Lymphoma & Plasma Cell Disorders

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Researcher in the lab

Photo by Darren Baker

By agreeing upon—and addressing—the aspects of lymphoma research that need the most improvement, the research community could advance the treatment of these diseases, according to a report published in Blood.

The report’s authors said limitations in research infrastructure, funding, and collaborative approaches across research centers present potential challenges on the road to developing better treatments.

And they outlined several “priority areas” that, they believe, require particular attention.

“[Our report] draws focus to our most pressing needs, which, if unaddressed, will prevent transformative changes to how we study and treat these diseases,” said David M. Weinstock, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Directing our collaborative efforts toward the most high-impact areas will enable us to more rapidly bring life-saving treatments to our patients.”

The report lists the following priority areas:

• Infrastructure

  • Develop an adequate number of disease models for each lymphoma subtype
  • Establish a central repository of biospecimens, cell lines, and in vivo models with open access
  • Organize patient advocacy to support research.

• Research

  • Catalogue how lymphoma cells differ across disease subtypes
  • Better define and identify mutations and other abnormalities associated with the disease
  • Develop strategies to identify high-risk patients who may benefit most from clinical trials
  • Enhance efforts to use immune therapies to cure lymphoma
  • Better understand how lymphoma cells communicate with normal cells.

“[W]e invite clinicians, scientists, advocates, and patients to weigh in on this strategic roadmap so that it reflects the input of everyone in the community,” Dr Weinstock said. “We will share these priorities with funding agencies, advocacy groups, and others who can help us address the challenges we have identified, and thereby accelerate the development of new approaches to understand and eradicate lymphoma.”

To weigh in, visit: http://www.hematology.org/lymphoma-roadmap.

This report was developed after a review of the state of the science in lymphoma that took place at a special ASH Meeting on Lymphoma Biology in August 2014. A second ASH Meeting on Lymphoma Biology is planned for the summer of 2016.

Researcher in the lab

Photo by Darren Baker

By agreeing upon—and addressing—the aspects of lymphoma research that need the most improvement, the research community could advance the treatment of these diseases, according to a report published in Blood.

The report’s authors said limitations in research infrastructure, funding, and collaborative approaches across research centers present potential challenges on the road to developing better treatments.

And they outlined several “priority areas” that, they believe, require particular attention.

“[Our report] draws focus to our most pressing needs, which, if unaddressed, will prevent transformative changes to how we study and treat these diseases,” said David M. Weinstock, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Directing our collaborative efforts toward the most high-impact areas will enable us to more rapidly bring life-saving treatments to our patients.”

The report lists the following priority areas:

• Infrastructure

  • Develop an adequate number of disease models for each lymphoma subtype
  • Establish a central repository of biospecimens, cell lines, and in vivo models with open access
  • Organize patient advocacy to support research.

• Research

  • Catalogue how lymphoma cells differ across disease subtypes
  • Better define and identify mutations and other abnormalities associated with the disease
  • Develop strategies to identify high-risk patients who may benefit most from clinical trials
  • Enhance efforts to use immune therapies to cure lymphoma
  • Better understand how lymphoma cells communicate with normal cells.

“[W]e invite clinicians, scientists, advocates, and patients to weigh in on this strategic roadmap so that it reflects the input of everyone in the community,” Dr Weinstock said. “We will share these priorities with funding agencies, advocacy groups, and others who can help us address the challenges we have identified, and thereby accelerate the development of new approaches to understand and eradicate lymphoma.”

To weigh in, visit: http://www.hematology.org/lymphoma-roadmap.

This report was developed after a review of the state of the science in lymphoma that took place at a special ASH Meeting on Lymphoma Biology in August 2014. A second ASH Meeting on Lymphoma Biology is planned for the summer of 2016.

Researcher in the lab

Photo by Darren Baker

By agreeing upon—and addressing—the aspects of lymphoma research that need the most improvement, the research community could advance the treatment of these diseases, according to a report published in Blood.

The report’s authors said limitations in research infrastructure, funding, and collaborative approaches across research centers present potential challenges on the road to developing better treatments.

And they outlined several “priority areas” that, they believe, require particular attention.

“[Our report] draws focus to our most pressing needs, which, if unaddressed, will prevent transformative changes to how we study and treat these diseases,” said David M. Weinstock, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Directing our collaborative efforts toward the most high-impact areas will enable us to more rapidly bring life-saving treatments to our patients.”

The report lists the following priority areas:

• Infrastructure

  • Develop an adequate number of disease models for each lymphoma subtype
  • Establish a central repository of biospecimens, cell lines, and in vivo models with open access
  • Organize patient advocacy to support research.

• Research

  • Catalogue how lymphoma cells differ across disease subtypes
  • Better define and identify mutations and other abnormalities associated with the disease
  • Develop strategies to identify high-risk patients who may benefit most from clinical trials
  • Enhance efforts to use immune therapies to cure lymphoma
  • Better understand how lymphoma cells communicate with normal cells.

“[W]e invite clinicians, scientists, advocates, and patients to weigh in on this strategic roadmap so that it reflects the input of everyone in the community,” Dr Weinstock said. “We will share these priorities with funding agencies, advocacy groups, and others who can help us address the challenges we have identified, and thereby accelerate the development of new approaches to understand and eradicate lymphoma.”

To weigh in, visit: http://www.hematology.org/lymphoma-roadmap.

This report was developed after a review of the state of the science in lymphoma that took place at a special ASH Meeting on Lymphoma Biology in August 2014. A second ASH Meeting on Lymphoma Biology is planned for the summer of 2016.

Red blood cells

Preclinical research suggests an enzyme found in hematopoietic stem cells (HSCs) is key to maintaining periods of inactivity, thereby decreasing the odds that HSCs will divide too often and acquire mutations or cell damage.

Experiments showed that animals lacking this enzyme, inositol trisphosphate 3-kinase B (Itpkb), experience dangerous HSC activation and ultimately succumb to lethal anemia.

“These HSCs remain active too long and then disappear,” said Karsten Sauer, PhD, of The Scripps Research Institute in La Jolla, California.

“As a consequence, the mice lose their red blood cells and die.”

With this new understanding of Itpkb, Dr Sauer and his colleagues believe they are closer to improving therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, and lymphoma.

The team described their research in Blood.

The group set out to investigate the mechanisms that activate and deactivate HSCs. They focused on Itpkb because it is produced in HSCs, and the enzyme is known to dampen activating signaling in other cells.

“We hypothesized that Itpkb might do the same in HSCs to keep them at rest,” Dr Sauer said. “Moreover, Itpkb is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”

The researchers started with a strain of mice that lacked the gene to produce Itpkb. As expected, these mice developed hyperactive HSCs. Eventually, the mutant HSCs exhausted themselves and stopped producing progenitor cells, so the mice developed severe anemia and died.

Dr Sauer and his colleagues linked the abnormal behavior of the mutant HSCs to a chain of events at the molecular level.

Itpkb’s job is to attach phosphates to molecules called inositols, which then send messages to other parts of the cell. The researchers found that Itpkb can turn one inositol, IP3, into another inositol known as IP4.

This is significant because IP4 controls cell proliferation, cellular metabolism, and aspects of the immune system. The study showed that IP4 also protects HSCs by dampening PI3K/Akt/mTOR signaling.

To confirm this finding, the researchers treated the animals with the mTOR inhibitor rapamycin. The drug halted the abnormal signaling process and prevented the excessive division of HSCs lacking Itpkb. This supported the notion that Itpkb maintains HSCs’ quiescence by dampening PI3K/Akt/mTOR signaling.

Dr Sauer said future research in his lab will focus on studying whether Itpkb has a similar function in human HSCs.

“A major question is whether we can translate our findings into innovative therapies,” he said. “If we can show that Itpkb also keeps human HSCs healthy, this could open avenues to target Itpkb to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”

Red blood cells

Preclinical research suggests an enzyme found in hematopoietic stem cells (HSCs) is key to maintaining periods of inactivity, thereby decreasing the odds that HSCs will divide too often and acquire mutations or cell damage.

Experiments showed that animals lacking this enzyme, inositol trisphosphate 3-kinase B (Itpkb), experience dangerous HSC activation and ultimately succumb to lethal anemia.

“These HSCs remain active too long and then disappear,” said Karsten Sauer, PhD, of The Scripps Research Institute in La Jolla, California.

“As a consequence, the mice lose their red blood cells and die.”

With this new understanding of Itpkb, Dr Sauer and his colleagues believe they are closer to improving therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, and lymphoma.

The team described their research in Blood.

The group set out to investigate the mechanisms that activate and deactivate HSCs. They focused on Itpkb because it is produced in HSCs, and the enzyme is known to dampen activating signaling in other cells.

“We hypothesized that Itpkb might do the same in HSCs to keep them at rest,” Dr Sauer said. “Moreover, Itpkb is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”

The researchers started with a strain of mice that lacked the gene to produce Itpkb. As expected, these mice developed hyperactive HSCs. Eventually, the mutant HSCs exhausted themselves and stopped producing progenitor cells, so the mice developed severe anemia and died.

Dr Sauer and his colleagues linked the abnormal behavior of the mutant HSCs to a chain of events at the molecular level.

Itpkb’s job is to attach phosphates to molecules called inositols, which then send messages to other parts of the cell. The researchers found that Itpkb can turn one inositol, IP3, into another inositol known as IP4.

This is significant because IP4 controls cell proliferation, cellular metabolism, and aspects of the immune system. The study showed that IP4 also protects HSCs by dampening PI3K/Akt/mTOR signaling.

To confirm this finding, the researchers treated the animals with the mTOR inhibitor rapamycin. The drug halted the abnormal signaling process and prevented the excessive division of HSCs lacking Itpkb. This supported the notion that Itpkb maintains HSCs’ quiescence by dampening PI3K/Akt/mTOR signaling.

Dr Sauer said future research in his lab will focus on studying whether Itpkb has a similar function in human HSCs.

“A major question is whether we can translate our findings into innovative therapies,” he said. “If we can show that Itpkb also keeps human HSCs healthy, this could open avenues to target Itpkb to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”

Red blood cells

Preclinical research suggests an enzyme found in hematopoietic stem cells (HSCs) is key to maintaining periods of inactivity, thereby decreasing the odds that HSCs will divide too often and acquire mutations or cell damage.

Experiments showed that animals lacking this enzyme, inositol trisphosphate 3-kinase B (Itpkb), experience dangerous HSC activation and ultimately succumb to lethal anemia.

“These HSCs remain active too long and then disappear,” said Karsten Sauer, PhD, of The Scripps Research Institute in La Jolla, California.

“As a consequence, the mice lose their red blood cells and die.”

With this new understanding of Itpkb, Dr Sauer and his colleagues believe they are closer to improving therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, and lymphoma.

The team described their research in Blood.

The group set out to investigate the mechanisms that activate and deactivate HSCs. They focused on Itpkb because it is produced in HSCs, and the enzyme is known to dampen activating signaling in other cells.

“We hypothesized that Itpkb might do the same in HSCs to keep them at rest,” Dr Sauer said. “Moreover, Itpkb is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”

The researchers started with a strain of mice that lacked the gene to produce Itpkb. As expected, these mice developed hyperactive HSCs. Eventually, the mutant HSCs exhausted themselves and stopped producing progenitor cells, so the mice developed severe anemia and died.

Dr Sauer and his colleagues linked the abnormal behavior of the mutant HSCs to a chain of events at the molecular level.

Itpkb’s job is to attach phosphates to molecules called inositols, which then send messages to other parts of the cell. The researchers found that Itpkb can turn one inositol, IP3, into another inositol known as IP4.

This is significant because IP4 controls cell proliferation, cellular metabolism, and aspects of the immune system. The study showed that IP4 also protects HSCs by dampening PI3K/Akt/mTOR signaling.

To confirm this finding, the researchers treated the animals with the mTOR inhibitor rapamycin. The drug halted the abnormal signaling process and prevented the excessive division of HSCs lacking Itpkb. This supported the notion that Itpkb maintains HSCs’ quiescence by dampening PI3K/Akt/mTOR signaling.

Dr Sauer said future research in his lab will focus on studying whether Itpkb has a similar function in human HSCs.

“A major question is whether we can translate our findings into innovative therapies,” he said. “If we can show that Itpkb also keeps human HSCs healthy, this could open avenues to target Itpkb to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”

 

 

Farmer spraying pesticide

Photo by John Messina

 

The International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization, has found evidence suggesting that 5 organophosphate pesticides may be carcinogenic.

The IARC classified the herbicide glyphosate and the insecticides malathion and diazinon as “probably carcinogenic” to humans and the insecticides tetrachlorvinphos and parathion as “possibly carcinogenic” to humans.

A summary of these findings has been published in The Lancet Oncology.

Glyphosate

For the herbicide glyphosate, the IARC found limited evidence of carcinogenicity in humans. Case-control studies of occupational exposure to glyphosate in the US, Canada, and Sweden showed increased risks for non-Hodgkin lymphoma (NHL).

However, the Agricultural Health Study (AHS) showed no significantly increased risk of NHL in subjects exposed to glyphosate.

A study of community residents showed increases in blood markers of chromosomal damage after glyphosate formulations were sprayed nearby. And glyphosate was shown to cause DNA and chromosomal damage in human cells, although bacterial mutagenesis tests were negative.

In studies of male mice, glyphosate increased the incidence of renal tubule carcinoma and hemangiosarcoma. Glyphosate also increased the incidence of pancreatic islet-cell adenoma in male rats, and a glyphosate formulation promoted skin tumors in mice.

The IARC said glyphosate has the highest global production volume of all herbicides. It is used in agriculture, forestry, urban, and home applications.

Glyphosate has been detected in the air during spraying, in water, and in food. The general population is exposed to the chemical primarily by living near sprayed areas, home use, and diet. But the IARC said the level of exposure observed is generally low.

Malathion

The IARC classified malathion as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL and prostate cancer. Occupational use of malathion was associated with an increased risk of prostate cancer in a Canadian case-control study and in the AHS.

Studies of occupational exposures in the US, Canada, and Sweden revealed positive associations between malathion and NHL. However, results of the AHS did not show an association between the insecticide and NHL.

Studies showed that malathion induced DNA and chromosomal damage in humans and animals, although bacterial mutagenesis tests were negative. Results also suggested malathion disrupts hormone pathways.

Experiments in mice showed malathion increased the incidence of hepatocellular adenoma or carcinoma (combined). In rats, the insecticide increased the incidence of thyroid carcinoma in males, hepatocellular adenoma or carcinoma (combined) in females, and mammary gland adenocarcinoma after subcutaneous injection in females.

The IARC said malathion is used in “substantial volumes throughout the world” to control insects in agricultural and residential areas.

Workers may be exposed to malathion during the use and production of the product. The general population may be exposed if they live near sprayed areas, use the product at home, or consume food exposed to the chemical.

Diazinon

The IARC classified diazinon as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL, leukemia, and lung cancer.

Two multicenter, case-control studies of agricultural exposures suggested a positive association between diazinon and NHL. The AHS showed positive associations with specific subtypes of NHL but no overall increased risk of NHL. The AHS also suggested an increased risk of leukemia and lung cancer in subjects exposed to diazinon.

Evidence suggested that diazinon induced DNA or chromosomal damage in human and mammalian cells in vitro. In vivo, diazinon increased the incidence of hepatocellular carcinoma in mice and leukemia or lymphoma (combined) in rats, but only in males receiving the low dose in each study.

Diazinon has been used to control insects in agricultural and residential areas. The IARC said production volumes have been relatively low and decreased further after 2006 due to restrictions in the US and the European Union (EU). There was limited information on the use of this pesticide in other countries.

Tetrachlorvinphos

The insecticide tetrachlorvinphos was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals. The IARC said the evidence in humans was inadequate.

However, tetrachlorvinphos was shown to induce hepatocellular tumors (benign or malignant) in mice, renal tubule tumors (benign or malignant) in male mice, and spleen hemangioma in male rats.

Tetrachlorvinphos is banned in the EU. In the US, the insecticide is still used on livestock and pets (in flea collars). The IARC said there was no information available on tetrachlorvinphos use in other countries.

Parathion

The insecticide parathion was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals.

Researchers have observed associations between the insecticide and cancers in several tissues in occupational studies. But the IARC said the evidence that parathion is carcinogenic in humans remains sparse.

Experiments in mice showed that parathion increased the incidence of bronchioloalveolar adenoma and/or carcinoma in males and lymphoma in females. In rats, parathion induced adrenal cortical adenoma or carcinoma (combined), malignant pancreatic tumors, and thyroid follicular cell adenoma in males, and mammary gland adenocarcinoma (after subcutaneous injection in females).

Parathion use has been severely restricted since the 1980s, and all authorized uses of this chemical were cancelled in the EU and the US by 2003.

 

 

Farmer spraying pesticide

Photo by John Messina

 

The International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization, has found evidence suggesting that 5 organophosphate pesticides may be carcinogenic.

The IARC classified the herbicide glyphosate and the insecticides malathion and diazinon as “probably carcinogenic” to humans and the insecticides tetrachlorvinphos and parathion as “possibly carcinogenic” to humans.

A summary of these findings has been published in The Lancet Oncology.

Glyphosate

For the herbicide glyphosate, the IARC found limited evidence of carcinogenicity in humans. Case-control studies of occupational exposure to glyphosate in the US, Canada, and Sweden showed increased risks for non-Hodgkin lymphoma (NHL).

However, the Agricultural Health Study (AHS) showed no significantly increased risk of NHL in subjects exposed to glyphosate.

A study of community residents showed increases in blood markers of chromosomal damage after glyphosate formulations were sprayed nearby. And glyphosate was shown to cause DNA and chromosomal damage in human cells, although bacterial mutagenesis tests were negative.

In studies of male mice, glyphosate increased the incidence of renal tubule carcinoma and hemangiosarcoma. Glyphosate also increased the incidence of pancreatic islet-cell adenoma in male rats, and a glyphosate formulation promoted skin tumors in mice.

The IARC said glyphosate has the highest global production volume of all herbicides. It is used in agriculture, forestry, urban, and home applications.

Glyphosate has been detected in the air during spraying, in water, and in food. The general population is exposed to the chemical primarily by living near sprayed areas, home use, and diet. But the IARC said the level of exposure observed is generally low.

Malathion

The IARC classified malathion as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL and prostate cancer. Occupational use of malathion was associated with an increased risk of prostate cancer in a Canadian case-control study and in the AHS.

Studies of occupational exposures in the US, Canada, and Sweden revealed positive associations between malathion and NHL. However, results of the AHS did not show an association between the insecticide and NHL.

Studies showed that malathion induced DNA and chromosomal damage in humans and animals, although bacterial mutagenesis tests were negative. Results also suggested malathion disrupts hormone pathways.

Experiments in mice showed malathion increased the incidence of hepatocellular adenoma or carcinoma (combined). In rats, the insecticide increased the incidence of thyroid carcinoma in males, hepatocellular adenoma or carcinoma (combined) in females, and mammary gland adenocarcinoma after subcutaneous injection in females.

The IARC said malathion is used in “substantial volumes throughout the world” to control insects in agricultural and residential areas.

Workers may be exposed to malathion during the use and production of the product. The general population may be exposed if they live near sprayed areas, use the product at home, or consume food exposed to the chemical.

Diazinon

The IARC classified diazinon as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL, leukemia, and lung cancer.

Two multicenter, case-control studies of agricultural exposures suggested a positive association between diazinon and NHL. The AHS showed positive associations with specific subtypes of NHL but no overall increased risk of NHL. The AHS also suggested an increased risk of leukemia and lung cancer in subjects exposed to diazinon.

Evidence suggested that diazinon induced DNA or chromosomal damage in human and mammalian cells in vitro. In vivo, diazinon increased the incidence of hepatocellular carcinoma in mice and leukemia or lymphoma (combined) in rats, but only in males receiving the low dose in each study.

Diazinon has been used to control insects in agricultural and residential areas. The IARC said production volumes have been relatively low and decreased further after 2006 due to restrictions in the US and the European Union (EU). There was limited information on the use of this pesticide in other countries.

Tetrachlorvinphos

The insecticide tetrachlorvinphos was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals. The IARC said the evidence in humans was inadequate.

However, tetrachlorvinphos was shown to induce hepatocellular tumors (benign or malignant) in mice, renal tubule tumors (benign or malignant) in male mice, and spleen hemangioma in male rats.

Tetrachlorvinphos is banned in the EU. In the US, the insecticide is still used on livestock and pets (in flea collars). The IARC said there was no information available on tetrachlorvinphos use in other countries.

Parathion

The insecticide parathion was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals.

Researchers have observed associations between the insecticide and cancers in several tissues in occupational studies. But the IARC said the evidence that parathion is carcinogenic in humans remains sparse.

Experiments in mice showed that parathion increased the incidence of bronchioloalveolar adenoma and/or carcinoma in males and lymphoma in females. In rats, parathion induced adrenal cortical adenoma or carcinoma (combined), malignant pancreatic tumors, and thyroid follicular cell adenoma in males, and mammary gland adenocarcinoma (after subcutaneous injection in females).

Parathion use has been severely restricted since the 1980s, and all authorized uses of this chemical were cancelled in the EU and the US by 2003.

 

 

Farmer spraying pesticide

Photo by John Messina

 

The International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization, has found evidence suggesting that 5 organophosphate pesticides may be carcinogenic.

The IARC classified the herbicide glyphosate and the insecticides malathion and diazinon as “probably carcinogenic” to humans and the insecticides tetrachlorvinphos and parathion as “possibly carcinogenic” to humans.

A summary of these findings has been published in The Lancet Oncology.

Glyphosate

For the herbicide glyphosate, the IARC found limited evidence of carcinogenicity in humans. Case-control studies of occupational exposure to glyphosate in the US, Canada, and Sweden showed increased risks for non-Hodgkin lymphoma (NHL).

However, the Agricultural Health Study (AHS) showed no significantly increased risk of NHL in subjects exposed to glyphosate.

A study of community residents showed increases in blood markers of chromosomal damage after glyphosate formulations were sprayed nearby. And glyphosate was shown to cause DNA and chromosomal damage in human cells, although bacterial mutagenesis tests were negative.

In studies of male mice, glyphosate increased the incidence of renal tubule carcinoma and hemangiosarcoma. Glyphosate also increased the incidence of pancreatic islet-cell adenoma in male rats, and a glyphosate formulation promoted skin tumors in mice.

The IARC said glyphosate has the highest global production volume of all herbicides. It is used in agriculture, forestry, urban, and home applications.

Glyphosate has been detected in the air during spraying, in water, and in food. The general population is exposed to the chemical primarily by living near sprayed areas, home use, and diet. But the IARC said the level of exposure observed is generally low.

Malathion

The IARC classified malathion as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL and prostate cancer. Occupational use of malathion was associated with an increased risk of prostate cancer in a Canadian case-control study and in the AHS.

Studies of occupational exposures in the US, Canada, and Sweden revealed positive associations between malathion and NHL. However, results of the AHS did not show an association between the insecticide and NHL.

Studies showed that malathion induced DNA and chromosomal damage in humans and animals, although bacterial mutagenesis tests were negative. Results also suggested malathion disrupts hormone pathways.

Experiments in mice showed malathion increased the incidence of hepatocellular adenoma or carcinoma (combined). In rats, the insecticide increased the incidence of thyroid carcinoma in males, hepatocellular adenoma or carcinoma (combined) in females, and mammary gland adenocarcinoma after subcutaneous injection in females.

The IARC said malathion is used in “substantial volumes throughout the world” to control insects in agricultural and residential areas.

Workers may be exposed to malathion during the use and production of the product. The general population may be exposed if they live near sprayed areas, use the product at home, or consume food exposed to the chemical.

Diazinon

The IARC classified diazinon as “probably carcinogenic” for humans based on limited evidence linking the insecticide to NHL, leukemia, and lung cancer.

Two multicenter, case-control studies of agricultural exposures suggested a positive association between diazinon and NHL. The AHS showed positive associations with specific subtypes of NHL but no overall increased risk of NHL. The AHS also suggested an increased risk of leukemia and lung cancer in subjects exposed to diazinon.

Evidence suggested that diazinon induced DNA or chromosomal damage in human and mammalian cells in vitro. In vivo, diazinon increased the incidence of hepatocellular carcinoma in mice and leukemia or lymphoma (combined) in rats, but only in males receiving the low dose in each study.

Diazinon has been used to control insects in agricultural and residential areas. The IARC said production volumes have been relatively low and decreased further after 2006 due to restrictions in the US and the European Union (EU). There was limited information on the use of this pesticide in other countries.

Tetrachlorvinphos

The insecticide tetrachlorvinphos was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals. The IARC said the evidence in humans was inadequate.

However, tetrachlorvinphos was shown to induce hepatocellular tumors (benign or malignant) in mice, renal tubule tumors (benign or malignant) in male mice, and spleen hemangioma in male rats.

Tetrachlorvinphos is banned in the EU. In the US, the insecticide is still used on livestock and pets (in flea collars). The IARC said there was no information available on tetrachlorvinphos use in other countries.

Parathion

The insecticide parathion was classified as “possibly carcinogenic” to humans based on convincing evidence that the agent causes cancer in lab animals.

Researchers have observed associations between the insecticide and cancers in several tissues in occupational studies. But the IARC said the evidence that parathion is carcinogenic in humans remains sparse.

Experiments in mice showed that parathion increased the incidence of bronchioloalveolar adenoma and/or carcinoma in males and lymphoma in females. In rats, parathion induced adrenal cortical adenoma or carcinoma (combined), malignant pancreatic tumors, and thyroid follicular cell adenoma in males, and mammary gland adenocarcinoma (after subcutaneous injection in females).

Parathion use has been severely restricted since the 1980s, and all authorized uses of this chemical were cancelled in the EU and the US by 2003.

Micrograph showing HL

The anti-CD30 antibody-drug conjugate brentuximab vedotin can prolong progression-free survival (PFS) in Hodgkin lymphoma (HL) patients who have undergone autologous stem cell transplant (ASCT), results of the phase 3 AETHERA trial have shown.

The median PFS for patients who received brentuximab vedotin immediately after ASCT was nearly twice that of patients who received placebo—42.9 months and 24.1 months, respectively.

“No medication available today has had such dramatic results in patients with hard-to-treat Hodgkin lymphoma,” said Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Moskowitz and his colleagues detailed these results in The Lancet. The results were previously presented at the 2014 ASH Annual Meeting. The research was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.

The AETHERA study included 329 HL patients age 18 or older who were thought to be at high risk of relapse or progression after ASCT. Patients were randomized to receive placebo or 16 cycles of brentuximab vedotin once every 3 weeks.

After a median observation time of 30 months (range, 0-50 months), the rate of PFS was significantly higher in the brentuximab vedotin arm than the placebo arm. The hazard ratio was 0.57 (P=0.0013), according to an independent review group.

The estimated 2-year PFS was 63% in the brentuximab vedotin arm and 51% in the placebo arm, according to the independent review group. But according to investigators, the estimated 2-year PFS was 65% in the brentuximab vedotin arm and 45% in the placebo arm.

“Nearly all of these patients who are progression-free at 2 years are likely to be cured, since relapse 2 years after a transplant is unlikely,” Dr Moskowitz noted.

An interim analysis revealed no significant difference between the treatment arms with regard to overall survival.

The researchers said brentuximab vedotin was generally well-tolerated. The most common adverse events were peripheral neuropathy—occurring in 67% of brentuximab vedotin-treated patients and 13% of placebo-treated patients—and neutropenia—occurring in 35% and 12%, respectively.

In all, 53 patients died, 17% of those in the brentuximab vedotin arm and 16% of those in the placebo arm. The proportion of patients who died from disease-related illness was the same in both arms—11%.

“The bottom line is that brentuximab vedotin is a very effective drug in poor-risk Hodgkin lymphoma, and it spares patients from the harmful effects of further traditional chemotherapy by breaking down inside the cell, resulting in less toxicity,” Dr Moskowitz said.

Writing in a linked comment article, Andreas Engert, MD, of the University Hospital of Cologne in Germany, discussed how best to define which patients are at high risk of relapse and should receive brentuximab vedotin.

“AETHERA is a positive study establishing a promising new treatment approach for patients with Hodgkin’s lymphoma at high risk for relapse,” he wrote. “However, with a progression-free survival of about 50% at 24 months in the placebo group, whether this patient population is indeed high-risk could be debated.”

“An international consortium is currently reassessing the effect of risk factors in patients with relapsed Hodgkin’s lymphoma to define a high-risk patient population in need of consolidation treatment. We look forward to a better definition of patients with relapsed Hodgkin’s lymphoma who should receive consolidation treatment with brentuximab vedotin.”

Micrograph showing HL

The anti-CD30 antibody-drug conjugate brentuximab vedotin can prolong progression-free survival (PFS) in Hodgkin lymphoma (HL) patients who have undergone autologous stem cell transplant (ASCT), results of the phase 3 AETHERA trial have shown.

The median PFS for patients who received brentuximab vedotin immediately after ASCT was nearly twice that of patients who received placebo—42.9 months and 24.1 months, respectively.

“No medication available today has had such dramatic results in patients with hard-to-treat Hodgkin lymphoma,” said Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Moskowitz and his colleagues detailed these results in The Lancet. The results were previously presented at the 2014 ASH Annual Meeting. The research was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.

The AETHERA study included 329 HL patients age 18 or older who were thought to be at high risk of relapse or progression after ASCT. Patients were randomized to receive placebo or 16 cycles of brentuximab vedotin once every 3 weeks.

After a median observation time of 30 months (range, 0-50 months), the rate of PFS was significantly higher in the brentuximab vedotin arm than the placebo arm. The hazard ratio was 0.57 (P=0.0013), according to an independent review group.

The estimated 2-year PFS was 63% in the brentuximab vedotin arm and 51% in the placebo arm, according to the independent review group. But according to investigators, the estimated 2-year PFS was 65% in the brentuximab vedotin arm and 45% in the placebo arm.

“Nearly all of these patients who are progression-free at 2 years are likely to be cured, since relapse 2 years after a transplant is unlikely,” Dr Moskowitz noted.

An interim analysis revealed no significant difference between the treatment arms with regard to overall survival.

The researchers said brentuximab vedotin was generally well-tolerated. The most common adverse events were peripheral neuropathy—occurring in 67% of brentuximab vedotin-treated patients and 13% of placebo-treated patients—and neutropenia—occurring in 35% and 12%, respectively.

In all, 53 patients died, 17% of those in the brentuximab vedotin arm and 16% of those in the placebo arm. The proportion of patients who died from disease-related illness was the same in both arms—11%.

“The bottom line is that brentuximab vedotin is a very effective drug in poor-risk Hodgkin lymphoma, and it spares patients from the harmful effects of further traditional chemotherapy by breaking down inside the cell, resulting in less toxicity,” Dr Moskowitz said.

Writing in a linked comment article, Andreas Engert, MD, of the University Hospital of Cologne in Germany, discussed how best to define which patients are at high risk of relapse and should receive brentuximab vedotin.

“AETHERA is a positive study establishing a promising new treatment approach for patients with Hodgkin’s lymphoma at high risk for relapse,” he wrote. “However, with a progression-free survival of about 50% at 24 months in the placebo group, whether this patient population is indeed high-risk could be debated.”

“An international consortium is currently reassessing the effect of risk factors in patients with relapsed Hodgkin’s lymphoma to define a high-risk patient population in need of consolidation treatment. We look forward to a better definition of patients with relapsed Hodgkin’s lymphoma who should receive consolidation treatment with brentuximab vedotin.”

Micrograph showing HL

The anti-CD30 antibody-drug conjugate brentuximab vedotin can prolong progression-free survival (PFS) in Hodgkin lymphoma (HL) patients who have undergone autologous stem cell transplant (ASCT), results of the phase 3 AETHERA trial have shown.

The median PFS for patients who received brentuximab vedotin immediately after ASCT was nearly twice that of patients who received placebo—42.9 months and 24.1 months, respectively.

“No medication available today has had such dramatic results in patients with hard-to-treat Hodgkin lymphoma,” said Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Moskowitz and his colleagues detailed these results in The Lancet. The results were previously presented at the 2014 ASH Annual Meeting. The research was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab vedotin.

The AETHERA study included 329 HL patients age 18 or older who were thought to be at high risk of relapse or progression after ASCT. Patients were randomized to receive placebo or 16 cycles of brentuximab vedotin once every 3 weeks.

After a median observation time of 30 months (range, 0-50 months), the rate of PFS was significantly higher in the brentuximab vedotin arm than the placebo arm. The hazard ratio was 0.57 (P=0.0013), according to an independent review group.

The estimated 2-year PFS was 63% in the brentuximab vedotin arm and 51% in the placebo arm, according to the independent review group. But according to investigators, the estimated 2-year PFS was 65% in the brentuximab vedotin arm and 45% in the placebo arm.

“Nearly all of these patients who are progression-free at 2 years are likely to be cured, since relapse 2 years after a transplant is unlikely,” Dr Moskowitz noted.

An interim analysis revealed no significant difference between the treatment arms with regard to overall survival.

The researchers said brentuximab vedotin was generally well-tolerated. The most common adverse events were peripheral neuropathy—occurring in 67% of brentuximab vedotin-treated patients and 13% of placebo-treated patients—and neutropenia—occurring in 35% and 12%, respectively.

In all, 53 patients died, 17% of those in the brentuximab vedotin arm and 16% of those in the placebo arm. The proportion of patients who died from disease-related illness was the same in both arms—11%.

“The bottom line is that brentuximab vedotin is a very effective drug in poor-risk Hodgkin lymphoma, and it spares patients from the harmful effects of further traditional chemotherapy by breaking down inside the cell, resulting in less toxicity,” Dr Moskowitz said.

Writing in a linked comment article, Andreas Engert, MD, of the University Hospital of Cologne in Germany, discussed how best to define which patients are at high risk of relapse and should receive brentuximab vedotin.

“AETHERA is a positive study establishing a promising new treatment approach for patients with Hodgkin’s lymphoma at high risk for relapse,” he wrote. “However, with a progression-free survival of about 50% at 24 months in the placebo group, whether this patient population is indeed high-risk could be debated.”

“An international consortium is currently reassessing the effect of risk factors in patients with relapsed Hodgkin’s lymphoma to define a high-risk patient population in need of consolidation treatment. We look forward to a better definition of patients with relapsed Hodgkin’s lymphoma who should receive consolidation treatment with brentuximab vedotin.”

Brentuximab vedotin (Adcetris) increased progression-free survival to 43 months when given to adults with hard-to-treat Hodgkin’s lymphoma immediately after stem cell transplant, compared to 24 months for placebo, according to research published online March 18 in The Lancet.

As part of the AETHERA phase III trial, 329 patients with Hodgkin’s lymphoma who were at high risk of relapse or progression after autologous stem cell transplant were given brentuximab vedotin infusions or placebo every 3 weeks for up to 16 cycles. After a 2-year follow-up, the cancer had not progressed in 65% of the patients in the treatment group, compared with 45% in the placebo group.

The most common side effects were peripheral neuropathy (67% vs. 13% placebo) and neutropenia (35% vs. 12% placebo), noted Dr. Craig Moskowitz of Memorial Sloan Kettering Cancer Center, New York, and his associates.

Read the full article here.

Brentuximab vedotin (Adcetris) increased progression-free survival to 43 months when given to adults with hard-to-treat Hodgkin’s lymphoma immediately after stem cell transplant, compared to 24 months for placebo, according to research published online March 18 in The Lancet.

As part of the AETHERA phase III trial, 329 patients with Hodgkin’s lymphoma who were at high risk of relapse or progression after autologous stem cell transplant were given brentuximab vedotin infusions or placebo every 3 weeks for up to 16 cycles. After a 2-year follow-up, the cancer had not progressed in 65% of the patients in the treatment group, compared with 45% in the placebo group.

The most common side effects were peripheral neuropathy (67% vs. 13% placebo) and neutropenia (35% vs. 12% placebo), noted Dr. Craig Moskowitz of Memorial Sloan Kettering Cancer Center, New York, and his associates.

Read the full article here.

Brentuximab vedotin (Adcetris) increased progression-free survival to 43 months when given to adults with hard-to-treat Hodgkin’s lymphoma immediately after stem cell transplant, compared to 24 months for placebo, according to research published online March 18 in The Lancet.

As part of the AETHERA phase III trial, 329 patients with Hodgkin’s lymphoma who were at high risk of relapse or progression after autologous stem cell transplant were given brentuximab vedotin infusions or placebo every 3 weeks for up to 16 cycles. After a 2-year follow-up, the cancer had not progressed in 65% of the patients in the treatment group, compared with 45% in the placebo group.

The most common side effects were peripheral neuropathy (67% vs. 13% placebo) and neutropenia (35% vs. 12% placebo), noted Dr. Craig Moskowitz of Memorial Sloan Kettering Cancer Center, New York, and his associates.

Read the full article here.

US dollars

Photo by Petr Kratochvil

Increasingly high prices for cancer drugs are affecting patient care and the overall healthcare system in the US, according to authors of an article in Mayo Clinic Proceedings.

The authors noted that the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000, and to more than $100,000 by 2012.

Over nearly the same period, the average household income in the US decreased by about 8%.

“Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries,” said author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“As oncologists, we have a moral obligation to advocate for affordable cancer drugs for our patients.”

Dr Rajkumar and co-author Hagop Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, rebutted the major arguments the pharmaceutical industry uses to justify the high price of cancer drugs; namely, the expense of conducting research and drug development, the comparative benefits to patients, that market forces will settle prices to reasonable levels, and that price controls on cancer drugs will stifle innovation.

“One of the facts that people do not realize is that cancer drugs, for the most part, are not operating under a free market economy,” Dr Rajkumar said. “The fact that there are 5 approved drugs to treat an incurable cancer does not mean there is competition.”

“Typically, the standard of care is that each drug is used sequentially or in combination, so that each new drug represents a monopoly with exclusivity granted by patent protection for many years.”

Drs Rajkumar and Kantarjian said other reasons for the high cost of cancer drugs include legislation that prevents Medicare from being able to negotiate drug prices and a lack of value-based pricing, which ties the cost of a drug to its relative effectiveness compared to other drugs.

The authors recommended a set of potential solutions to help control and reduce the high cost of cancer drugs in the US. Some of their recommendations are already in practice in other developed countries. Their recommendations include:

• Allow Medicare to negotiate drug prices
• Develop cancer treatment pathways/guidelines that incorporate the cost and benefit of cancer drugs
• Allow the Food and Drug Administration or physician panels to recommend target prices based on a drug’s magnitude of benefit (value-based pricing)
• Eliminate “pay-for-delay” strategies in which a pharmaceutical company with a brand name drug shares profits on that drug with a generic drug manufacturer for the remainder of a patent period, effectively eliminating a patent challenge and competition
• Allow the importation of drugs from abroad for personal use
• Allow the Patient-Centered Outcomes Research Institute and other cancer advocacy groups to consider cost in their recommendations
• Create patient-driven grassroots movements and organizations to advocate effectively for the interests of patients with cancer to balance advocacy efforts of pharmaceutical companies, insurance companies, pharmacy outlets, and hospitals.

Dr Kantarjian has organized a petition, which is available on change.org, asking the federal government to implement these changes.

US dollars

Photo by Petr Kratochvil

Increasingly high prices for cancer drugs are affecting patient care and the overall healthcare system in the US, according to authors of an article in Mayo Clinic Proceedings.

The authors noted that the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000, and to more than $100,000 by 2012.

Over nearly the same period, the average household income in the US decreased by about 8%.

“Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries,” said author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“As oncologists, we have a moral obligation to advocate for affordable cancer drugs for our patients.”

Dr Rajkumar and co-author Hagop Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, rebutted the major arguments the pharmaceutical industry uses to justify the high price of cancer drugs; namely, the expense of conducting research and drug development, the comparative benefits to patients, that market forces will settle prices to reasonable levels, and that price controls on cancer drugs will stifle innovation.

“One of the facts that people do not realize is that cancer drugs, for the most part, are not operating under a free market economy,” Dr Rajkumar said. “The fact that there are 5 approved drugs to treat an incurable cancer does not mean there is competition.”

“Typically, the standard of care is that each drug is used sequentially or in combination, so that each new drug represents a monopoly with exclusivity granted by patent protection for many years.”

Drs Rajkumar and Kantarjian said other reasons for the high cost of cancer drugs include legislation that prevents Medicare from being able to negotiate drug prices and a lack of value-based pricing, which ties the cost of a drug to its relative effectiveness compared to other drugs.

The authors recommended a set of potential solutions to help control and reduce the high cost of cancer drugs in the US. Some of their recommendations are already in practice in other developed countries. Their recommendations include:

• Allow Medicare to negotiate drug prices
• Develop cancer treatment pathways/guidelines that incorporate the cost and benefit of cancer drugs
• Allow the Food and Drug Administration or physician panels to recommend target prices based on a drug’s magnitude of benefit (value-based pricing)
• Eliminate “pay-for-delay” strategies in which a pharmaceutical company with a brand name drug shares profits on that drug with a generic drug manufacturer for the remainder of a patent period, effectively eliminating a patent challenge and competition
• Allow the importation of drugs from abroad for personal use
• Allow the Patient-Centered Outcomes Research Institute and other cancer advocacy groups to consider cost in their recommendations
• Create patient-driven grassroots movements and organizations to advocate effectively for the interests of patients with cancer to balance advocacy efforts of pharmaceutical companies, insurance companies, pharmacy outlets, and hospitals.

Dr Kantarjian has organized a petition, which is available on change.org, asking the federal government to implement these changes.

US dollars

Photo by Petr Kratochvil

Increasingly high prices for cancer drugs are affecting patient care and the overall healthcare system in the US, according to authors of an article in Mayo Clinic Proceedings.

The authors noted that the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000, and to more than $100,000 by 2012.

Over nearly the same period, the average household income in the US decreased by about 8%.

“Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries,” said author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“As oncologists, we have a moral obligation to advocate for affordable cancer drugs for our patients.”

Dr Rajkumar and co-author Hagop Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, rebutted the major arguments the pharmaceutical industry uses to justify the high price of cancer drugs; namely, the expense of conducting research and drug development, the comparative benefits to patients, that market forces will settle prices to reasonable levels, and that price controls on cancer drugs will stifle innovation.

“One of the facts that people do not realize is that cancer drugs, for the most part, are not operating under a free market economy,” Dr Rajkumar said. “The fact that there are 5 approved drugs to treat an incurable cancer does not mean there is competition.”

“Typically, the standard of care is that each drug is used sequentially or in combination, so that each new drug represents a monopoly with exclusivity granted by patent protection for many years.”

Drs Rajkumar and Kantarjian said other reasons for the high cost of cancer drugs include legislation that prevents Medicare from being able to negotiate drug prices and a lack of value-based pricing, which ties the cost of a drug to its relative effectiveness compared to other drugs.

The authors recommended a set of potential solutions to help control and reduce the high cost of cancer drugs in the US. Some of their recommendations are already in practice in other developed countries. Their recommendations include:

• Allow Medicare to negotiate drug prices
• Develop cancer treatment pathways/guidelines that incorporate the cost and benefit of cancer drugs
• Allow the Food and Drug Administration or physician panels to recommend target prices based on a drug’s magnitude of benefit (value-based pricing)
• Eliminate “pay-for-delay” strategies in which a pharmaceutical company with a brand name drug shares profits on that drug with a generic drug manufacturer for the remainder of a patent period, effectively eliminating a patent challenge and competition
• Allow the importation of drugs from abroad for personal use
• Allow the Patient-Centered Outcomes Research Institute and other cancer advocacy groups to consider cost in their recommendations
• Create patient-driven grassroots movements and organizations to advocate effectively for the interests of patients with cancer to balance advocacy efforts of pharmaceutical companies, insurance companies, pharmacy outlets, and hospitals.

Dr Kantarjian has organized a petition, which is available on change.org, asking the federal government to implement these changes.