Hematology Times

Female chimpanzee

Photo courtesy of

Sesh Sundararaman,

University of Pennsylvania

By studying malaria parasites found in chimpanzees, researchers believe they have gained new insights regarding a malaria parasite that infects humans.

The team used a selective amplification technique to sequence the genomes of 2 divergent Plasmodium species, P reichenowi and P gaboni, from chimpanzee blood.

This revealed clues about the evolution and pathogenicity of P falciparum, the deadliest malaria parasite that affects humans.

The researchers described this work in Nature Communications.

They noted that African apes harbor at least 6 Plasmodium species that have been classified into a separate subgenus, called Laverania. Three of these Laverania species, including P reichenowi and P gaboni, reside in chimps.

Three others—including P praefalciparum, which gave rise to P falciparum—reside in gorillas. The gorilla origin of P falciparum was discovered several years ago by this same group of investigators.

“We want to know why Plasmodium falciparum is so deadly,” said Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“The answer must lie in the blueprint—the genome—of its chimpanzee and gorilla cousins. We also want to know how and when the gorilla precursor of Plasmodium falciparum jumped into humans and why this happened only once.”

In an attempt to answer these questions, Dr Hahn and her colleagues used their selective amplification method to sequence Laverania genomes.

They used small amounts of unprocessed blood collected during routine health screens of chimpanzees living in sanctuaries. With their technique, the team found they could generate “high-quality” Laverania genome sequences.

The researchers said the chimpanzee parasite genomes contain information about the evolutionary origins of the malaria parasites infecting humans. One of the first things to emerge from genome-wide analyses was that the parasites represent distinct, non-interbreeding species.

In addition, members of each chimpanzee parasite species display about 10 times more genetic diversity than human parasites.

“The chimpanzee parasites really highlight the lack of diversity in Plasmodium falciparum,” said Paul Sharp, PhD, of the University of Edinburgh in the UK.

“This is most likely because these parasites went through a severe bottleneck when first transmitted to humans, perhaps within the past 10,000 years.”

By comparing the different parasite genomes, the researchers found an expansion of a multi-gene family, which governs red blood cell remodeling and therefore helps the parasite to evade host immune cells and clearance by the spleen.

“The remodeling process is a key part of severe malaria pathology in human Plasmodium falciparum infections,” said Julian Rayner, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“The expansion of this gene family from a single gene in all other Plasmodium parasites to up to 21 genes in Laverania suggests that remodeling evolved early in the radiation of this group of primate parasites and contributed not only to their unique biology but perhaps also to their successful expansion.”

“We also found a short region of the genome, including 2 essential invasion genes, where Plasmodium falciparum was much more different from its close relatives than we expected,” said Lindsey Plenderleith, PhD, of the University of Edinburgh.

Further analysis yielded the surprising finding that this fragment of DNA was horizontally transferred—from one species to another—into the gorilla ancestor of P falciparum.

“It is tempting to speculate that this unusual event somehow predisposed the precursor of Plasmodium falciparum to colonize humans,” Dr Hahn said. “However, this gene transfer clearly is not the entire story.”

Although the origin of P falciparum is considered well-established, nothing is known about the circumstances that led to its emergence.

“Coaxing entire parasite genome sequences out of small quantities of unprocessed ape blood will help us to better understand what happened and whether it can happen again,” said Sesh Sundararaman, an MD/PhD student at the University of Pennsylvania.

The team plans, as a next step, to use their select genome amplification technique to sequence additional ape parasite genomes to identify host-specific interactions and transmission requirements. They believe this would reveal vulnerabilities that might be exploited to combat malaria in humans.

Female chimpanzee

Photo courtesy of

Sesh Sundararaman,

University of Pennsylvania

By studying malaria parasites found in chimpanzees, researchers believe they have gained new insights regarding a malaria parasite that infects humans.

The team used a selective amplification technique to sequence the genomes of 2 divergent Plasmodium species, P reichenowi and P gaboni, from chimpanzee blood.

This revealed clues about the evolution and pathogenicity of P falciparum, the deadliest malaria parasite that affects humans.

The researchers described this work in Nature Communications.

They noted that African apes harbor at least 6 Plasmodium species that have been classified into a separate subgenus, called Laverania. Three of these Laverania species, including P reichenowi and P gaboni, reside in chimps.

Three others—including P praefalciparum, which gave rise to P falciparum—reside in gorillas. The gorilla origin of P falciparum was discovered several years ago by this same group of investigators.

“We want to know why Plasmodium falciparum is so deadly,” said Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“The answer must lie in the blueprint—the genome—of its chimpanzee and gorilla cousins. We also want to know how and when the gorilla precursor of Plasmodium falciparum jumped into humans and why this happened only once.”

In an attempt to answer these questions, Dr Hahn and her colleagues used their selective amplification method to sequence Laverania genomes.

They used small amounts of unprocessed blood collected during routine health screens of chimpanzees living in sanctuaries. With their technique, the team found they could generate “high-quality” Laverania genome sequences.

The researchers said the chimpanzee parasite genomes contain information about the evolutionary origins of the malaria parasites infecting humans. One of the first things to emerge from genome-wide analyses was that the parasites represent distinct, non-interbreeding species.

In addition, members of each chimpanzee parasite species display about 10 times more genetic diversity than human parasites.

“The chimpanzee parasites really highlight the lack of diversity in Plasmodium falciparum,” said Paul Sharp, PhD, of the University of Edinburgh in the UK.

“This is most likely because these parasites went through a severe bottleneck when first transmitted to humans, perhaps within the past 10,000 years.”

By comparing the different parasite genomes, the researchers found an expansion of a multi-gene family, which governs red blood cell remodeling and therefore helps the parasite to evade host immune cells and clearance by the spleen.

“The remodeling process is a key part of severe malaria pathology in human Plasmodium falciparum infections,” said Julian Rayner, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“The expansion of this gene family from a single gene in all other Plasmodium parasites to up to 21 genes in Laverania suggests that remodeling evolved early in the radiation of this group of primate parasites and contributed not only to their unique biology but perhaps also to their successful expansion.”

“We also found a short region of the genome, including 2 essential invasion genes, where Plasmodium falciparum was much more different from its close relatives than we expected,” said Lindsey Plenderleith, PhD, of the University of Edinburgh.

Further analysis yielded the surprising finding that this fragment of DNA was horizontally transferred—from one species to another—into the gorilla ancestor of P falciparum.

“It is tempting to speculate that this unusual event somehow predisposed the precursor of Plasmodium falciparum to colonize humans,” Dr Hahn said. “However, this gene transfer clearly is not the entire story.”

Although the origin of P falciparum is considered well-established, nothing is known about the circumstances that led to its emergence.

“Coaxing entire parasite genome sequences out of small quantities of unprocessed ape blood will help us to better understand what happened and whether it can happen again,” said Sesh Sundararaman, an MD/PhD student at the University of Pennsylvania.

The team plans, as a next step, to use their select genome amplification technique to sequence additional ape parasite genomes to identify host-specific interactions and transmission requirements. They believe this would reveal vulnerabilities that might be exploited to combat malaria in humans.

Female chimpanzee

Photo courtesy of

Sesh Sundararaman,

University of Pennsylvania

By studying malaria parasites found in chimpanzees, researchers believe they have gained new insights regarding a malaria parasite that infects humans.

The team used a selective amplification technique to sequence the genomes of 2 divergent Plasmodium species, P reichenowi and P gaboni, from chimpanzee blood.

This revealed clues about the evolution and pathogenicity of P falciparum, the deadliest malaria parasite that affects humans.

The researchers described this work in Nature Communications.

They noted that African apes harbor at least 6 Plasmodium species that have been classified into a separate subgenus, called Laverania. Three of these Laverania species, including P reichenowi and P gaboni, reside in chimps.

Three others—including P praefalciparum, which gave rise to P falciparum—reside in gorillas. The gorilla origin of P falciparum was discovered several years ago by this same group of investigators.

“We want to know why Plasmodium falciparum is so deadly,” said Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“The answer must lie in the blueprint—the genome—of its chimpanzee and gorilla cousins. We also want to know how and when the gorilla precursor of Plasmodium falciparum jumped into humans and why this happened only once.”

In an attempt to answer these questions, Dr Hahn and her colleagues used their selective amplification method to sequence Laverania genomes.

They used small amounts of unprocessed blood collected during routine health screens of chimpanzees living in sanctuaries. With their technique, the team found they could generate “high-quality” Laverania genome sequences.

The researchers said the chimpanzee parasite genomes contain information about the evolutionary origins of the malaria parasites infecting humans. One of the first things to emerge from genome-wide analyses was that the parasites represent distinct, non-interbreeding species.

In addition, members of each chimpanzee parasite species display about 10 times more genetic diversity than human parasites.

“The chimpanzee parasites really highlight the lack of diversity in Plasmodium falciparum,” said Paul Sharp, PhD, of the University of Edinburgh in the UK.

“This is most likely because these parasites went through a severe bottleneck when first transmitted to humans, perhaps within the past 10,000 years.”

By comparing the different parasite genomes, the researchers found an expansion of a multi-gene family, which governs red blood cell remodeling and therefore helps the parasite to evade host immune cells and clearance by the spleen.

“The remodeling process is a key part of severe malaria pathology in human Plasmodium falciparum infections,” said Julian Rayner, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“The expansion of this gene family from a single gene in all other Plasmodium parasites to up to 21 genes in Laverania suggests that remodeling evolved early in the radiation of this group of primate parasites and contributed not only to their unique biology but perhaps also to their successful expansion.”

“We also found a short region of the genome, including 2 essential invasion genes, where Plasmodium falciparum was much more different from its close relatives than we expected,” said Lindsey Plenderleith, PhD, of the University of Edinburgh.

Further analysis yielded the surprising finding that this fragment of DNA was horizontally transferred—from one species to another—into the gorilla ancestor of P falciparum.

“It is tempting to speculate that this unusual event somehow predisposed the precursor of Plasmodium falciparum to colonize humans,” Dr Hahn said. “However, this gene transfer clearly is not the entire story.”

Although the origin of P falciparum is considered well-established, nothing is known about the circumstances that led to its emergence.

“Coaxing entire parasite genome sequences out of small quantities of unprocessed ape blood will help us to better understand what happened and whether it can happen again,” said Sesh Sundararaman, an MD/PhD student at the University of Pennsylvania.

The team plans, as a next step, to use their select genome amplification technique to sequence additional ape parasite genomes to identify host-specific interactions and transmission requirements. They believe this would reveal vulnerabilities that might be exploited to combat malaria in humans.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About EBV-CTLs

The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About EBV-CTLs

The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

The European Medicines Agency (EMA) has recommended orphan designation for an allogeneic cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) as a treatment for patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About EBV-CTLs

The EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Biotherapeutics, Inc., the company developing the EBV-CTL product, is planning to launch a multi-center, early access clinical trial for EBV-CTLs in mid-2016, followed by 2 phase 3 trials in EBV-PTLD later in the year.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

Atara’s EBV-CTL product already has orphan designation in the US for the treatment of patients with EBV-PTLD after hematopoietic stem cell transplant or solid organ transplant. The product has breakthrough designation for this indication as well.

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.

NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.

The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.

“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.

The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.

The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.

The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Efficacy

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.

Safety

No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.

There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.

The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.

NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.

The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.

“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.

The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.

The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.

The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Efficacy

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.

Safety

No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.

There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.

The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to NI-0501 for the treatment of patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory disease or recurrent/progressive disease during conventional therapy.

NI-0501 is a fully human monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) that is being developed by Novimmune.

The biological activity of IFNγ, which is considered to have a pivotal pathogenic role in HLH, is neutralized by NI-0501.

“The FDA’s designation of NI-0501 as a breakthrough therapy recognizes the potential of NI-0501 to address an important unmet medical need in a disease with still high mortality, and for which there are no approved treatments,” said Novimmune Chairman and Chief Executive Officer Eduard Holdener.

The breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.

The FDA granted breakthrough designation to NI-0501 on the basis of data from a phase 2 study in children with primary HLH. Preliminary results from this study were presented at the 2015 ASH Annual Meeting.

The trial included 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13).

Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).

NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5 mg/m² to 10 mg/m², but dexamethasone could be tapered during the treatment course.

The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.

Efficacy

One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients were still receiving treatment as of the ASH presentation, and 13 have completed treatment.

Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.

Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 were awaiting HSCT at the time of the ASH presentation, with their disease well-controlled.

Post-transplant follow-up is still early for most patients, but 2 patients have follow-up greater than 1 year. One child died of graft-vs-host disease around day 45, but the remaining patients who went on to HSCT were still alive as of the ASH presentation.

Safety

No off-target effects of NI-0501 were observed, and none of the patients withdrew from the study for safety reasons.

There were 14 serious adverse events reported in 8 patients, but only 1 of these events was considered treatment-related.

The patient had necrotizing fasciitis following P aeruginosa skin infection, which resolved. This event was considered treatment-related by an investigator but not by the data monitoring committee or the sponsor.

Three patients had died as of the ASH presentation, but none of the deaths were related to NI-0501. Two patients died of HLH/multi-organ failure, and 1 died of graft-vs-host disease.

Pregnant woman

Photo by Nina Matthews

Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.

Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.

However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.

Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.

Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.

With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.

Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.

The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.

The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.

The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.

Outcomes

Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).

CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).

The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.

In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.

Impact of specific drugs

In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).

Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m² increments (HR=0.82, P<0.0001).

In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m² (HR=0.22, P=0.020) and at doses of 450 mg/m² or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m² or greater (HR=0.41, P=0.046).

Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).

Limitations and implications

The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.

And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.

The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.

“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”

“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”

Pregnant woman

Photo by Nina Matthews

Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.

Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.

However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.

Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.

Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.

With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.

Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.

The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.

The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.

The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.

Outcomes

Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).

CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).

The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.

In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.

Impact of specific drugs

In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).

Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m² increments (HR=0.82, P<0.0001).

In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m² (HR=0.22, P=0.020) and at doses of 450 mg/m² or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m² or greater (HR=0.41, P=0.046).

Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).

Limitations and implications

The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.

And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.

The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.

“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”

“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”

Pregnant woman

Photo by Nina Matthews

Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.

Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.

However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.

Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.

Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.

With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.

Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.

The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.

The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.

The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.

Outcomes

Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).

CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).

The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.

In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.

Impact of specific drugs

In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).

Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m² increments (HR=0.82, P<0.0001).

In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m² (HR=0.22, P=0.020) and at doses of 450 mg/m² or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m² or greater (HR=0.41, P=0.046).

Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).

Limitations and implications

The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.

And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.

The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.

“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”

“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”

Men install laminate flooring

while woman looks on

US government agencies have released a revised report on the health risks associated with formaldehyde in certain types of laminate flooring.

The new report corrects a previous error and reveals an increase in the estimated lifetime risk of cancers, including leukemias, for individuals who regularly breathe in formaldehyde from the flooring.

The report also suggests that irritation and breathing problems can result in anyone exposed to the flooring.

The report was compiled by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention’s National Center for Environmental Health (NCEH).

About the report

On March 1, 2015, the CBS news program 60 Minutes reported that an American company, Lumber Liquidators®, was selling laminate wood flooring produced in China that released elevated levels of formaldehyde.

Based on this allegation, the US Consumer Product Safety Commission (CPSC) tested laminate flooring samples manufactured in China from 2012 to 2014 that were sold at Lumber Liquidators® stores. The CPSC then requested that the NCEH and ATSDR evaluate the test results for possible health effects.

The NCEH and ATSDR published a report detailing the possible health effects on February 10, 2016. But the report was pulled on February 19, 2016, after the agencies were informed that the report’s indoor air model incorporated an incorrect value for ceiling height.

As a result, the health risks were calculated using airborne concentration estimates about 3 times lower than they should have been.

Since the discovery of the error, the NCEH and ATSDR revised the value in the model, conducted a review of the revised results, and re-evaluated the possible health implications.

In addition, the revised report has been reviewed by outside experts and experts from the CPSC, the US Environmental Protection Agency, and the US Department of Housing and Urban Development.

Results 

The revised report concludes that irritation and breathing problems could occur in everyone exposed to formaldehyde in the tested flooring.

The previous report suggested such problems might only occur in sensitive groups (eg, children) and people with pre-existing health conditions (eg, asthma).

The new report also increased the estimated lifetime cancer risk from breathing the highest levels of formaldehyde from the affected flooring all day, every day for 2 years.

The previous estimate of lifetime cancer risk was 2 to 9 extra cases for every 100,000 people.

The new estimate is 6 to 30 extra cases per 100,000 people.

There is conflicting data regarding the types of cancers associated with formaldehyde exposure, but many studies have suggested that formaldehyde causes cancer of the nasopharynx, sinuses, and nasal cavity, as well as leukemia, particularly myeloid leukemia.

Recommendations

Although the revised report shows an increase in health risks associated with the flooring, the NCEH and ATSDR said their recommendations remain the same.

They recommend that people with the affected flooring:

• Reduce their exposure to formaldehyde in their homes by opening windows, running exhaust fans, avoiding use of other products containing formaldehyde, etc.
• See a doctor for ongoing health symptoms such as breathing problems or irritation of the eyes, nose, or throat
• Weigh the pros and cons of professional air testing
• Consult a professional before removing the flooring, as removing it may release more formaldehyde into the home.
  

Men install laminate flooring

while woman looks on

US government agencies have released a revised report on the health risks associated with formaldehyde in certain types of laminate flooring.

The new report corrects a previous error and reveals an increase in the estimated lifetime risk of cancers, including leukemias, for individuals who regularly breathe in formaldehyde from the flooring.

The report also suggests that irritation and breathing problems can result in anyone exposed to the flooring.

The report was compiled by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention’s National Center for Environmental Health (NCEH).

About the report

On March 1, 2015, the CBS news program 60 Minutes reported that an American company, Lumber Liquidators®, was selling laminate wood flooring produced in China that released elevated levels of formaldehyde.

Based on this allegation, the US Consumer Product Safety Commission (CPSC) tested laminate flooring samples manufactured in China from 2012 to 2014 that were sold at Lumber Liquidators® stores. The CPSC then requested that the NCEH and ATSDR evaluate the test results for possible health effects.

The NCEH and ATSDR published a report detailing the possible health effects on February 10, 2016. But the report was pulled on February 19, 2016, after the agencies were informed that the report’s indoor air model incorporated an incorrect value for ceiling height.

As a result, the health risks were calculated using airborne concentration estimates about 3 times lower than they should have been.

Since the discovery of the error, the NCEH and ATSDR revised the value in the model, conducted a review of the revised results, and re-evaluated the possible health implications.

In addition, the revised report has been reviewed by outside experts and experts from the CPSC, the US Environmental Protection Agency, and the US Department of Housing and Urban Development.

Results 

The revised report concludes that irritation and breathing problems could occur in everyone exposed to formaldehyde in the tested flooring.

The previous report suggested such problems might only occur in sensitive groups (eg, children) and people with pre-existing health conditions (eg, asthma).

The new report also increased the estimated lifetime cancer risk from breathing the highest levels of formaldehyde from the affected flooring all day, every day for 2 years.

The previous estimate of lifetime cancer risk was 2 to 9 extra cases for every 100,000 people.

The new estimate is 6 to 30 extra cases per 100,000 people.

There is conflicting data regarding the types of cancers associated with formaldehyde exposure, but many studies have suggested that formaldehyde causes cancer of the nasopharynx, sinuses, and nasal cavity, as well as leukemia, particularly myeloid leukemia.

Recommendations

Although the revised report shows an increase in health risks associated with the flooring, the NCEH and ATSDR said their recommendations remain the same.

They recommend that people with the affected flooring:

• Reduce their exposure to formaldehyde in their homes by opening windows, running exhaust fans, avoiding use of other products containing formaldehyde, etc.
• See a doctor for ongoing health symptoms such as breathing problems or irritation of the eyes, nose, or throat
• Weigh the pros and cons of professional air testing
• Consult a professional before removing the flooring, as removing it may release more formaldehyde into the home.
  

Men install laminate flooring

while woman looks on

US government agencies have released a revised report on the health risks associated with formaldehyde in certain types of laminate flooring.

The new report corrects a previous error and reveals an increase in the estimated lifetime risk of cancers, including leukemias, for individuals who regularly breathe in formaldehyde from the flooring.

The report also suggests that irritation and breathing problems can result in anyone exposed to the flooring.

The report was compiled by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention’s National Center for Environmental Health (NCEH).

About the report

On March 1, 2015, the CBS news program 60 Minutes reported that an American company, Lumber Liquidators®, was selling laminate wood flooring produced in China that released elevated levels of formaldehyde.

Based on this allegation, the US Consumer Product Safety Commission (CPSC) tested laminate flooring samples manufactured in China from 2012 to 2014 that were sold at Lumber Liquidators® stores. The CPSC then requested that the NCEH and ATSDR evaluate the test results for possible health effects.

The NCEH and ATSDR published a report detailing the possible health effects on February 10, 2016. But the report was pulled on February 19, 2016, after the agencies were informed that the report’s indoor air model incorporated an incorrect value for ceiling height.

As a result, the health risks were calculated using airborne concentration estimates about 3 times lower than they should have been.

Since the discovery of the error, the NCEH and ATSDR revised the value in the model, conducted a review of the revised results, and re-evaluated the possible health implications.

In addition, the revised report has been reviewed by outside experts and experts from the CPSC, the US Environmental Protection Agency, and the US Department of Housing and Urban Development.

Results 

The revised report concludes that irritation and breathing problems could occur in everyone exposed to formaldehyde in the tested flooring.

The previous report suggested such problems might only occur in sensitive groups (eg, children) and people with pre-existing health conditions (eg, asthma).

The new report also increased the estimated lifetime cancer risk from breathing the highest levels of formaldehyde from the affected flooring all day, every day for 2 years.

The previous estimate of lifetime cancer risk was 2 to 9 extra cases for every 100,000 people.

The new estimate is 6 to 30 extra cases per 100,000 people.

There is conflicting data regarding the types of cancers associated with formaldehyde exposure, but many studies have suggested that formaldehyde causes cancer of the nasopharynx, sinuses, and nasal cavity, as well as leukemia, particularly myeloid leukemia.

Recommendations

Although the revised report shows an increase in health risks associated with the flooring, the NCEH and ATSDR said their recommendations remain the same.

They recommend that people with the affected flooring:

• Reduce their exposure to formaldehyde in their homes by opening windows, running exhaust fans, avoiding use of other products containing formaldehyde, etc.
• See a doctor for ongoing health symptoms such as breathing problems or irritation of the eyes, nose, or throat
• Weigh the pros and cons of professional air testing
• Consult a professional before removing the flooring, as removing it may release more formaldehyde into the home.
  

Plasmodium parasite

infecting a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

Researchers say they have documented how competition among different malaria parasite strains in human hosts could influence the spread of drug resistance.

“We found that when hosts are co-infected with drug-resistant and drug-sensitive strains, both strains are competitively suppressed,” said Mary Bushman, of Emory University in Atlanta, Georgia.

“Antimalarial therapy, by clearing drug-sensitive parasites from mixed infections, may result in competitive release of resistant strains.”

Bushman and her colleagues described these findings in Proceedings of the Royal Society B.

The researchers focused on the parasite Plasmodium falciparum, which has developed resistance to former first-line therapies chloroquine and sulfadoxine-pyrimethamine.

“We’re now down to our last treatment, artemisinin combination therapy, or ACT, and resistance to that recently emerged in Southeast Asia,” Bushman said. “If ACT resistance continues to follow the same pattern, the world may soon be without reliable antimalarial drugs.”

In addition, people infected with P falciparum often have multiple strains of the parasite, especially in high-transmission areas such as sub-Saharan Africa, where infectious mosquito bites occur frequently. Many people have developed partial immunity, making asymptomatic infections common and further complicating control efforts.

With previous work in lab mice, the researchers found that competition between mixed strains of malaria parasites were a crucial determinant to the spread of resistance.

“In the mouse studies, we found that drug-sensitive parasites suppress resistant parasites,” said Jaap de Roode, PhD, of Emory University.

“We also found that by clearing these sensitive parasites with drugs, the resistant parasites had a big advantage, growing up to high numbers and transmitting to mosquitoes at high rates. Ever since doing that work, I have wanted to see if the same could apply to humans.”

To find out, Dr de Roode and his colleagues analyzed 1341 blood samples from untreated children with malaria living in Angola, Ghana, and Tanzania.

The researchers extracted the DNA of malaria parasites from the blood samples and used polymerase chain reaction technology to determine the densities of drug-resistant strains and drug-sensitive ones. About 15% of the samples had mixtures of both types.

Analyses showed that, in mixed-strain infections, densities of chloroquine-sensitive and chloroquine-resistant strains were reduced in the presence of competitors.

The results also showed that, in the absence of chloroquine, the resistant strains had lower densities than sensitive strains.

“The results were really clear cut, which rarely happens in human studies,” Bushman said. “We found almost complete consistency between the 3 data sets [divided by country].”

Bushman added that the tendency is to use a “one-size-fits-all” strategy for controlling malaria, but this research suggests that more tailored approaches are needed.

For example, a strategy of mass drug administration might be effective in a place with a low prevalence of malaria and less likelihood of mixed-strain infections. However, that same strategy might actually boost drug resistance without reducing the burden of disease in areas where most of the population is infected with multiple strains of malaria parasites.

“The epidemiology of malaria infection is different for different places and different conditions,” Bushman said. “We hope that our work will spur development of new strategies to minimize resistance while maximizing the benefits of control measures.”

However, more questions must be answered to guide the development of these new strategies.

“As a first step, we need to determine if the observed suppression of resistance in humans also results in reduced transmission to mosquitoes,” Dr de Roode said.

Another avenue to explore is resistance among patients who have received antimalarial treatment.

“We need to find out if drug treatment of people infected with malaria removes competition and gives resistance a boost, as we have found in mice before,” Dr de Roode noted.

Plasmodium parasite

infecting a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

Researchers say they have documented how competition among different malaria parasite strains in human hosts could influence the spread of drug resistance.

“We found that when hosts are co-infected with drug-resistant and drug-sensitive strains, both strains are competitively suppressed,” said Mary Bushman, of Emory University in Atlanta, Georgia.

“Antimalarial therapy, by clearing drug-sensitive parasites from mixed infections, may result in competitive release of resistant strains.”

Bushman and her colleagues described these findings in Proceedings of the Royal Society B.

The researchers focused on the parasite Plasmodium falciparum, which has developed resistance to former first-line therapies chloroquine and sulfadoxine-pyrimethamine.

“We’re now down to our last treatment, artemisinin combination therapy, or ACT, and resistance to that recently emerged in Southeast Asia,” Bushman said. “If ACT resistance continues to follow the same pattern, the world may soon be without reliable antimalarial drugs.”

In addition, people infected with P falciparum often have multiple strains of the parasite, especially in high-transmission areas such as sub-Saharan Africa, where infectious mosquito bites occur frequently. Many people have developed partial immunity, making asymptomatic infections common and further complicating control efforts.

With previous work in lab mice, the researchers found that competition between mixed strains of malaria parasites were a crucial determinant to the spread of resistance.

“In the mouse studies, we found that drug-sensitive parasites suppress resistant parasites,” said Jaap de Roode, PhD, of Emory University.

“We also found that by clearing these sensitive parasites with drugs, the resistant parasites had a big advantage, growing up to high numbers and transmitting to mosquitoes at high rates. Ever since doing that work, I have wanted to see if the same could apply to humans.”

To find out, Dr de Roode and his colleagues analyzed 1341 blood samples from untreated children with malaria living in Angola, Ghana, and Tanzania.

The researchers extracted the DNA of malaria parasites from the blood samples and used polymerase chain reaction technology to determine the densities of drug-resistant strains and drug-sensitive ones. About 15% of the samples had mixtures of both types.

Analyses showed that, in mixed-strain infections, densities of chloroquine-sensitive and chloroquine-resistant strains were reduced in the presence of competitors.

The results also showed that, in the absence of chloroquine, the resistant strains had lower densities than sensitive strains.

“The results were really clear cut, which rarely happens in human studies,” Bushman said. “We found almost complete consistency between the 3 data sets [divided by country].”

Bushman added that the tendency is to use a “one-size-fits-all” strategy for controlling malaria, but this research suggests that more tailored approaches are needed.

For example, a strategy of mass drug administration might be effective in a place with a low prevalence of malaria and less likelihood of mixed-strain infections. However, that same strategy might actually boost drug resistance without reducing the burden of disease in areas where most of the population is infected with multiple strains of malaria parasites.

“The epidemiology of malaria infection is different for different places and different conditions,” Bushman said. “We hope that our work will spur development of new strategies to minimize resistance while maximizing the benefits of control measures.”

However, more questions must be answered to guide the development of these new strategies.

“As a first step, we need to determine if the observed suppression of resistance in humans also results in reduced transmission to mosquitoes,” Dr de Roode said.

Another avenue to explore is resistance among patients who have received antimalarial treatment.

“We need to find out if drug treatment of people infected with malaria removes competition and gives resistance a boost, as we have found in mice before,” Dr de Roode noted.

Plasmodium parasite

infecting a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

Researchers say they have documented how competition among different malaria parasite strains in human hosts could influence the spread of drug resistance.

“We found that when hosts are co-infected with drug-resistant and drug-sensitive strains, both strains are competitively suppressed,” said Mary Bushman, of Emory University in Atlanta, Georgia.

“Antimalarial therapy, by clearing drug-sensitive parasites from mixed infections, may result in competitive release of resistant strains.”

Bushman and her colleagues described these findings in Proceedings of the Royal Society B.

The researchers focused on the parasite Plasmodium falciparum, which has developed resistance to former first-line therapies chloroquine and sulfadoxine-pyrimethamine.

“We’re now down to our last treatment, artemisinin combination therapy, or ACT, and resistance to that recently emerged in Southeast Asia,” Bushman said. “If ACT resistance continues to follow the same pattern, the world may soon be without reliable antimalarial drugs.”

In addition, people infected with P falciparum often have multiple strains of the parasite, especially in high-transmission areas such as sub-Saharan Africa, where infectious mosquito bites occur frequently. Many people have developed partial immunity, making asymptomatic infections common and further complicating control efforts.

With previous work in lab mice, the researchers found that competition between mixed strains of malaria parasites were a crucial determinant to the spread of resistance.

“In the mouse studies, we found that drug-sensitive parasites suppress resistant parasites,” said Jaap de Roode, PhD, of Emory University.

“We also found that by clearing these sensitive parasites with drugs, the resistant parasites had a big advantage, growing up to high numbers and transmitting to mosquitoes at high rates. Ever since doing that work, I have wanted to see if the same could apply to humans.”

To find out, Dr de Roode and his colleagues analyzed 1341 blood samples from untreated children with malaria living in Angola, Ghana, and Tanzania.

The researchers extracted the DNA of malaria parasites from the blood samples and used polymerase chain reaction technology to determine the densities of drug-resistant strains and drug-sensitive ones. About 15% of the samples had mixtures of both types.

Analyses showed that, in mixed-strain infections, densities of chloroquine-sensitive and chloroquine-resistant strains were reduced in the presence of competitors.

The results also showed that, in the absence of chloroquine, the resistant strains had lower densities than sensitive strains.

“The results were really clear cut, which rarely happens in human studies,” Bushman said. “We found almost complete consistency between the 3 data sets [divided by country].”

Bushman added that the tendency is to use a “one-size-fits-all” strategy for controlling malaria, but this research suggests that more tailored approaches are needed.

For example, a strategy of mass drug administration might be effective in a place with a low prevalence of malaria and less likelihood of mixed-strain infections. However, that same strategy might actually boost drug resistance without reducing the burden of disease in areas where most of the population is infected with multiple strains of malaria parasites.

“The epidemiology of malaria infection is different for different places and different conditions,” Bushman said. “We hope that our work will spur development of new strategies to minimize resistance while maximizing the benefits of control measures.”

However, more questions must be answered to guide the development of these new strategies.

“As a first step, we need to determine if the observed suppression of resistance in humans also results in reduced transmission to mosquitoes,” Dr de Roode said.

Another avenue to explore is resistance among patients who have received antimalarial treatment.

“We need to find out if drug treatment of people infected with malaria removes competition and gives resistance a boost, as we have found in mice before,” Dr de Roode noted.

Diffuse large B-cell lymphoma

New research suggests there are 4 different “locks” that keep the CARD11 protein in check.

Researchers say these locks, also known as “repressive elements,” work together to prevent unwarranted CARD11 signaling.

But mutations in CARD11 can perturb or bypass the action of the repressive elements, which leads to a level of hyperactive CARD11 signaling that supports lymphoma growth.

Joel Pomerantz, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in 2 articles published in The Journal of Biological Chemistry.^1,2

The researchers noted that mutated CARD11 proteins are sometimes found in patients with lymphoma, particularly diffuse large B-cell lymphoma. But none of the mutations exist in the “lock region” of CARD11, known as the autoinhibitory domain.

To find out why, the team conducted experiments with T cells. They first genetically deleted CARD11’s autoinhibitory domain so that the protein was always “on” and signaling.

Then, to figure out which region of the autoinhibitory domain accounted for its function, the researchers systematically deleted 6 different segments of it one at a time, rather than deleting the whole thing.

They expected most of the deletions to keep CARD11 inactive and 1 or 2 to “unlock” it. However, none of the deletions unlocked it, which suggested there was more than 1 repressive element within the autoinhibitory domain.

To see if that was the case and to find out how many repressive elements there might be, the researchers deleted the full autoinhibitory domain again, then added back small regions of it.

In this way, they pieced together the presence of 4 different biochemical regions, or repressive elements, that are each capable of locking CARD11 on their own.

“Having 4 redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr Pomerantz said. “A mutation in any one of the repressive elements would only unlock 1 of the 4 locks, keeping CARD11’s signaling under the control of the other 3.”

So where do the lymphoma-associated mutations occur, and how do they circumvent CARD11’s quadruple locks? Clinical data show that the mutations occur in 3 other regions of CARD11—the CARD, LATCH, and coiled-coil regions.

Dr Pomerantz and his colleagues conducted biochemical tests on T cells and found that those 3 regions clasp the autoinhibitory domain to keep CARD11’s activity on lockdown. This makes sense, Dr Pomerantz said, because CARD11 uses those same regions to connect with other signaling proteins to send its message.

“When they are interacting with the autoinhibitory domain, they can’t be interacting with other proteins,” he said.

According to Dr Pomerantz, single mutations in the CARD, LATCH, or coiled-coil regions appear to be sufficient to disable the 4 repressive elements. And the ultimate goal is to advance the development of therapies that rein in hyperactive CARD11 in patients with lymphoma.

“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug,” he said. “We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis.”

1. Cooperative Control of Caspase Recruitment Domain-Containing Protein 11 (CARD11) Signaling by an Unusual Array of Redundant Repressive Elements

2. Intramolecular Interactions and Regulation of Cofactor Binding by the Four Repressive Elements in the Caspase Recruitment Domain-Containing Protein 11 (CARD11) Inhibitory Domain

Diffuse large B-cell lymphoma

New research suggests there are 4 different “locks” that keep the CARD11 protein in check.

Researchers say these locks, also known as “repressive elements,” work together to prevent unwarranted CARD11 signaling.

But mutations in CARD11 can perturb or bypass the action of the repressive elements, which leads to a level of hyperactive CARD11 signaling that supports lymphoma growth.

Joel Pomerantz, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in 2 articles published in The Journal of Biological Chemistry.^1,2

The researchers noted that mutated CARD11 proteins are sometimes found in patients with lymphoma, particularly diffuse large B-cell lymphoma. But none of the mutations exist in the “lock region” of CARD11, known as the autoinhibitory domain.

To find out why, the team conducted experiments with T cells. They first genetically deleted CARD11’s autoinhibitory domain so that the protein was always “on” and signaling.

Then, to figure out which region of the autoinhibitory domain accounted for its function, the researchers systematically deleted 6 different segments of it one at a time, rather than deleting the whole thing.

They expected most of the deletions to keep CARD11 inactive and 1 or 2 to “unlock” it. However, none of the deletions unlocked it, which suggested there was more than 1 repressive element within the autoinhibitory domain.

To see if that was the case and to find out how many repressive elements there might be, the researchers deleted the full autoinhibitory domain again, then added back small regions of it.

In this way, they pieced together the presence of 4 different biochemical regions, or repressive elements, that are each capable of locking CARD11 on their own.

“Having 4 redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr Pomerantz said. “A mutation in any one of the repressive elements would only unlock 1 of the 4 locks, keeping CARD11’s signaling under the control of the other 3.”

So where do the lymphoma-associated mutations occur, and how do they circumvent CARD11’s quadruple locks? Clinical data show that the mutations occur in 3 other regions of CARD11—the CARD, LATCH, and coiled-coil regions.

Dr Pomerantz and his colleagues conducted biochemical tests on T cells and found that those 3 regions clasp the autoinhibitory domain to keep CARD11’s activity on lockdown. This makes sense, Dr Pomerantz said, because CARD11 uses those same regions to connect with other signaling proteins to send its message.

“When they are interacting with the autoinhibitory domain, they can’t be interacting with other proteins,” he said.

According to Dr Pomerantz, single mutations in the CARD, LATCH, or coiled-coil regions appear to be sufficient to disable the 4 repressive elements. And the ultimate goal is to advance the development of therapies that rein in hyperactive CARD11 in patients with lymphoma.

“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug,” he said. “We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis.”

1. Cooperative Control of Caspase Recruitment Domain-Containing Protein 11 (CARD11) Signaling by an Unusual Array of Redundant Repressive Elements

2. Intramolecular Interactions and Regulation of Cofactor Binding by the Four Repressive Elements in the Caspase Recruitment Domain-Containing Protein 11 (CARD11) Inhibitory Domain

Diffuse large B-cell lymphoma

New research suggests there are 4 different “locks” that keep the CARD11 protein in check.

Researchers say these locks, also known as “repressive elements,” work together to prevent unwarranted CARD11 signaling.

But mutations in CARD11 can perturb or bypass the action of the repressive elements, which leads to a level of hyperactive CARD11 signaling that supports lymphoma growth.

Joel Pomerantz, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in 2 articles published in The Journal of Biological Chemistry.^1,2

The researchers noted that mutated CARD11 proteins are sometimes found in patients with lymphoma, particularly diffuse large B-cell lymphoma. But none of the mutations exist in the “lock region” of CARD11, known as the autoinhibitory domain.

To find out why, the team conducted experiments with T cells. They first genetically deleted CARD11’s autoinhibitory domain so that the protein was always “on” and signaling.

Then, to figure out which region of the autoinhibitory domain accounted for its function, the researchers systematically deleted 6 different segments of it one at a time, rather than deleting the whole thing.

They expected most of the deletions to keep CARD11 inactive and 1 or 2 to “unlock” it. However, none of the deletions unlocked it, which suggested there was more than 1 repressive element within the autoinhibitory domain.

To see if that was the case and to find out how many repressive elements there might be, the researchers deleted the full autoinhibitory domain again, then added back small regions of it.

In this way, they pieced together the presence of 4 different biochemical regions, or repressive elements, that are each capable of locking CARD11 on their own.

“Having 4 redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr Pomerantz said. “A mutation in any one of the repressive elements would only unlock 1 of the 4 locks, keeping CARD11’s signaling under the control of the other 3.”

So where do the lymphoma-associated mutations occur, and how do they circumvent CARD11’s quadruple locks? Clinical data show that the mutations occur in 3 other regions of CARD11—the CARD, LATCH, and coiled-coil regions.

Dr Pomerantz and his colleagues conducted biochemical tests on T cells and found that those 3 regions clasp the autoinhibitory domain to keep CARD11’s activity on lockdown. This makes sense, Dr Pomerantz said, because CARD11 uses those same regions to connect with other signaling proteins to send its message.

“When they are interacting with the autoinhibitory domain, they can’t be interacting with other proteins,” he said.

According to Dr Pomerantz, single mutations in the CARD, LATCH, or coiled-coil regions appear to be sufficient to disable the 4 repressive elements. And the ultimate goal is to advance the development of therapies that rein in hyperactive CARD11 in patients with lymphoma.

“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug,” he said. “We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis.”

1. Cooperative Control of Caspase Recruitment Domain-Containing Protein 11 (CARD11) Signaling by an Unusual Array of Redundant Repressive Elements

2. Intramolecular Interactions and Regulation of Cofactor Binding by the Four Repressive Elements in the Caspase Recruitment Domain-Containing Protein 11 (CARD11) Inhibitory Domain

HSCT preparation

Photo by Chad McNeeley

Results from the 2014 Transplant Activity Survey suggest the use of hematopoietic stem cell transplant (HSCT) is still on the rise in Europe.

The European Society for Blood and Marrow Transplantation (EBMT) introduced this survey in 1990 to assess the use of HSCT in Europe.

Every year, all EBMT members and affiliated teams report their number of transplant patients by indication, donor type, and stem cell source.

Results from the 2014 survey revealed that 40,829 HSCTs were conducted in 36,469 patients at 656 centers in 47 countries. Fifty-seven percent of these transplants were autologous (n=20,704), and 43% were allogeneic (n=15,765).

When compared to data from the 2013 survey, the total number of transplants increased by 4.1%—4.5% for allogeneic HSCT and 3.8% for autologous HSCT.

The greatest increases in allogeneic HSCT occurred in Romania, Russia, Turkey, Croatia, Lithuania, and Serbia. And the greatest increases for autologous HSCT occurred in Romania, Serbia, Russia, Turkey, and Iran.

The most common indication for HSCT in 2014 was lymphoid neoplasias (57%, n=20,802), followed by leukemias (33%, n=11,853), non-malignant disorders (6%, n=2203), and solid tumors (4%, n=1458).

Compared to data from 2013, there was an increase in allogeneic HSCT for a few indications. There was a 13% increase in allogeneic HSCT for acute myeloid leukemia in first complete remission, a 14% increase for myeloproliferative neoplasms, and a 12% increase for severe aplastic anemia.

For autologous HSCT, there was a 21% decrease for chronic lymphocytic leukemia, a 5% increase for myeloma, a 44% increase for amyloidosis, an 8% increase for Hodgkin lymphoma, and a 40% increase for autoimmune diseases.

For more details, see the full report in Bone Marrow Transplantation.

HSCT preparation

Photo by Chad McNeeley

Results from the 2014 Transplant Activity Survey suggest the use of hematopoietic stem cell transplant (HSCT) is still on the rise in Europe.

The European Society for Blood and Marrow Transplantation (EBMT) introduced this survey in 1990 to assess the use of HSCT in Europe.

Every year, all EBMT members and affiliated teams report their number of transplant patients by indication, donor type, and stem cell source.

Results from the 2014 survey revealed that 40,829 HSCTs were conducted in 36,469 patients at 656 centers in 47 countries. Fifty-seven percent of these transplants were autologous (n=20,704), and 43% were allogeneic (n=15,765).

When compared to data from the 2013 survey, the total number of transplants increased by 4.1%—4.5% for allogeneic HSCT and 3.8% for autologous HSCT.

The greatest increases in allogeneic HSCT occurred in Romania, Russia, Turkey, Croatia, Lithuania, and Serbia. And the greatest increases for autologous HSCT occurred in Romania, Serbia, Russia, Turkey, and Iran.

The most common indication for HSCT in 2014 was lymphoid neoplasias (57%, n=20,802), followed by leukemias (33%, n=11,853), non-malignant disorders (6%, n=2203), and solid tumors (4%, n=1458).

Compared to data from 2013, there was an increase in allogeneic HSCT for a few indications. There was a 13% increase in allogeneic HSCT for acute myeloid leukemia in first complete remission, a 14% increase for myeloproliferative neoplasms, and a 12% increase for severe aplastic anemia.

For autologous HSCT, there was a 21% decrease for chronic lymphocytic leukemia, a 5% increase for myeloma, a 44% increase for amyloidosis, an 8% increase for Hodgkin lymphoma, and a 40% increase for autoimmune diseases.

For more details, see the full report in Bone Marrow Transplantation.

HSCT preparation

Photo by Chad McNeeley

Results from the 2014 Transplant Activity Survey suggest the use of hematopoietic stem cell transplant (HSCT) is still on the rise in Europe.

The European Society for Blood and Marrow Transplantation (EBMT) introduced this survey in 1990 to assess the use of HSCT in Europe.

Every year, all EBMT members and affiliated teams report their number of transplant patients by indication, donor type, and stem cell source.

Results from the 2014 survey revealed that 40,829 HSCTs were conducted in 36,469 patients at 656 centers in 47 countries. Fifty-seven percent of these transplants were autologous (n=20,704), and 43% were allogeneic (n=15,765).

When compared to data from the 2013 survey, the total number of transplants increased by 4.1%—4.5% for allogeneic HSCT and 3.8% for autologous HSCT.

The greatest increases in allogeneic HSCT occurred in Romania, Russia, Turkey, Croatia, Lithuania, and Serbia. And the greatest increases for autologous HSCT occurred in Romania, Serbia, Russia, Turkey, and Iran.

The most common indication for HSCT in 2014 was lymphoid neoplasias (57%, n=20,802), followed by leukemias (33%, n=11,853), non-malignant disorders (6%, n=2203), and solid tumors (4%, n=1458).

Compared to data from 2013, there was an increase in allogeneic HSCT for a few indications. There was a 13% increase in allogeneic HSCT for acute myeloid leukemia in first complete remission, a 14% increase for myeloproliferative neoplasms, and a 12% increase for severe aplastic anemia.

For autologous HSCT, there was a 21% decrease for chronic lymphocytic leukemia, a 5% increase for myeloma, a 44% increase for amyloidosis, an 8% increase for Hodgkin lymphoma, and a 40% increase for autoimmune diseases.

For more details, see the full report in Bone Marrow Transplantation.

Patient consults pharmacist

Photo by Rhoda Baer

A new study suggests that older adults in the US may be using potentially deadly combinations of prescription drugs, over-the-counter medications, and dietary supplements.

Investigators observed a significant increase in the proportion of adults ages 62 to 85 who were at risk of major drug-drug interactions—from 8% in 2005-2006 to 15% in 2010-2011.

Most of the combinations consisted of preventative cardiovascular medications such as antiplatelet drugs, statins, and omega-3 fish oil supplements.

Dima Mazen Qato, PharmD, of the University of Illinois at Chicago, and her colleagues reported these results in JAMA Internal Medicine.

The investigators examined changes in medication use in a nationally representative sample of adults between the ages of 62 and 85. The team conducted in-home interviews to accurately identify medications. They interviewed 2351 subjects in 2005-2006 and 2206 subjects in 2010-2011.

The results showed a significant increase in the proportion of subjects taking at least 1 prescription medication—from 84.1% in 2005-2006 to 87.7% in 2010-2011 (P=0.003).

The proportion of subjects taking at least 5 prescription medications rose significantly as well—from 30.6% to 35.8% (P=0.02).

The investigators said factors that may account for these increases include the implementation of Medicare Part D, changes in treatment guidelines, and the increased availability of generics for many commonly used drugs.

As an example, use of the statin simvastatin (Zocor)—which became available as a generic in 2006—rose from 10.3% in 2005-2006 to 22.5% in 2010-2011.

The use of over-the-counter medications declined from 44.4% in 2005-2006 to 37.9% in 2010-2011 (P<0.001), while the use of dietary supplements increased from 51.8% to 63.7% (P<0.001).

Drug-drug interactions

The investigators identified 15 potentially life-threatening combinations of the most commonly used medications and supplements in the study.

They found that 15.1% of subjects were at risk for a potential major drug-drug interaction in 2010-2011, compared with an estimated 8.4% in 2005-2006 (P<0.001).

Dr Qato noted that more than half of the potential interactions involved a nonprescription medication or dietary supplement.

Preventative cardiovascular medications such as statins (particularly, simvastatin), antiplatelet drugs (such as clopidogrel and aspirin), and supplements (specifically, omega-3 fish oil) accounted for the vast majority of these combinations.

“Many older patients seeking to improve their cardiovascular health are also regularly using interacting drug combinations that may worsen cardiovascular risk,” Dr Qato said.

“For example, the use of clopidogrel in combination with the proton-pump inhibitor omeprazole, aspirin, or naproxen—all over-the-counter medications—is associated with an increased risk of heart attacks, bleeding complications, or death. However, about 1.8%—or 1 million—older adults regularly use clopidogrel in interacting combinations.”

Dr Qato added that healthcare professionals should consider the adverse effects of commonly used prescription and nonprescription medication combinations when treating older adults and counsel patients about the risks.

“Improving safety in the use of interacting medication combinations has the potential to reduce preventable, potentially fatal, adverse drug events,” she said.

Patient consults pharmacist

Photo by Rhoda Baer

A new study suggests that older adults in the US may be using potentially deadly combinations of prescription drugs, over-the-counter medications, and dietary supplements.

Investigators observed a significant increase in the proportion of adults ages 62 to 85 who were at risk of major drug-drug interactions—from 8% in 2005-2006 to 15% in 2010-2011.

Most of the combinations consisted of preventative cardiovascular medications such as antiplatelet drugs, statins, and omega-3 fish oil supplements.

Dima Mazen Qato, PharmD, of the University of Illinois at Chicago, and her colleagues reported these results in JAMA Internal Medicine.

The investigators examined changes in medication use in a nationally representative sample of adults between the ages of 62 and 85. The team conducted in-home interviews to accurately identify medications. They interviewed 2351 subjects in 2005-2006 and 2206 subjects in 2010-2011.

The results showed a significant increase in the proportion of subjects taking at least 1 prescription medication—from 84.1% in 2005-2006 to 87.7% in 2010-2011 (P=0.003).

The proportion of subjects taking at least 5 prescription medications rose significantly as well—from 30.6% to 35.8% (P=0.02).

The investigators said factors that may account for these increases include the implementation of Medicare Part D, changes in treatment guidelines, and the increased availability of generics for many commonly used drugs.

As an example, use of the statin simvastatin (Zocor)—which became available as a generic in 2006—rose from 10.3% in 2005-2006 to 22.5% in 2010-2011.

The use of over-the-counter medications declined from 44.4% in 2005-2006 to 37.9% in 2010-2011 (P<0.001), while the use of dietary supplements increased from 51.8% to 63.7% (P<0.001).

Drug-drug interactions

The investigators identified 15 potentially life-threatening combinations of the most commonly used medications and supplements in the study.

They found that 15.1% of subjects were at risk for a potential major drug-drug interaction in 2010-2011, compared with an estimated 8.4% in 2005-2006 (P<0.001).

Dr Qato noted that more than half of the potential interactions involved a nonprescription medication or dietary supplement.

Preventative cardiovascular medications such as statins (particularly, simvastatin), antiplatelet drugs (such as clopidogrel and aspirin), and supplements (specifically, omega-3 fish oil) accounted for the vast majority of these combinations.

“Many older patients seeking to improve their cardiovascular health are also regularly using interacting drug combinations that may worsen cardiovascular risk,” Dr Qato said.

“For example, the use of clopidogrel in combination with the proton-pump inhibitor omeprazole, aspirin, or naproxen—all over-the-counter medications—is associated with an increased risk of heart attacks, bleeding complications, or death. However, about 1.8%—or 1 million—older adults regularly use clopidogrel in interacting combinations.”

Dr Qato added that healthcare professionals should consider the adverse effects of commonly used prescription and nonprescription medication combinations when treating older adults and counsel patients about the risks.

“Improving safety in the use of interacting medication combinations has the potential to reduce preventable, potentially fatal, adverse drug events,” she said.

Patient consults pharmacist

Photo by Rhoda Baer

A new study suggests that older adults in the US may be using potentially deadly combinations of prescription drugs, over-the-counter medications, and dietary supplements.

Investigators observed a significant increase in the proportion of adults ages 62 to 85 who were at risk of major drug-drug interactions—from 8% in 2005-2006 to 15% in 2010-2011.

Most of the combinations consisted of preventative cardiovascular medications such as antiplatelet drugs, statins, and omega-3 fish oil supplements.

Dima Mazen Qato, PharmD, of the University of Illinois at Chicago, and her colleagues reported these results in JAMA Internal Medicine.

The investigators examined changes in medication use in a nationally representative sample of adults between the ages of 62 and 85. The team conducted in-home interviews to accurately identify medications. They interviewed 2351 subjects in 2005-2006 and 2206 subjects in 2010-2011.

The results showed a significant increase in the proportion of subjects taking at least 1 prescription medication—from 84.1% in 2005-2006 to 87.7% in 2010-2011 (P=0.003).

The proportion of subjects taking at least 5 prescription medications rose significantly as well—from 30.6% to 35.8% (P=0.02).

The investigators said factors that may account for these increases include the implementation of Medicare Part D, changes in treatment guidelines, and the increased availability of generics for many commonly used drugs.

As an example, use of the statin simvastatin (Zocor)—which became available as a generic in 2006—rose from 10.3% in 2005-2006 to 22.5% in 2010-2011.

The use of over-the-counter medications declined from 44.4% in 2005-2006 to 37.9% in 2010-2011 (P<0.001), while the use of dietary supplements increased from 51.8% to 63.7% (P<0.001).

Drug-drug interactions

The investigators identified 15 potentially life-threatening combinations of the most commonly used medications and supplements in the study.

They found that 15.1% of subjects were at risk for a potential major drug-drug interaction in 2010-2011, compared with an estimated 8.4% in 2005-2006 (P<0.001).

Dr Qato noted that more than half of the potential interactions involved a nonprescription medication or dietary supplement.

Preventative cardiovascular medications such as statins (particularly, simvastatin), antiplatelet drugs (such as clopidogrel and aspirin), and supplements (specifically, omega-3 fish oil) accounted for the vast majority of these combinations.

“Many older patients seeking to improve their cardiovascular health are also regularly using interacting drug combinations that may worsen cardiovascular risk,” Dr Qato said.

“For example, the use of clopidogrel in combination with the proton-pump inhibitor omeprazole, aspirin, or naproxen—all over-the-counter medications—is associated with an increased risk of heart attacks, bleeding complications, or death. However, about 1.8%—or 1 million—older adults regularly use clopidogrel in interacting combinations.”

Dr Qato added that healthcare professionals should consider the adverse effects of commonly used prescription and nonprescription medication combinations when treating older adults and counsel patients about the risks.

“Improving safety in the use of interacting medication combinations has the potential to reduce preventable, potentially fatal, adverse drug events,” she said.