.

The researchers believe these findings, published in The Journal of Clinical Investigation, could translate to MM patients.

“A low platelet count is a big issue for people who receive bortezomib for this cancer,” said study author Andrew S. Weyrich, PhD, of the University of Utah in Salt Lake City.

“When platelet levels drop too low, it can mean interrupting treatment to allow the platelet count to recover. Fasudil potentially could help keep platelet counts normal while multiple myeloma patients receive bortezomib.”

Dr Weyrich and his colleagues found that bortezomib-induced proteasome inhibition prevented the production of proplatelets in both human and mouse megakaryocytes.

Megakaryocytes isolated from mice lacking PSMC1, an essential subunit of the 26S proteasome, also failed to produce proplatelets.

Further study revealed that the megakaryocytes’ inability to generate platelets was caused by the hyperactivation of RhoA, a protein that helps megakaryocytes maintain the proper shape to produce platelets.

When the researchers inhibited RhoA or its downstream target, Rho-associated protein kinase, in vitro, they were able to restore megakaryocyte proplatelet formation in the setting of proteasome inhibition.

Likewise, the Rho kinase inhibitor fasudil restored platelet counts in adult mice that had thrombocytopenia induced by proteasome inhibition.

Fasudil is approved in Japan and elsewhere to treat cerebral vasospasms, or constricted arteries that arise as a complication of brain aneurysms.

The drug is under investigation in US clinical trials for treating high blood pressure, diabetic macular edema, and other health issues.

There are no trials investigating fasudil’s effects on thrombocytopenia, but Dr Weyrich and his colleagues hope their study might change that. And if clinical trials produce favorable results, fasudil might be made available for MM patients much faster than a new drug.

“If the Food and Drug Administration did approve fasudil for use by multiple myeloma patients, it could, in principle, be moved to the clinic relatively fast in the United States,” Dr Weyrich said.

Two megakaryocytes (purple)

in the bone marrow

Researchers say they’ve identified a previously unknown but crucial component of the platelet production process.

And this discovery could help spare multiple myeloma (MM) patients from thrombocytopenia induced by the proteasome inhibitor bortezomib.

The researchers found that proteasome inhibition blocked platelet production in vitro and in vivo.

But fasudil, a Rho kinase inhibitor that is approved for use outside the US, restored platelet counts.

The researchers believe these findings, published in The Journal of Clinical Investigation, could translate to MM patients.

“A low platelet count is a big issue for people who receive bortezomib for this cancer,” said study author Andrew S. Weyrich, PhD, of the University of Utah in Salt Lake City.

“When platelet levels drop too low, it can mean interrupting treatment to allow the platelet count to recover. Fasudil potentially could help keep platelet counts normal while multiple myeloma patients receive bortezomib.”

Dr Weyrich and his colleagues found that bortezomib-induced proteasome inhibition prevented the production of proplatelets in both human and mouse megakaryocytes.

Megakaryocytes isolated from mice lacking PSMC1, an essential subunit of the 26S proteasome, also failed to produce proplatelets.

Further study revealed that the megakaryocytes’ inability to generate platelets was caused by the hyperactivation of RhoA, a protein that helps megakaryocytes maintain the proper shape to produce platelets.

When the researchers inhibited RhoA or its downstream target, Rho-associated protein kinase, in vitro, they were able to restore megakaryocyte proplatelet formation in the setting of proteasome inhibition.

Likewise, the Rho kinase inhibitor fasudil restored platelet counts in adult mice that had thrombocytopenia induced by proteasome inhibition.

Fasudil is approved in Japan and elsewhere to treat cerebral vasospasms, or constricted arteries that arise as a complication of brain aneurysms.

The drug is under investigation in US clinical trials for treating high blood pressure, diabetic macular edema, and other health issues.

There are no trials investigating fasudil’s effects on thrombocytopenia, but Dr Weyrich and his colleagues hope their study might change that. And if clinical trials produce favorable results, fasudil might be made available for MM patients much faster than a new drug.

“If the Food and Drug Administration did approve fasudil for use by multiple myeloma patients, it could, in principle, be moved to the clinic relatively fast in the United States,” Dr Weyrich said.

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Following a healthy lifestyle can decrease the risk of metabolic syndrome in childhood cancer survivors, according to a study published in Cancer.

Unfortunately, only about a quarter of the survivors studied actually practiced healthy lifestyle habits, such as engaging in moderate physical activity; eating the recommended daily serving of fruits, vegetables, and complex carbohydrates; and consuming red meat, alcohol, and sodium in moderation.

Childhood cancer survivors are known to have an increased risk of developing metabolic syndrome.

The syndrome is actually a number of conditions—high blood pressure, increased body fat, and abnormal cholesterol and glucose levels—that, when they occur together, increase a person’s risk of heart disease, stroke, and diabetes.

Kirsten Ness, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues wanted to determine if lifestyle habits might affect the risk of metabolic syndrome among childhood cancer survivors.

So the team analyzed 1598 survivors who were cancer-free for at least 10 years. They had a median age of 32.7 years (range, 18.9 to 60).

The analysis showed that failure to follow healthy lifestyle guidelines roughly doubled the survivors’ risk of developing metabolic syndrome. Women had a 2.4-times greater risk, and men had a 2.2-times greater risk of the syndrome if they did not follow the guidelines.

Metabolic syndrome was present in 31.8% of the participants—32.5% of males and 31% of females.

The researchers considered a subject to have metabolic syndrome if he had or received treatment for 3 or more of the following:

• Abdominal obesity (waist circumference of > 102 cm in males and > 88 cm in females)
• Triglycerides ≥ 150 mg/dL
• High-density lipoprotein cholesterol (< 40 mg/dL in males and < 50 mg/dL in females)
• Hypertension (systolic pressure ≥ 130 mm Hg or diastolic pressure ≥ 85 mm Hg)
• Fasting plasma glucose ≥ 100 mg/dL.

Questionnaires and tests helped the researchers assess whether participants followed healthy lifestyle recommendations issued by the World Cancer Research Fund and American Institute for Cancer Research.

The recommendations include:

• Having a body mass index of 25 or lower
• Engaging in moderate physical activity for 150 minutes each week
• Eating 5 or more servings of fruits and vegetables each day
• Consuming 400 g or more of complex carbohydrates daily
• Eating less than 80 g of red meat each day
• Consuming less than 2400 mg of sodium each day
• Low daily alcohol consumption (less than 14 g for females and less than 28 g for males).

Subjects who met at least 4 of these 7 criteria were classified as following the guidelines. And 27% of the participants—25.2% of males and 28.8% of females—were classified as such.

“These findings are important because they indicate that adults who were treated for cancer as children have the opportunity to influence their own health outcomes,” Dr Ness said.

“[A]dopting a lifestyle that includes maintaining a healthy body weight, regular physical activity, and a diet that includes fruits and vegetables and that limits refined sugars, excessive alcohol, red meat, and salt has potential to prevent development of metabolic syndrome.”

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Following a healthy lifestyle can decrease the risk of metabolic syndrome in childhood cancer survivors, according to a study published in Cancer.

Unfortunately, only about a quarter of the survivors studied actually practiced healthy lifestyle habits, such as engaging in moderate physical activity; eating the recommended daily serving of fruits, vegetables, and complex carbohydrates; and consuming red meat, alcohol, and sodium in moderation.

Childhood cancer survivors are known to have an increased risk of developing metabolic syndrome.

The syndrome is actually a number of conditions—high blood pressure, increased body fat, and abnormal cholesterol and glucose levels—that, when they occur together, increase a person’s risk of heart disease, stroke, and diabetes.

Kirsten Ness, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues wanted to determine if lifestyle habits might affect the risk of metabolic syndrome among childhood cancer survivors.

So the team analyzed 1598 survivors who were cancer-free for at least 10 years. They had a median age of 32.7 years (range, 18.9 to 60).

The analysis showed that failure to follow healthy lifestyle guidelines roughly doubled the survivors’ risk of developing metabolic syndrome. Women had a 2.4-times greater risk, and men had a 2.2-times greater risk of the syndrome if they did not follow the guidelines.

Metabolic syndrome was present in 31.8% of the participants—32.5% of males and 31% of females.

The researchers considered a subject to have metabolic syndrome if he had or received treatment for 3 or more of the following:

• Abdominal obesity (waist circumference of > 102 cm in males and > 88 cm in females)
• Triglycerides ≥ 150 mg/dL
• High-density lipoprotein cholesterol (< 40 mg/dL in males and < 50 mg/dL in females)
• Hypertension (systolic pressure ≥ 130 mm Hg or diastolic pressure ≥ 85 mm Hg)
• Fasting plasma glucose ≥ 100 mg/dL.

Questionnaires and tests helped the researchers assess whether participants followed healthy lifestyle recommendations issued by the World Cancer Research Fund and American Institute for Cancer Research.

The recommendations include:

• Having a body mass index of 25 or lower
• Engaging in moderate physical activity for 150 minutes each week
• Eating 5 or more servings of fruits and vegetables each day
• Consuming 400 g or more of complex carbohydrates daily
• Eating less than 80 g of red meat each day
• Consuming less than 2400 mg of sodium each day
• Low daily alcohol consumption (less than 14 g for females and less than 28 g for males).

Subjects who met at least 4 of these 7 criteria were classified as following the guidelines. And 27% of the participants—25.2% of males and 28.8% of females—were classified as such.

“These findings are important because they indicate that adults who were treated for cancer as children have the opportunity to influence their own health outcomes,” Dr Ness said.

“[A]dopting a lifestyle that includes maintaining a healthy body weight, regular physical activity, and a diet that includes fruits and vegetables and that limits refined sugars, excessive alcohol, red meat, and salt has potential to prevent development of metabolic syndrome.”

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Following a healthy lifestyle can decrease the risk of metabolic syndrome in childhood cancer survivors, according to a study published in Cancer.

Unfortunately, only about a quarter of the survivors studied actually practiced healthy lifestyle habits, such as engaging in moderate physical activity; eating the recommended daily serving of fruits, vegetables, and complex carbohydrates; and consuming red meat, alcohol, and sodium in moderation.

Childhood cancer survivors are known to have an increased risk of developing metabolic syndrome.

The syndrome is actually a number of conditions—high blood pressure, increased body fat, and abnormal cholesterol and glucose levels—that, when they occur together, increase a person’s risk of heart disease, stroke, and diabetes.

Kirsten Ness, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues wanted to determine if lifestyle habits might affect the risk of metabolic syndrome among childhood cancer survivors.

So the team analyzed 1598 survivors who were cancer-free for at least 10 years. They had a median age of 32.7 years (range, 18.9 to 60).

The analysis showed that failure to follow healthy lifestyle guidelines roughly doubled the survivors’ risk of developing metabolic syndrome. Women had a 2.4-times greater risk, and men had a 2.2-times greater risk of the syndrome if they did not follow the guidelines.

Metabolic syndrome was present in 31.8% of the participants—32.5% of males and 31% of females.

The researchers considered a subject to have metabolic syndrome if he had or received treatment for 3 or more of the following:

• Abdominal obesity (waist circumference of > 102 cm in males and > 88 cm in females)
• Triglycerides ≥ 150 mg/dL
• High-density lipoprotein cholesterol (< 40 mg/dL in males and < 50 mg/dL in females)
• Hypertension (systolic pressure ≥ 130 mm Hg or diastolic pressure ≥ 85 mm Hg)
• Fasting plasma glucose ≥ 100 mg/dL.

Questionnaires and tests helped the researchers assess whether participants followed healthy lifestyle recommendations issued by the World Cancer Research Fund and American Institute for Cancer Research.

The recommendations include:

• Having a body mass index of 25 or lower
• Engaging in moderate physical activity for 150 minutes each week
• Eating 5 or more servings of fruits and vegetables each day
• Consuming 400 g or more of complex carbohydrates daily
• Eating less than 80 g of red meat each day
• Consuming less than 2400 mg of sodium each day
• Low daily alcohol consumption (less than 14 g for females and less than 28 g for males).

Subjects who met at least 4 of these 7 criteria were classified as following the guidelines. And 27% of the participants—25.2% of males and 28.8% of females—were classified as such.

“These findings are important because they indicate that adults who were treated for cancer as children have the opportunity to influence their own health outcomes,” Dr Ness said.

“[A]dopting a lifestyle that includes maintaining a healthy body weight, regular physical activity, and a diet that includes fruits and vegetables and that limits refined sugars, excessive alcohol, red meat, and salt has potential to prevent development of metabolic syndrome.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Investigators have reported success in the first clinical trial demonstrating controlled malaria infection in an African nation.

The study established that a product containing Plasmodium falciparum sporozoites can be used to safely infect volunteers with malaria in controlled lab conditions in a malaria-endemic country.

This represents a significant milestone in the search for new malaria drugs and vaccines, according to the investigators.

“We are extremely excited by the good results of this malaria challenge test, which opens up unprecedented opportunity for evaluation of new malaria drugs and vaccines in Africa,” said Salim Abdullah, PhD, of the Ifakara Health Institute Bagamoyo Research and Training Centre in Tanzania, where the study took place.

Dr Abdullah and his colleagues reported the results in the American Journal of Tropical Medicine and Hygiene. A related editorial is also available.

The researchers tested sporozoites that were grown in mosquitoes in the lab and then packaged in a purified, aseptic form acceptable for clinical trials. The product is known as PfSPZ Challenge and is owned by Sanaria, Inc., a privately held company in Rockville, Maryland.

Prior to this innovation, the ability to challenge a vaccine’s effectiveness required deliberately infecting vaccinated volunteers with malaria by exposing them to mosquito bites in an insectary.

Few such malaria insectaries exist, and due to the resources needed, these are limited to a handful in the US and Europe, far from the countries where malaria takes its toll.

This clinical trial established that injecting volunteers with cryopreserved, aseptic parasites can safely and effectively infect adult volunteers with P falciparum malaria in a malaria-endemic country.

“This innovation is a game-changer for malaria research and development in Africa,” said study author Stephen L. Hoffman, MD, of Sanaria, Inc. “This is about making available within Africa the same research tools to study malaria that we have in the USA and Europe.”

To test PfSPZ Challenge, the investigators recruited a group of 30 Tanzanian men, residents of Dar es Salaam, who had minimal exposure to malaria during the previous 5 years.

The volunteers were injected intradermally with 10,000 sporozoites (n=12), 25,000 sporozoites (n=11), or normal saline (n=6). Investigators and subjects were blinded to the intervention.

The investigators then compared the infection rate to that of volunteers who participated in a similar study in The Netherlands a few years ago.

After about 2 weeks, all but 2 of the 23 Tanzanian volunteers injected with sporozoites developed active infections, a rate similar to the Dutch volunteers.

Once active infection was established, the volunteers were immediately treated for malaria and cleared of parasites.

None of the volunteers developed serious side effects related to the study. Mild side effects included low-grade fever, headaches, and fatigue.

“This is a real step forward for developing a vaccine against malaria, which has killed more human beings throughout history than any other single cause,” said study author Christopher Plowe, MD, MPH, of the University of Maryland in Baltimore.

“The ability to safely administer malaria parasites by injection rather than by mosquito bite makes it possible to test new malaria vaccines, as well as drugs, anywhere in the world.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Investigators have reported success in the first clinical trial demonstrating controlled malaria infection in an African nation.

The study established that a product containing Plasmodium falciparum sporozoites can be used to safely infect volunteers with malaria in controlled lab conditions in a malaria-endemic country.

This represents a significant milestone in the search for new malaria drugs and vaccines, according to the investigators.

“We are extremely excited by the good results of this malaria challenge test, which opens up unprecedented opportunity for evaluation of new malaria drugs and vaccines in Africa,” said Salim Abdullah, PhD, of the Ifakara Health Institute Bagamoyo Research and Training Centre in Tanzania, where the study took place.

Dr Abdullah and his colleagues reported the results in the American Journal of Tropical Medicine and Hygiene. A related editorial is also available.

The researchers tested sporozoites that were grown in mosquitoes in the lab and then packaged in a purified, aseptic form acceptable for clinical trials. The product is known as PfSPZ Challenge and is owned by Sanaria, Inc., a privately held company in Rockville, Maryland.

Prior to this innovation, the ability to challenge a vaccine’s effectiveness required deliberately infecting vaccinated volunteers with malaria by exposing them to mosquito bites in an insectary.

Few such malaria insectaries exist, and due to the resources needed, these are limited to a handful in the US and Europe, far from the countries where malaria takes its toll.

This clinical trial established that injecting volunteers with cryopreserved, aseptic parasites can safely and effectively infect adult volunteers with P falciparum malaria in a malaria-endemic country.

“This innovation is a game-changer for malaria research and development in Africa,” said study author Stephen L. Hoffman, MD, of Sanaria, Inc. “This is about making available within Africa the same research tools to study malaria that we have in the USA and Europe.”

To test PfSPZ Challenge, the investigators recruited a group of 30 Tanzanian men, residents of Dar es Salaam, who had minimal exposure to malaria during the previous 5 years.

The volunteers were injected intradermally with 10,000 sporozoites (n=12), 25,000 sporozoites (n=11), or normal saline (n=6). Investigators and subjects were blinded to the intervention.

The investigators then compared the infection rate to that of volunteers who participated in a similar study in The Netherlands a few years ago.

After about 2 weeks, all but 2 of the 23 Tanzanian volunteers injected with sporozoites developed active infections, a rate similar to the Dutch volunteers.

Once active infection was established, the volunteers were immediately treated for malaria and cleared of parasites.

None of the volunteers developed serious side effects related to the study. Mild side effects included low-grade fever, headaches, and fatigue.

“This is a real step forward for developing a vaccine against malaria, which has killed more human beings throughout history than any other single cause,” said study author Christopher Plowe, MD, MPH, of the University of Maryland in Baltimore.

“The ability to safely administer malaria parasites by injection rather than by mosquito bite makes it possible to test new malaria vaccines, as well as drugs, anywhere in the world.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Investigators have reported success in the first clinical trial demonstrating controlled malaria infection in an African nation.

The study established that a product containing Plasmodium falciparum sporozoites can be used to safely infect volunteers with malaria in controlled lab conditions in a malaria-endemic country.

This represents a significant milestone in the search for new malaria drugs and vaccines, according to the investigators.

“We are extremely excited by the good results of this malaria challenge test, which opens up unprecedented opportunity for evaluation of new malaria drugs and vaccines in Africa,” said Salim Abdullah, PhD, of the Ifakara Health Institute Bagamoyo Research and Training Centre in Tanzania, where the study took place.

Dr Abdullah and his colleagues reported the results in the American Journal of Tropical Medicine and Hygiene. A related editorial is also available.

The researchers tested sporozoites that were grown in mosquitoes in the lab and then packaged in a purified, aseptic form acceptable for clinical trials. The product is known as PfSPZ Challenge and is owned by Sanaria, Inc., a privately held company in Rockville, Maryland.

Prior to this innovation, the ability to challenge a vaccine’s effectiveness required deliberately infecting vaccinated volunteers with malaria by exposing them to mosquito bites in an insectary.

Few such malaria insectaries exist, and due to the resources needed, these are limited to a handful in the US and Europe, far from the countries where malaria takes its toll.

This clinical trial established that injecting volunteers with cryopreserved, aseptic parasites can safely and effectively infect adult volunteers with P falciparum malaria in a malaria-endemic country.

“This innovation is a game-changer for malaria research and development in Africa,” said study author Stephen L. Hoffman, MD, of Sanaria, Inc. “This is about making available within Africa the same research tools to study malaria that we have in the USA and Europe.”

To test PfSPZ Challenge, the investigators recruited a group of 30 Tanzanian men, residents of Dar es Salaam, who had minimal exposure to malaria during the previous 5 years.

The volunteers were injected intradermally with 10,000 sporozoites (n=12), 25,000 sporozoites (n=11), or normal saline (n=6). Investigators and subjects were blinded to the intervention.

The investigators then compared the infection rate to that of volunteers who participated in a similar study in The Netherlands a few years ago.

After about 2 weeks, all but 2 of the 23 Tanzanian volunteers injected with sporozoites developed active infections, a rate similar to the Dutch volunteers.

Once active infection was established, the volunteers were immediately treated for malaria and cleared of parasites.

None of the volunteers developed serious side effects related to the study. Mild side effects included low-grade fever, headaches, and fatigue.

“This is a real step forward for developing a vaccine against malaria, which has killed more human beings throughout history than any other single cause,” said study author Christopher Plowe, MD, MPH, of the University of Maryland in Baltimore.

“The ability to safely administer malaria parasites by injection rather than by mosquito bite makes it possible to test new malaria vaccines, as well as drugs, anywhere in the world.”