Hematology Times

Radiation therapist preparing

woman for radiation

Photo by Rhoda Baer

A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.

The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.

To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.

They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.

Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.

The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”

A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.

On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.

Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.

The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.

“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.

“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”

If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.

Radiation therapist preparing

woman for radiation

Photo by Rhoda Baer

A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.

The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.

To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.

They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.

Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.

The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”

A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.

On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.

Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.

The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.

“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.

“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”

If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.

Radiation therapist preparing

woman for radiation

Photo by Rhoda Baer

A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.

The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.

To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.

They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.

Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.

The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”

A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.

On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.

Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.

The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.

“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.

“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”

If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.

Drosophila melanogaster

Photo by Andre Karwath

New research has revealed a mechanism that allows cancer cells to respond and grow rapidly when blood sugar levels rise.

This may help to explain why people who develop conditions in which they have chronically high blood sugar levels, such as obesity, also have an increased risk of developing certain cancers.

Susumu Hirabayashi, PhD, of Imperial College London in the UK, and Ross Cagan, PhD, of Mount Sinai Hospital in New York, New York, described the mechanism in eLife.

In a study published 2 years ago, the pair engineered fruit flies (Drosophila melanogaster) to activate the genes Ras and Src, which are activated in a range of malignancies.

The researchers activated Ras and Src in the flies’ developing eye tissue. Flies that were fed a normal diet grew small, benign tumors. But when flies were fed a high-sugar diet, they developed large, malignant tumors.

In flies fed a high-sugar diet, the normal cells became insulin-resistant, but the tumor cells didn’t. The tumor cells actually became more sensitive to insulin because they turned on a metabolic switch that triggered them to produce extra receptors for insulin. But this study did not explain how the tumor cells turned on this metabolic switch.

Now, after studying the same flies in more detail, Drs Hirabayashi and Cagan have found the tumor cells detect glucose availability indirectly, through a protein called salt-inducible kinase (SIK). When glucose levels are high, SIK sends a signal along the Hippo signaling pathway.

The Hippo signaling pathway is known to play a role in controlling cell growth. When it’s turned on, it keeps cell growth under control, but if it’s turned off, the cell can continue growing and may ultimately develop into a tumor.

Drs Hirabayashi and Cagan found that SIK acts like a sugar sensor, turning the Hippo signaling pathway off in response to raised glucose levels. This allows the tumor cells to continue to grow.

“Ras and Src co-activated tumors use SIK to sense that there’s lots of glucose available outside of their cells and to tell the cells to take advantage of that,” Dr Hirabayashi said. “Together, Ras and Src co-activated tumors use SIK to efficiently respond to glucose availability and ensure the tumors grow in nutrient-rich conditions such as obesity. We still don’t know if tumors caused by other genes respond to sugar in the same way.”

“Our results suggest that if we can develop drugs to target SIK, and stop it from alerting cancer cells in this way, then we may be able to stop cancer cells from thriving in an insulin-resistant environment and break the connection between obesity and cancer.”

Drosophila melanogaster

Photo by Andre Karwath

New research has revealed a mechanism that allows cancer cells to respond and grow rapidly when blood sugar levels rise.

This may help to explain why people who develop conditions in which they have chronically high blood sugar levels, such as obesity, also have an increased risk of developing certain cancers.

Susumu Hirabayashi, PhD, of Imperial College London in the UK, and Ross Cagan, PhD, of Mount Sinai Hospital in New York, New York, described the mechanism in eLife.

In a study published 2 years ago, the pair engineered fruit flies (Drosophila melanogaster) to activate the genes Ras and Src, which are activated in a range of malignancies.

The researchers activated Ras and Src in the flies’ developing eye tissue. Flies that were fed a normal diet grew small, benign tumors. But when flies were fed a high-sugar diet, they developed large, malignant tumors.

In flies fed a high-sugar diet, the normal cells became insulin-resistant, but the tumor cells didn’t. The tumor cells actually became more sensitive to insulin because they turned on a metabolic switch that triggered them to produce extra receptors for insulin. But this study did not explain how the tumor cells turned on this metabolic switch.

Now, after studying the same flies in more detail, Drs Hirabayashi and Cagan have found the tumor cells detect glucose availability indirectly, through a protein called salt-inducible kinase (SIK). When glucose levels are high, SIK sends a signal along the Hippo signaling pathway.

The Hippo signaling pathway is known to play a role in controlling cell growth. When it’s turned on, it keeps cell growth under control, but if it’s turned off, the cell can continue growing and may ultimately develop into a tumor.

Drs Hirabayashi and Cagan found that SIK acts like a sugar sensor, turning the Hippo signaling pathway off in response to raised glucose levels. This allows the tumor cells to continue to grow.

“Ras and Src co-activated tumors use SIK to sense that there’s lots of glucose available outside of their cells and to tell the cells to take advantage of that,” Dr Hirabayashi said. “Together, Ras and Src co-activated tumors use SIK to efficiently respond to glucose availability and ensure the tumors grow in nutrient-rich conditions such as obesity. We still don’t know if tumors caused by other genes respond to sugar in the same way.”

“Our results suggest that if we can develop drugs to target SIK, and stop it from alerting cancer cells in this way, then we may be able to stop cancer cells from thriving in an insulin-resistant environment and break the connection between obesity and cancer.”

Drosophila melanogaster

Photo by Andre Karwath

New research has revealed a mechanism that allows cancer cells to respond and grow rapidly when blood sugar levels rise.

This may help to explain why people who develop conditions in which they have chronically high blood sugar levels, such as obesity, also have an increased risk of developing certain cancers.

Susumu Hirabayashi, PhD, of Imperial College London in the UK, and Ross Cagan, PhD, of Mount Sinai Hospital in New York, New York, described the mechanism in eLife.

In a study published 2 years ago, the pair engineered fruit flies (Drosophila melanogaster) to activate the genes Ras and Src, which are activated in a range of malignancies.

The researchers activated Ras and Src in the flies’ developing eye tissue. Flies that were fed a normal diet grew small, benign tumors. But when flies were fed a high-sugar diet, they developed large, malignant tumors.

In flies fed a high-sugar diet, the normal cells became insulin-resistant, but the tumor cells didn’t. The tumor cells actually became more sensitive to insulin because they turned on a metabolic switch that triggered them to produce extra receptors for insulin. But this study did not explain how the tumor cells turned on this metabolic switch.

Now, after studying the same flies in more detail, Drs Hirabayashi and Cagan have found the tumor cells detect glucose availability indirectly, through a protein called salt-inducible kinase (SIK). When glucose levels are high, SIK sends a signal along the Hippo signaling pathway.

The Hippo signaling pathway is known to play a role in controlling cell growth. When it’s turned on, it keeps cell growth under control, but if it’s turned off, the cell can continue growing and may ultimately develop into a tumor.

Drs Hirabayashi and Cagan found that SIK acts like a sugar sensor, turning the Hippo signaling pathway off in response to raised glucose levels. This allows the tumor cells to continue to grow.

“Ras and Src co-activated tumors use SIK to sense that there’s lots of glucose available outside of their cells and to tell the cells to take advantage of that,” Dr Hirabayashi said. “Together, Ras and Src co-activated tumors use SIK to efficiently respond to glucose availability and ensure the tumors grow in nutrient-rich conditions such as obesity. We still don’t know if tumors caused by other genes respond to sugar in the same way.”

“Our results suggest that if we can develop drugs to target SIK, and stop it from alerting cancer cells in this way, then we may be able to stop cancer cells from thriving in an insulin-resistant environment and break the connection between obesity and cancer.”

 

 

Micrograph showing FL

 

Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.

They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.

And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.

Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.

“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.

“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”

Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.

In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.

Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.

“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”

The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.

“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”

 

 

Micrograph showing FL

 

Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.

They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.

And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.

Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.

“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.

“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”

Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.

In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.

Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.

“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”

The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.

“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”

 

 

Micrograph showing FL

 

Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.

They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.

And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.

Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.

“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.

“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”

Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.

In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.

Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.

“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”

The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.

“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”

Researcher in the lab

Photo by Bill Branson

Two new studies suggest biomedical research may be hindered by poor reporting and a lack of transparency.

In one study, researchers analyzed more than 400 biomedical science articles and found the papers rarely provided full protocol information, complete data, and the necessary level of transparency to verify or replicate the work.

In the other study, researchers analyzed more than 500 preclinical experiments and found that most didn’t contain sufficient information on the animals used.

Both studies were published in PLOS Biology.

For the first study, Shareen Iqbal, PhD, of Emory University in Atlanta, Georgia, and her colleagues analyzed papers published between 2000 and 2014.

The team set out to determine the extent to which researchers report key information necessary for properly evaluating and replicating published research, including availability of protocols, data, and the frequency of published novel or replication studies.

Out of 441 articles drawn from across the biomedical literature, only 1 paper provided a full protocol, and none of the papers made all the data available. The majority of studies didn’t state funding or conflicts of interest, and replication studies were very rare.

Dr Iqbal and her colleagues said they hope their study will further sensitize scientists, funders, journals, and other science-related stakeholders about the need to improve these indicators.

For the second study, Ulrich Dirnagl, MD, of Charité Universitätsmedizin in Berlin, Germany, and his colleagues examined 100 papers describing preclinical research on stroke and cancer. These papers contained accounts of 316 experiments on infarct volume and 206 experiments on tumor shrinkage.

The vast majority of the reports didn’t contain sufficient information on how many animals were used in the experiments. What’s more, in many papers, animals “vanished” over the course of the study.

Using a computer model, the researchers simulated the effects of such animal loss on the validity of the experiments. They found that the more animals lost or removed, the shakier or more biased the experimental conclusions.

“The study began with an attempt to look at the robustness of findings in a handful of preclinical papers, but the sheer number of missing animals stopped us in our tracks,” said author Constance Holman, a graduate student at Charité Universitätsmedizin.

Researchers from both studies believe their findings add to the list of concerns about bias and reporting in research, but the results also establish ways in which research can become more transparent and potentially more reproducible.

Researcher in the lab

Photo by Bill Branson

Two new studies suggest biomedical research may be hindered by poor reporting and a lack of transparency.

In one study, researchers analyzed more than 400 biomedical science articles and found the papers rarely provided full protocol information, complete data, and the necessary level of transparency to verify or replicate the work.

In the other study, researchers analyzed more than 500 preclinical experiments and found that most didn’t contain sufficient information on the animals used.

Both studies were published in PLOS Biology.

For the first study, Shareen Iqbal, PhD, of Emory University in Atlanta, Georgia, and her colleagues analyzed papers published between 2000 and 2014.

The team set out to determine the extent to which researchers report key information necessary for properly evaluating and replicating published research, including availability of protocols, data, and the frequency of published novel or replication studies.

Out of 441 articles drawn from across the biomedical literature, only 1 paper provided a full protocol, and none of the papers made all the data available. The majority of studies didn’t state funding or conflicts of interest, and replication studies were very rare.

Dr Iqbal and her colleagues said they hope their study will further sensitize scientists, funders, journals, and other science-related stakeholders about the need to improve these indicators.

For the second study, Ulrich Dirnagl, MD, of Charité Universitätsmedizin in Berlin, Germany, and his colleagues examined 100 papers describing preclinical research on stroke and cancer. These papers contained accounts of 316 experiments on infarct volume and 206 experiments on tumor shrinkage.

The vast majority of the reports didn’t contain sufficient information on how many animals were used in the experiments. What’s more, in many papers, animals “vanished” over the course of the study.

Using a computer model, the researchers simulated the effects of such animal loss on the validity of the experiments. They found that the more animals lost or removed, the shakier or more biased the experimental conclusions.

“The study began with an attempt to look at the robustness of findings in a handful of preclinical papers, but the sheer number of missing animals stopped us in our tracks,” said author Constance Holman, a graduate student at Charité Universitätsmedizin.

Researchers from both studies believe their findings add to the list of concerns about bias and reporting in research, but the results also establish ways in which research can become more transparent and potentially more reproducible.

Researcher in the lab

Photo by Bill Branson

Two new studies suggest biomedical research may be hindered by poor reporting and a lack of transparency.

In one study, researchers analyzed more than 400 biomedical science articles and found the papers rarely provided full protocol information, complete data, and the necessary level of transparency to verify or replicate the work.

In the other study, researchers analyzed more than 500 preclinical experiments and found that most didn’t contain sufficient information on the animals used.

Both studies were published in PLOS Biology.

For the first study, Shareen Iqbal, PhD, of Emory University in Atlanta, Georgia, and her colleagues analyzed papers published between 2000 and 2014.

The team set out to determine the extent to which researchers report key information necessary for properly evaluating and replicating published research, including availability of protocols, data, and the frequency of published novel or replication studies.

Out of 441 articles drawn from across the biomedical literature, only 1 paper provided a full protocol, and none of the papers made all the data available. The majority of studies didn’t state funding or conflicts of interest, and replication studies were very rare.

Dr Iqbal and her colleagues said they hope their study will further sensitize scientists, funders, journals, and other science-related stakeholders about the need to improve these indicators.

For the second study, Ulrich Dirnagl, MD, of Charité Universitätsmedizin in Berlin, Germany, and his colleagues examined 100 papers describing preclinical research on stroke and cancer. These papers contained accounts of 316 experiments on infarct volume and 206 experiments on tumor shrinkage.

The vast majority of the reports didn’t contain sufficient information on how many animals were used in the experiments. What’s more, in many papers, animals “vanished” over the course of the study.

Using a computer model, the researchers simulated the effects of such animal loss on the validity of the experiments. They found that the more animals lost or removed, the shakier or more biased the experimental conclusions.

“The study began with an attempt to look at the robustness of findings in a handful of preclinical papers, but the sheer number of missing animals stopped us in our tracks,” said author Constance Holman, a graduate student at Charité Universitätsmedizin.

Researchers from both studies believe their findings add to the list of concerns about bias and reporting in research, but the results also establish ways in which research can become more transparent and potentially more reproducible.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Doctor with clipboard

Doctors may convey racial bias with their body language, according to research published in The Journal of Pain and Symptom Management.

In this small study, a group of physicians, most of whom were white males, gave less compassionate nonverbal cues when interacting with black actors portraying seriously ill patients than when interacting with white actors portraying seriously ill patients.

“Although we found that physicians said the same things to their black and white patients, communication is not just the spoken word. It also involves nonverbal cues, such as eye contact, body positioning, and touch,” said study author Amber Barnato, MD, of the University of Pittsburg in Pennsylvania.

“Poor nonverbal communication—something the physician may not even be aware he or she is doing—could explain why many black patients perceive discrimination in the healthcare setting.”

For this study, Dr Barnato and her colleagues recruited 33 hospital-based attending emergency medicine physicians, hospitalists, and intensivists from Allegheny County, Pennsylvania, and put them in realistic simulations where actors portrayed dying black and white patients accompanied by a family member.

The actors portrayed comparable medical conditions—plummeting vital signs related to either metastatic gastric or pancreatic cancer—and read from matching scripts. The physicians were unaware of what the trial was testing.

The majority of the physicians were white men, so the researchers could not derive any statistically significant conclusions about whether a physician’s race impacted his or her actions.

Physicians were scored on a point system for both their verbal and nonverbal communication skills when interacting with the patient and family member. The physicians averaged 7% lower scores for their nonverbal interactions with the black patients than with the white patients.

“When explaining what was happening and what the next steps for care could be, with the white patients, the physicians were more likely to stand right at the patient’s bedside and touch them in a sympathetic manner,” Dr Barnato said.

She explained that something as simple as a physician staying near the door and holding a binder in front of his body could be perceived by the patient and family as defensive or disengaged. This could lead to a cascade of misunderstandings that result in patients and their families requesting extraordinary life-saving measures because they don’t trust the doctor has their best interests in mind when suggesting gentler, end-of-life care options.

“When you survey people in the community about their feelings on end-of-life care, blacks are only slightly more likely than whites to say they want aggressive, life-sustaining measures when terminally ill,” Dr Barnato said.

“However, blacks are much more likely than whites to request such care when they are faced with making the decision in the hospital. Body language is a significant tool in building trust—or mistrust—and physicians need to ensure that their body language isn’t contributing to that decision.”

“To help black patients and their families feel welcome and encouraged to be partners in medical decision-making, it is critical that doctors be aware of their verbal and nonverbal communication and any unintentional biases.”

Doctor with clipboard

Doctors may convey racial bias with their body language, according to research published in The Journal of Pain and Symptom Management.

In this small study, a group of physicians, most of whom were white males, gave less compassionate nonverbal cues when interacting with black actors portraying seriously ill patients than when interacting with white actors portraying seriously ill patients.

“Although we found that physicians said the same things to their black and white patients, communication is not just the spoken word. It also involves nonverbal cues, such as eye contact, body positioning, and touch,” said study author Amber Barnato, MD, of the University of Pittsburg in Pennsylvania.

“Poor nonverbal communication—something the physician may not even be aware he or she is doing—could explain why many black patients perceive discrimination in the healthcare setting.”

For this study, Dr Barnato and her colleagues recruited 33 hospital-based attending emergency medicine physicians, hospitalists, and intensivists from Allegheny County, Pennsylvania, and put them in realistic simulations where actors portrayed dying black and white patients accompanied by a family member.

The actors portrayed comparable medical conditions—plummeting vital signs related to either metastatic gastric or pancreatic cancer—and read from matching scripts. The physicians were unaware of what the trial was testing.

The majority of the physicians were white men, so the researchers could not derive any statistically significant conclusions about whether a physician’s race impacted his or her actions.

Physicians were scored on a point system for both their verbal and nonverbal communication skills when interacting with the patient and family member. The physicians averaged 7% lower scores for their nonverbal interactions with the black patients than with the white patients.

“When explaining what was happening and what the next steps for care could be, with the white patients, the physicians were more likely to stand right at the patient’s bedside and touch them in a sympathetic manner,” Dr Barnato said.

She explained that something as simple as a physician staying near the door and holding a binder in front of his body could be perceived by the patient and family as defensive or disengaged. This could lead to a cascade of misunderstandings that result in patients and their families requesting extraordinary life-saving measures because they don’t trust the doctor has their best interests in mind when suggesting gentler, end-of-life care options.

“When you survey people in the community about their feelings on end-of-life care, blacks are only slightly more likely than whites to say they want aggressive, life-sustaining measures when terminally ill,” Dr Barnato said.

“However, blacks are much more likely than whites to request such care when they are faced with making the decision in the hospital. Body language is a significant tool in building trust—or mistrust—and physicians need to ensure that their body language isn’t contributing to that decision.”

“To help black patients and their families feel welcome and encouraged to be partners in medical decision-making, it is critical that doctors be aware of their verbal and nonverbal communication and any unintentional biases.”

Doctor with clipboard

Doctors may convey racial bias with their body language, according to research published in The Journal of Pain and Symptom Management.

In this small study, a group of physicians, most of whom were white males, gave less compassionate nonverbal cues when interacting with black actors portraying seriously ill patients than when interacting with white actors portraying seriously ill patients.

“Although we found that physicians said the same things to their black and white patients, communication is not just the spoken word. It also involves nonverbal cues, such as eye contact, body positioning, and touch,” said study author Amber Barnato, MD, of the University of Pittsburg in Pennsylvania.

“Poor nonverbal communication—something the physician may not even be aware he or she is doing—could explain why many black patients perceive discrimination in the healthcare setting.”

For this study, Dr Barnato and her colleagues recruited 33 hospital-based attending emergency medicine physicians, hospitalists, and intensivists from Allegheny County, Pennsylvania, and put them in realistic simulations where actors portrayed dying black and white patients accompanied by a family member.

The actors portrayed comparable medical conditions—plummeting vital signs related to either metastatic gastric or pancreatic cancer—and read from matching scripts. The physicians were unaware of what the trial was testing.

The majority of the physicians were white men, so the researchers could not derive any statistically significant conclusions about whether a physician’s race impacted his or her actions.

Physicians were scored on a point system for both their verbal and nonverbal communication skills when interacting with the patient and family member. The physicians averaged 7% lower scores for their nonverbal interactions with the black patients than with the white patients.

“When explaining what was happening and what the next steps for care could be, with the white patients, the physicians were more likely to stand right at the patient’s bedside and touch them in a sympathetic manner,” Dr Barnato said.

She explained that something as simple as a physician staying near the door and holding a binder in front of his body could be perceived by the patient and family as defensive or disengaged. This could lead to a cascade of misunderstandings that result in patients and their families requesting extraordinary life-saving measures because they don’t trust the doctor has their best interests in mind when suggesting gentler, end-of-life care options.

“When you survey people in the community about their feelings on end-of-life care, blacks are only slightly more likely than whites to say they want aggressive, life-sustaining measures when terminally ill,” Dr Barnato said.

“However, blacks are much more likely than whites to request such care when they are faced with making the decision in the hospital. Body language is a significant tool in building trust—or mistrust—and physicians need to ensure that their body language isn’t contributing to that decision.”

“To help black patients and their families feel welcome and encouraged to be partners in medical decision-making, it is critical that doctors be aware of their verbal and nonverbal communication and any unintentional biases.”

Researchers in the lab

Photo by Rhoda Baer

Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.

The canSAR database brings together biological, chemical, and pharmacological data.

The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.

Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.

The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.

The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.

The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.

The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.

“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.

“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”

“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”

Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.

Researchers in the lab

Photo by Rhoda Baer

Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.

The canSAR database brings together biological, chemical, and pharmacological data.

The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.

Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.

The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.

The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.

The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.

The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.

“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.

“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”

“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”

Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.

Researchers in the lab

Photo by Rhoda Baer

Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.

The canSAR database brings together biological, chemical, and pharmacological data.

The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.

Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.

The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.

The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.

The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.

The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.

“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.

“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”

“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”

Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Bags and vials of blood

Photo by Daniel Gay

Researchers have discovered a bloodborne virus, known as human pegivirus 2 (HPgV-2), in patients with hepatitis C virus (HCV).

The team identified 8 complete strains of HPgV-2 and noted that the virus was only found in patients who tested positive for HCV RNA. However, it’s not clear if HPgV-2 causes hepatitis.

Charles Chiu, MD, PhD, of the University of California San Francisco, and his colleagues described their discovery of HPgV-2 in PLOS Pathogens.

The team identified the virus by sequencing plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology.

They said HPgV-2 is “highly divergent,” sharing less than 32% amino acid identity with its nearest relatives, rodent and bat pegiviruses.

After their initial discovery, the researchers screened an additional 2440 plasma samples and found 11 HPgV-2 RNA-positive samples.

All 12 HPgV-2 RNA-positive cases were found in patients who tested positive for HCV RNA, including 2 patients who were also infected with HIV.

The researchers performed longitudinal sampling in 2 patients and found that active HPgV-2 infection can persist in blood for at least 7 weeks, despite the presence of virus-specific antibodies.

The team also identified 1 patient with HPgV-2 and HCV RNA who was seronegative for both viruses. They said this suggests a high likelihood of simultaneous acquisition of HCV and HPgV-2 infection from an acute co-transmission event.

“Based on our findings, our team used the genetic makeup of the virus to develop both a molecular test for detecting it in the bloodstream and an antibody test for determining an immune response to the virus,” said John Hackett Jr, PhD, of Abbott Laboratories, Inc. in Abbott Park, Illinois.

“Our next step is to explore whether this new virus can cause disease, and if so, work with blood banks to continue to help safeguard the world’s blood supply against these types of new viruses. Research such as this is ultimately focused on unlocking new technologies that hold the potential for significant improvements to the practice of healthcare.”

Bags and vials of blood

Photo by Daniel Gay

Researchers have discovered a bloodborne virus, known as human pegivirus 2 (HPgV-2), in patients with hepatitis C virus (HCV).

The team identified 8 complete strains of HPgV-2 and noted that the virus was only found in patients who tested positive for HCV RNA. However, it’s not clear if HPgV-2 causes hepatitis.

Charles Chiu, MD, PhD, of the University of California San Francisco, and his colleagues described their discovery of HPgV-2 in PLOS Pathogens.

The team identified the virus by sequencing plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology.

They said HPgV-2 is “highly divergent,” sharing less than 32% amino acid identity with its nearest relatives, rodent and bat pegiviruses.

After their initial discovery, the researchers screened an additional 2440 plasma samples and found 11 HPgV-2 RNA-positive samples.

All 12 HPgV-2 RNA-positive cases were found in patients who tested positive for HCV RNA, including 2 patients who were also infected with HIV.

The researchers performed longitudinal sampling in 2 patients and found that active HPgV-2 infection can persist in blood for at least 7 weeks, despite the presence of virus-specific antibodies.

The team also identified 1 patient with HPgV-2 and HCV RNA who was seronegative for both viruses. They said this suggests a high likelihood of simultaneous acquisition of HCV and HPgV-2 infection from an acute co-transmission event.

“Based on our findings, our team used the genetic makeup of the virus to develop both a molecular test for detecting it in the bloodstream and an antibody test for determining an immune response to the virus,” said John Hackett Jr, PhD, of Abbott Laboratories, Inc. in Abbott Park, Illinois.

“Our next step is to explore whether this new virus can cause disease, and if so, work with blood banks to continue to help safeguard the world’s blood supply against these types of new viruses. Research such as this is ultimately focused on unlocking new technologies that hold the potential for significant improvements to the practice of healthcare.”

Bags and vials of blood

Photo by Daniel Gay

Researchers have discovered a bloodborne virus, known as human pegivirus 2 (HPgV-2), in patients with hepatitis C virus (HCV).

The team identified 8 complete strains of HPgV-2 and noted that the virus was only found in patients who tested positive for HCV RNA. However, it’s not clear if HPgV-2 causes hepatitis.

Charles Chiu, MD, PhD, of the University of California San Francisco, and his colleagues described their discovery of HPgV-2 in PLOS Pathogens.

The team identified the virus by sequencing plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology.

They said HPgV-2 is “highly divergent,” sharing less than 32% amino acid identity with its nearest relatives, rodent and bat pegiviruses.

After their initial discovery, the researchers screened an additional 2440 plasma samples and found 11 HPgV-2 RNA-positive samples.

All 12 HPgV-2 RNA-positive cases were found in patients who tested positive for HCV RNA, including 2 patients who were also infected with HIV.

The researchers performed longitudinal sampling in 2 patients and found that active HPgV-2 infection can persist in blood for at least 7 weeks, despite the presence of virus-specific antibodies.

The team also identified 1 patient with HPgV-2 and HCV RNA who was seronegative for both viruses. They said this suggests a high likelihood of simultaneous acquisition of HCV and HPgV-2 infection from an acute co-transmission event.

“Based on our findings, our team used the genetic makeup of the virus to develop both a molecular test for detecting it in the bloodstream and an antibody test for determining an immune response to the virus,” said John Hackett Jr, PhD, of Abbott Laboratories, Inc. in Abbott Park, Illinois.

“Our next step is to explore whether this new virus can cause disease, and if so, work with blood banks to continue to help safeguard the world’s blood supply against these types of new viruses. Research such as this is ultimately focused on unlocking new technologies that hold the potential for significant improvements to the practice of healthcare.”