Leukemia, Myelodysplasia, Transplantation

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

CLL in the bone marrow

The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.

Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.

The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.

The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.

Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.

The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.

The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.

“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”

The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.

Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.

The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.

CLL in the bone marrow

The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.

Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.

The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.

The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.

Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.

The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.

The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.

“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”

The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.

Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.

The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.

CLL in the bone marrow

The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.

Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.

The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.

The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.

Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.

The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.

The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.

“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”

The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.

Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.

The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Blood smear showing ATLL

The European Medicines Agency (EMA) has granted orphan drug designation for a therapeutic vaccine candidate known as THV02 to treat adult T-cell leukemia/lymphoma (ATLL).

THV02 is an experimental treatment composed of 2 lentiviral vectors to be used in a prime/boost regimen in ATLL patients infected by the HTLV-1 virus.

Both investigational drugs encode the same antigens, derived from 4 proteins of the HTLV-1 virus.

THV02 is intended to induce an immune response against HTLV antigens born by ATLL with the aim of enabling the patients’ immune system to fight leukemic cells.

Preclinical evaluation has suggested that THV02 is safe, and the vaccine has presented an “unprecedented” immunogenicity profile in several models, according to THERAVECTYS, the company developing THV02.

“Preclinical immunogenicity results obtained to date are very promising, and we are really excited by the prospect of bringing a safe and better-tolerated alternative to patients who are desperately in need of a treatment,” said Déborah Revaud, the senior scientist in charge of developing THV02.

The EMA grants orphan designation to drugs in development intended for the treatment, prevention, or diagnosis of life-threatening or chronically debilitating diseases occurring in fewer than 5 in 10,000 people.

The designation allows sponsors to benefit from an accelerated development process, financial incentives, and a 10-year period of market exclusivity once the drug is on the market.

“We are extremely pleased that the European Medicines Agency has granted an orphan drug status to our vaccine candidate against ATLL,” said Emmanuelle Sabbah-Petrover, PhD, head of regulatory affairs at THERAVECTYS.

“We expect to recruit our first patients towards the end of Q3 2015 in Europe and advance further developments in the US and in Japan in 2016.”

Should THV02 demonstrate a convincing safety and efficacy profile during its development against ATLL, THERAVECTYS said it will consider developing the vaccine for HTLV-related infections as treatment and possibly as prophylaxis.

Blood smear showing ATLL

The European Medicines Agency (EMA) has granted orphan drug designation for a therapeutic vaccine candidate known as THV02 to treat adult T-cell leukemia/lymphoma (ATLL).

THV02 is an experimental treatment composed of 2 lentiviral vectors to be used in a prime/boost regimen in ATLL patients infected by the HTLV-1 virus.

Both investigational drugs encode the same antigens, derived from 4 proteins of the HTLV-1 virus.

THV02 is intended to induce an immune response against HTLV antigens born by ATLL with the aim of enabling the patients’ immune system to fight leukemic cells.

Preclinical evaluation has suggested that THV02 is safe, and the vaccine has presented an “unprecedented” immunogenicity profile in several models, according to THERAVECTYS, the company developing THV02.

“Preclinical immunogenicity results obtained to date are very promising, and we are really excited by the prospect of bringing a safe and better-tolerated alternative to patients who are desperately in need of a treatment,” said Déborah Revaud, the senior scientist in charge of developing THV02.

The EMA grants orphan designation to drugs in development intended for the treatment, prevention, or diagnosis of life-threatening or chronically debilitating diseases occurring in fewer than 5 in 10,000 people.

The designation allows sponsors to benefit from an accelerated development process, financial incentives, and a 10-year period of market exclusivity once the drug is on the market.

“We are extremely pleased that the European Medicines Agency has granted an orphan drug status to our vaccine candidate against ATLL,” said Emmanuelle Sabbah-Petrover, PhD, head of regulatory affairs at THERAVECTYS.

“We expect to recruit our first patients towards the end of Q3 2015 in Europe and advance further developments in the US and in Japan in 2016.”

Should THV02 demonstrate a convincing safety and efficacy profile during its development against ATLL, THERAVECTYS said it will consider developing the vaccine for HTLV-related infections as treatment and possibly as prophylaxis.

Blood smear showing ATLL

The European Medicines Agency (EMA) has granted orphan drug designation for a therapeutic vaccine candidate known as THV02 to treat adult T-cell leukemia/lymphoma (ATLL).

THV02 is an experimental treatment composed of 2 lentiviral vectors to be used in a prime/boost regimen in ATLL patients infected by the HTLV-1 virus.

Both investigational drugs encode the same antigens, derived from 4 proteins of the HTLV-1 virus.

THV02 is intended to induce an immune response against HTLV antigens born by ATLL with the aim of enabling the patients’ immune system to fight leukemic cells.

Preclinical evaluation has suggested that THV02 is safe, and the vaccine has presented an “unprecedented” immunogenicity profile in several models, according to THERAVECTYS, the company developing THV02.

“Preclinical immunogenicity results obtained to date are very promising, and we are really excited by the prospect of bringing a safe and better-tolerated alternative to patients who are desperately in need of a treatment,” said Déborah Revaud, the senior scientist in charge of developing THV02.

The EMA grants orphan designation to drugs in development intended for the treatment, prevention, or diagnosis of life-threatening or chronically debilitating diseases occurring in fewer than 5 in 10,000 people.

The designation allows sponsors to benefit from an accelerated development process, financial incentives, and a 10-year period of market exclusivity once the drug is on the market.

“We are extremely pleased that the European Medicines Agency has granted an orphan drug status to our vaccine candidate against ATLL,” said Emmanuelle Sabbah-Petrover, PhD, head of regulatory affairs at THERAVECTYS.

“We expect to recruit our first patients towards the end of Q3 2015 in Europe and advance further developments in the US and in Japan in 2016.”

Should THV02 demonstrate a convincing safety and efficacy profile during its development against ATLL, THERAVECTYS said it will consider developing the vaccine for HTLV-related infections as treatment and possibly as prophylaxis.

In his monthly podcast for The Journal of Community and Supportive Oncology, Dr David Henry looks at Original Reports on the comparison of atropine-diphenoxylate and hyoscyamine in lowering the rates of irinotecan-related cholinergic syndrome; the effects of age and comorbidities in the management of rectal cancer in elderly patients at an institution in Portugal; the impact of a telehealth intervention on quality of life and symptom distress in patients with head and neck cancer; and the beneficial effects of animal-assisted visits on quality of life during multimodal radiation-chemotherapy regimens. He also discusses a Research Report in which the authors attempt, possibly for the first time, to quantify radiation exposure from diagnostic procedures in patients with newly diagnosed breast cancer, as well as two feature articles – a round-up of some of the presentations at the 2014 San Antonio Breast Cancer Symposium and a Journal Club presentation of therapies for lymphoproliferative disorders.

In his monthly podcast for The Journal of Community and Supportive Oncology, Dr David Henry looks at Original Reports on the comparison of atropine-diphenoxylate and hyoscyamine in lowering the rates of irinotecan-related cholinergic syndrome; the effects of age and comorbidities in the management of rectal cancer in elderly patients at an institution in Portugal; the impact of a telehealth intervention on quality of life and symptom distress in patients with head and neck cancer; and the beneficial effects of animal-assisted visits on quality of life during multimodal radiation-chemotherapy regimens. He also discusses a Research Report in which the authors attempt, possibly for the first time, to quantify radiation exposure from diagnostic procedures in patients with newly diagnosed breast cancer, as well as two feature articles – a round-up of some of the presentations at the 2014 San Antonio Breast Cancer Symposium and a Journal Club presentation of therapies for lymphoproliferative disorders.

In his monthly podcast for The Journal of Community and Supportive Oncology, Dr David Henry looks at Original Reports on the comparison of atropine-diphenoxylate and hyoscyamine in lowering the rates of irinotecan-related cholinergic syndrome; the effects of age and comorbidities in the management of rectal cancer in elderly patients at an institution in Portugal; the impact of a telehealth intervention on quality of life and symptom distress in patients with head and neck cancer; and the beneficial effects of animal-assisted visits on quality of life during multimodal radiation-chemotherapy regimens. He also discusses a Research Report in which the authors attempt, possibly for the first time, to quantify radiation exposure from diagnostic procedures in patients with newly diagnosed breast cancer, as well as two feature articles – a round-up of some of the presentations at the 2014 San Antonio Breast Cancer Symposium and a Journal Club presentation of therapies for lymphoproliferative disorders.

Slide showing LSCs

Credit: Robert Paulson

Inhibiting the cell-cycle kinase CDK6 may prevent leukemic relapse, according to research published in Blood.

Investigators found that CDK6 regulates the activation of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), which it does by inhibiting the transcription factor Egr1.

When CDK6 is lost, Egr1 becomes active and prevents stem cells from dividing.

However, the mechanism operates only when HSCs are stressed—such as in leukemia—and not in the normal physiological situation.

“CDK6 is absolutely necessary for leukemic stem cells to induce disease but plays no part in normal hematopoiesis,” said study author Ruth Scheicher, of the University of Veterinary Medicine, Vienna.

“We thus have a novel opportunity to target leukemia at its origin. Inhibiting CDK6 should attack leukemic stem cells while leaving healthy HSCs unaffected.”

Specifically, Scheicher and her colleagues found that Cdk6^−/− HSCs did not efficiently repopulate when transplanted into mice. And Cdk6^−/− mice could tolerate fewer cycles of treatment with 5-fluorouracil than wild-type mice.

Mice that received BCR-ABL^p210+–infected bone marrow harvested from Cdk6^−/− mice did not develop leukemia. However, the recipient mice did harbor LSCs.

And knocking down Egr1 in Cdk6^−/− BCR-ABL^p210+ LSCs enhanced the cells’ ability to form colonies.

The researchers said these results suggest CDK6 is “an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.”

Slide showing LSCs

Credit: Robert Paulson

Inhibiting the cell-cycle kinase CDK6 may prevent leukemic relapse, according to research published in Blood.

Investigators found that CDK6 regulates the activation of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), which it does by inhibiting the transcription factor Egr1.

When CDK6 is lost, Egr1 becomes active and prevents stem cells from dividing.

However, the mechanism operates only when HSCs are stressed—such as in leukemia—and not in the normal physiological situation.

“CDK6 is absolutely necessary for leukemic stem cells to induce disease but plays no part in normal hematopoiesis,” said study author Ruth Scheicher, of the University of Veterinary Medicine, Vienna.

“We thus have a novel opportunity to target leukemia at its origin. Inhibiting CDK6 should attack leukemic stem cells while leaving healthy HSCs unaffected.”

Specifically, Scheicher and her colleagues found that Cdk6^−/− HSCs did not efficiently repopulate when transplanted into mice. And Cdk6^−/− mice could tolerate fewer cycles of treatment with 5-fluorouracil than wild-type mice.

Mice that received BCR-ABL^p210+–infected bone marrow harvested from Cdk6^−/− mice did not develop leukemia. However, the recipient mice did harbor LSCs.

And knocking down Egr1 in Cdk6^−/− BCR-ABL^p210+ LSCs enhanced the cells’ ability to form colonies.

The researchers said these results suggest CDK6 is “an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.”

Slide showing LSCs

Credit: Robert Paulson

Inhibiting the cell-cycle kinase CDK6 may prevent leukemic relapse, according to research published in Blood.

Investigators found that CDK6 regulates the activation of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), which it does by inhibiting the transcription factor Egr1.

When CDK6 is lost, Egr1 becomes active and prevents stem cells from dividing.

However, the mechanism operates only when HSCs are stressed—such as in leukemia—and not in the normal physiological situation.

“CDK6 is absolutely necessary for leukemic stem cells to induce disease but plays no part in normal hematopoiesis,” said study author Ruth Scheicher, of the University of Veterinary Medicine, Vienna.

“We thus have a novel opportunity to target leukemia at its origin. Inhibiting CDK6 should attack leukemic stem cells while leaving healthy HSCs unaffected.”

Specifically, Scheicher and her colleagues found that Cdk6^−/− HSCs did not efficiently repopulate when transplanted into mice. And Cdk6^−/− mice could tolerate fewer cycles of treatment with 5-fluorouracil than wild-type mice.

Mice that received BCR-ABL^p210+–infected bone marrow harvested from Cdk6^−/− mice did not develop leukemia. However, the recipient mice did harbor LSCs.

And knocking down Egr1 in Cdk6^−/− BCR-ABL^p210+ LSCs enhanced the cells’ ability to form colonies.

The researchers said these results suggest CDK6 is “an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.”

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Dimitrios Stamou, PhD

Credit: Jes Andersen/

University of Copenhagen

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Study author Jun J. Yang, PhD

Credit: Peter Barta

Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.

The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.

The patients required dose reductions of as much as 92%.

And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.

These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.

“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”

With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.

The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.

Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)

The NUDT15 variant was rarer among patients of European or African ancestry.

This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.

TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.

The researchers suspect the NUDT15 variant acts in a similar fashion.

Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.

“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.

“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”

Study author Jun J. Yang, PhD

Credit: Peter Barta

Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.

The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.

The patients required dose reductions of as much as 92%.

And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.

These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.

“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”

With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.

The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.

Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)

The NUDT15 variant was rarer among patients of European or African ancestry.

This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.

TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.

The researchers suspect the NUDT15 variant acts in a similar fashion.

Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.

“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.

“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”

Study author Jun J. Yang, PhD

Credit: Peter Barta

Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.

The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.

The patients required dose reductions of as much as 92%.

And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.

These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.

“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”

With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.

The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.

Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)

The NUDT15 variant was rarer among patients of European or African ancestry.

This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.

TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.

The researchers suspect the NUDT15 variant acts in a similar fashion.

Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.

“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.

“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”

Lab mouse

In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.

The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in

mouse models of the disease.

Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.

An account of this study appears in The Journal of Clinical Investigation.

Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.

“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.

“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”

But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.

The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.

In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.

“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.

At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.

In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).

In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.

The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).

The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Lab mouse

In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.

The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in

mouse models of the disease.

Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.

An account of this study appears in The Journal of Clinical Investigation.

Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.

“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.

“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”

But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.

The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.

In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.

“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.

At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.

In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).

In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.

The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).

The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Lab mouse

In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.

The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in

mouse models of the disease.

Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.

An account of this study appears in The Journal of Clinical Investigation.

Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.

“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.

“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”

But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.

The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.

In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.

“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.

At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.

In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).

In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.

The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).

The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Leukemia patient

Credit: Bill Branson

Cancer deaths in children, adolescents, and young adults in the UK have fallen by 58% in the past 40 years, according to new figures from Cancer Research UK.*

Among cancer patients age 24 and under, the number of deaths each year dropped from about 1300 in the mid-1970s (1975-1977) to around 550 in more recent years (2010-2012).

And patients with leukemia have seen the steepest decline in mortality.

This is key because, according to Cancer Research UK, leukemia is the most commonly diagnosed cancer in children aged 14 and under and the sixth most commonly diagnosed cancer among 15- to 24-year-olds.

“These figures are testament to the real progress we’re making in treating children and young people with cancer,” said Pam Kearns, PhD, director of the Cancer Research UK Clinical Trials Unit in Birmingham.

“But hundreds of young people are dying from cancer each year in the UK, which means there’s still much more we need to do.”

Around 1600 children and 2200 adolescents and young adults are diagnosed with cancer every year in the UK.

And cancer remains the biggest killer of children and young people in the UK. It is the most common cause of death in children and young women aged 15 to 24 and the fourth most common cause of death in young men aged 15 to 24.

Still, the latest figures from Cancer Research UK show progress.

The mortality rate for all cancer patients ages 0 to 24 fell from 63.7 per million in 1975-1977 to 36.7 per million in 2001-2003 and then to 27.9 per million in 2010-2012. So the mortality rate has fallen 56% since 1975 and 24% in the last decade.

The average number of cancer deaths among children age 0 to 24 fell from 1325 in 1975-1977 to 681 in 2001-2003 and then to 550 in 2010-2012. That translates to a 58% decrease in deaths from 1975 and a 19% decrease in the last decade.

For leukemia patients ages 0 to 24, the mortality rate fell from 9.6 per million in 2001-2003 to 5.6 per million in 2010-2012, which translates to a 42% decrease. The annual average number of deaths dropped from 179 in 2001-2003 to 110 in 2010-2012, which translates to a 39% decrease.

“Cancer causes more deaths among children and young people than any other disease in the UK, so it’s hugely encouraging to see that death toll now falling steadily,” said Harpal Kumar, DSc, Cancer Research UK’s chief executive.

“But as the largest funder of research into children’s cancers in the UK, we will keep going until no young lives are lost to cancer.”

To that end, Cancer Research UK has launched “Cancer Research UK Kids & Teens,” an ongoing campaign to fund more research to find better treatments for young cancer patients.

“Money raised by ‘Cancer Research UK Kids & Teens’ will be restricted to research into cancers affecting children, teenagers, and young adults, enabling us to better understand these cancers and find better and kinder treatments and cures,” Dr Kumar said. “In the next 5 to 10 years, Cancer Research UK hopes to double the amount it spends on these cancers.”

*Some of the information in this article is not available on the Cancer Research UK website (and was sent to HematologyTimes upon request), but similar data and additional details are available on the organization’s Cancer Stats page.

Leukemia patient

Credit: Bill Branson

Cancer deaths in children, adolescents, and young adults in the UK have fallen by 58% in the past 40 years, according to new figures from Cancer Research UK.*

Among cancer patients age 24 and under, the number of deaths each year dropped from about 1300 in the mid-1970s (1975-1977) to around 550 in more recent years (2010-2012).

And patients with leukemia have seen the steepest decline in mortality.

This is key because, according to Cancer Research UK, leukemia is the most commonly diagnosed cancer in children aged 14 and under and the sixth most commonly diagnosed cancer among 15- to 24-year-olds.

“These figures are testament to the real progress we’re making in treating children and young people with cancer,” said Pam Kearns, PhD, director of the Cancer Research UK Clinical Trials Unit in Birmingham.

“But hundreds of young people are dying from cancer each year in the UK, which means there’s still much more we need to do.”

Around 1600 children and 2200 adolescents and young adults are diagnosed with cancer every year in the UK.

And cancer remains the biggest killer of children and young people in the UK. It is the most common cause of death in children and young women aged 15 to 24 and the fourth most common cause of death in young men aged 15 to 24.

Still, the latest figures from Cancer Research UK show progress.

The mortality rate for all cancer patients ages 0 to 24 fell from 63.7 per million in 1975-1977 to 36.7 per million in 2001-2003 and then to 27.9 per million in 2010-2012. So the mortality rate has fallen 56% since 1975 and 24% in the last decade.

The average number of cancer deaths among children age 0 to 24 fell from 1325 in 1975-1977 to 681 in 2001-2003 and then to 550 in 2010-2012. That translates to a 58% decrease in deaths from 1975 and a 19% decrease in the last decade.

For leukemia patients ages 0 to 24, the mortality rate fell from 9.6 per million in 2001-2003 to 5.6 per million in 2010-2012, which translates to a 42% decrease. The annual average number of deaths dropped from 179 in 2001-2003 to 110 in 2010-2012, which translates to a 39% decrease.

“Cancer causes more deaths among children and young people than any other disease in the UK, so it’s hugely encouraging to see that death toll now falling steadily,” said Harpal Kumar, DSc, Cancer Research UK’s chief executive.

“But as the largest funder of research into children’s cancers in the UK, we will keep going until no young lives are lost to cancer.”

To that end, Cancer Research UK has launched “Cancer Research UK Kids & Teens,” an ongoing campaign to fund more research to find better treatments for young cancer patients.

“Money raised by ‘Cancer Research UK Kids & Teens’ will be restricted to research into cancers affecting children, teenagers, and young adults, enabling us to better understand these cancers and find better and kinder treatments and cures,” Dr Kumar said. “In the next 5 to 10 years, Cancer Research UK hopes to double the amount it spends on these cancers.”

*Some of the information in this article is not available on the Cancer Research UK website (and was sent to HematologyTimes upon request), but similar data and additional details are available on the organization’s Cancer Stats page.

Leukemia patient

Credit: Bill Branson

Cancer deaths in children, adolescents, and young adults in the UK have fallen by 58% in the past 40 years, according to new figures from Cancer Research UK.*

Among cancer patients age 24 and under, the number of deaths each year dropped from about 1300 in the mid-1970s (1975-1977) to around 550 in more recent years (2010-2012).

And patients with leukemia have seen the steepest decline in mortality.

This is key because, according to Cancer Research UK, leukemia is the most commonly diagnosed cancer in children aged 14 and under and the sixth most commonly diagnosed cancer among 15- to 24-year-olds.

“These figures are testament to the real progress we’re making in treating children and young people with cancer,” said Pam Kearns, PhD, director of the Cancer Research UK Clinical Trials Unit in Birmingham.

“But hundreds of young people are dying from cancer each year in the UK, which means there’s still much more we need to do.”

Around 1600 children and 2200 adolescents and young adults are diagnosed with cancer every year in the UK.

And cancer remains the biggest killer of children and young people in the UK. It is the most common cause of death in children and young women aged 15 to 24 and the fourth most common cause of death in young men aged 15 to 24.

Still, the latest figures from Cancer Research UK show progress.

The mortality rate for all cancer patients ages 0 to 24 fell from 63.7 per million in 1975-1977 to 36.7 per million in 2001-2003 and then to 27.9 per million in 2010-2012. So the mortality rate has fallen 56% since 1975 and 24% in the last decade.

The average number of cancer deaths among children age 0 to 24 fell from 1325 in 1975-1977 to 681 in 2001-2003 and then to 550 in 2010-2012. That translates to a 58% decrease in deaths from 1975 and a 19% decrease in the last decade.

For leukemia patients ages 0 to 24, the mortality rate fell from 9.6 per million in 2001-2003 to 5.6 per million in 2010-2012, which translates to a 42% decrease. The annual average number of deaths dropped from 179 in 2001-2003 to 110 in 2010-2012, which translates to a 39% decrease.

“Cancer causes more deaths among children and young people than any other disease in the UK, so it’s hugely encouraging to see that death toll now falling steadily,” said Harpal Kumar, DSc, Cancer Research UK’s chief executive.

“But as the largest funder of research into children’s cancers in the UK, we will keep going until no young lives are lost to cancer.”

To that end, Cancer Research UK has launched “Cancer Research UK Kids & Teens,” an ongoing campaign to fund more research to find better treatments for young cancer patients.

“Money raised by ‘Cancer Research UK Kids & Teens’ will be restricted to research into cancers affecting children, teenagers, and young adults, enabling us to better understand these cancers and find better and kinder treatments and cures,” Dr Kumar said. “In the next 5 to 10 years, Cancer Research UK hopes to double the amount it spends on these cancers.”

*Some of the information in this article is not available on the Cancer Research UK website (and was sent to HematologyTimes upon request), but similar data and additional details are available on the organization’s Cancer Stats page.