HT Staff

Cells before (above) and after

(below) palbociclib treatment

Images courtesy of Iris Uras

and Vetmeduni Vienna

Palbociclib, a CDK4/6 kinase inhibitor approved to treat breast cancer, could also be used to treat acute myeloid leukemia (AML), according to research published in Blood.

The drug induced apoptosis in FLT3-mutant AML cells and inhibited tumor growth in mouse models of FLT3-ITD+ AML.

Palbociclib also demonstrated synergy with a range of FLT3 inhibitors.

The researchers said these results can be explained by the fact that CDK6 is “absolutely required” for the viability of FLT3-dependent leukemic cells and FLT3-ITD-induced leukemogenesis.

“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” said study author Iris Uras, PhD, of Vetmeduni Vienna in Austria.

Dr Uras and her colleagues first found that palbociclib acts specifically on FLT3-ITD+ AML cells, inhibiting their viability in a dose-dependent manner. Palbociclib induced cell-cycle arrest and apoptosis in these cells.

Palbociclib also arrested tumor growth in mouse models of FLT3-ITD+ AML, significantly decreasing tumor size when compared to untreated controls (P<0.05).

Further investigation revealed that CDK6—but not CDK4—directly regulates FLT3 expression.

CDK6 acts as a transcriptional regulator of FLT3 and the serine threonine kinase PIM1, which also plays a role in leukemogenesis. As palbociclib inhibits CDK6, it downregulates FLT3 and reduces PIM1 transcription.

To build upon these findings, the researchers tested palbociclib in combination with FLT3 inhibitors.

They observed “pronounced in vitro synergy” between palbociclib and TCS-359, tandutinib, and quizartinib in FLT3-ITD+ AML cell lines and samples from patients with FLT3-ITD+ AML.

“We are attacking FLT3 from two sides there—blocking its expression and inhibiting its activity,” Dr Uras said. “A combination therapy could be a breakthrough for many patients suffering from leukemia.”

Cells before (above) and after

(below) palbociclib treatment

Images courtesy of Iris Uras

and Vetmeduni Vienna

Palbociclib, a CDK4/6 kinase inhibitor approved to treat breast cancer, could also be used to treat acute myeloid leukemia (AML), according to research published in Blood.

The drug induced apoptosis in FLT3-mutant AML cells and inhibited tumor growth in mouse models of FLT3-ITD+ AML.

Palbociclib also demonstrated synergy with a range of FLT3 inhibitors.

The researchers said these results can be explained by the fact that CDK6 is “absolutely required” for the viability of FLT3-dependent leukemic cells and FLT3-ITD-induced leukemogenesis.

“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” said study author Iris Uras, PhD, of Vetmeduni Vienna in Austria.

Dr Uras and her colleagues first found that palbociclib acts specifically on FLT3-ITD+ AML cells, inhibiting their viability in a dose-dependent manner. Palbociclib induced cell-cycle arrest and apoptosis in these cells.

Palbociclib also arrested tumor growth in mouse models of FLT3-ITD+ AML, significantly decreasing tumor size when compared to untreated controls (P<0.05).

Further investigation revealed that CDK6—but not CDK4—directly regulates FLT3 expression.

CDK6 acts as a transcriptional regulator of FLT3 and the serine threonine kinase PIM1, which also plays a role in leukemogenesis. As palbociclib inhibits CDK6, it downregulates FLT3 and reduces PIM1 transcription.

To build upon these findings, the researchers tested palbociclib in combination with FLT3 inhibitors.

They observed “pronounced in vitro synergy” between palbociclib and TCS-359, tandutinib, and quizartinib in FLT3-ITD+ AML cell lines and samples from patients with FLT3-ITD+ AML.

“We are attacking FLT3 from two sides there—blocking its expression and inhibiting its activity,” Dr Uras said. “A combination therapy could be a breakthrough for many patients suffering from leukemia.”

Cells before (above) and after

(below) palbociclib treatment

Images courtesy of Iris Uras

and Vetmeduni Vienna

Palbociclib, a CDK4/6 kinase inhibitor approved to treat breast cancer, could also be used to treat acute myeloid leukemia (AML), according to research published in Blood.

The drug induced apoptosis in FLT3-mutant AML cells and inhibited tumor growth in mouse models of FLT3-ITD+ AML.

Palbociclib also demonstrated synergy with a range of FLT3 inhibitors.

The researchers said these results can be explained by the fact that CDK6 is “absolutely required” for the viability of FLT3-dependent leukemic cells and FLT3-ITD-induced leukemogenesis.

“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” said study author Iris Uras, PhD, of Vetmeduni Vienna in Austria.

Dr Uras and her colleagues first found that palbociclib acts specifically on FLT3-ITD+ AML cells, inhibiting their viability in a dose-dependent manner. Palbociclib induced cell-cycle arrest and apoptosis in these cells.

Palbociclib also arrested tumor growth in mouse models of FLT3-ITD+ AML, significantly decreasing tumor size when compared to untreated controls (P<0.05).

Further investigation revealed that CDK6—but not CDK4—directly regulates FLT3 expression.

CDK6 acts as a transcriptional regulator of FLT3 and the serine threonine kinase PIM1, which also plays a role in leukemogenesis. As palbociclib inhibits CDK6, it downregulates FLT3 and reduces PIM1 transcription.

To build upon these findings, the researchers tested palbociclib in combination with FLT3 inhibitors.

They observed “pronounced in vitro synergy” between palbociclib and TCS-359, tandutinib, and quizartinib in FLT3-ITD+ AML cell lines and samples from patients with FLT3-ITD+ AML.

“We are attacking FLT3 from two sides there—blocking its expression and inhibiting its activity,” Dr Uras said. “A combination therapy could be a breakthrough for many patients suffering from leukemia.”

Micrograph showing ALL

Patients with high-risk, relapsed/refractory acute lymphoblastic leukemia (ALL) may be sensitive to treatment with SMAC mimetics, according to researchers.

One SMAC mimetic in particular, birinapant, demonstrated varied activity in samples from ALL patients, but samples from patients with resistant disease were the most sensitive to the drug.

Birinapant also had “marked antileukemic effects” in some mice with ALL.

The researchers found this antileukemic activity was dependent on simultaneous activation of apoptosis and necroptosis.

The team reported these findings in Science Translational Medicine.

“Our research reveals that an alternative cell-death program, necroptosis, can be activated in human ALL cells,” said study author Beat Bornhauser, PhD, of the Children’s Hospital Zurich in Switzerland.

“This enables leukemia cells that barely respond to existing chemotherapeutic drugs to be killed off.”

In vitro and in vivo activity

The researchers tested the efficacy of SMAC mimetics in a set of 51 patient-derived B-cell precursor ALL xenografts, which was enriched for samples from relapsed and drug-resistant disease.

The response to birinapant varied greatly, but samples from high-risk or relapsed patients tended to be highly sensitive to the drug.

The researchers observed similar response profiles with the SMAC mimetic LCL161, although this drug proved less potent than birinapant.

The team also evaluated the antileukemic activity of SMAC mimetics in mouse models of ALL.

Birinapant delayed disease progression and induced complete responses in sensitive ALL cases. LCL161, on the other hand, did not display any in vivo activity.

Determining the mechanism of activity

The researchers used CRISPR-Cas9 to determine how SMAC mimetics fight ALL, and they discovered that the drugs trigger both apoptosis and necroptosis.

If the genes responsible for apoptosis were disabled via genome editing, leukemia cells died due to necroptosis after SMAC mimetics had been administered. If necroptotic genes were disabled, apoptosis led to cell death.

Only the simultaneous deactivation of apoptotic and necroptotic genes resulted in the complete resistance of leukemic cells to SMAC mimetics.

Therefore, the researchers concluded that simultaneous activation of apoptosis and necroptosis is responsible for the strong anti-leukemic effect of SMAC mimetics.

“SMAC mimetics have great potential to eliminate leukemia cells in patients that aren’t sensitive to established chemotherapeutic drugs,” Dr Bornhauser said. “They are effectively a double-edged sword. They kill cells that block apoptosis through necroptosis.”

The researchers are now looking for suitable biomarkers to identify patients who might benefit from treatment with SMAC mimetics in clinical trials.

Micrograph showing ALL

Patients with high-risk, relapsed/refractory acute lymphoblastic leukemia (ALL) may be sensitive to treatment with SMAC mimetics, according to researchers.

One SMAC mimetic in particular, birinapant, demonstrated varied activity in samples from ALL patients, but samples from patients with resistant disease were the most sensitive to the drug.

Birinapant also had “marked antileukemic effects” in some mice with ALL.

The researchers found this antileukemic activity was dependent on simultaneous activation of apoptosis and necroptosis.

The team reported these findings in Science Translational Medicine.

“Our research reveals that an alternative cell-death program, necroptosis, can be activated in human ALL cells,” said study author Beat Bornhauser, PhD, of the Children’s Hospital Zurich in Switzerland.

“This enables leukemia cells that barely respond to existing chemotherapeutic drugs to be killed off.”

In vitro and in vivo activity

The researchers tested the efficacy of SMAC mimetics in a set of 51 patient-derived B-cell precursor ALL xenografts, which was enriched for samples from relapsed and drug-resistant disease.

The response to birinapant varied greatly, but samples from high-risk or relapsed patients tended to be highly sensitive to the drug.

The researchers observed similar response profiles with the SMAC mimetic LCL161, although this drug proved less potent than birinapant.

The team also evaluated the antileukemic activity of SMAC mimetics in mouse models of ALL.

Birinapant delayed disease progression and induced complete responses in sensitive ALL cases. LCL161, on the other hand, did not display any in vivo activity.

Determining the mechanism of activity

The researchers used CRISPR-Cas9 to determine how SMAC mimetics fight ALL, and they discovered that the drugs trigger both apoptosis and necroptosis.

If the genes responsible for apoptosis were disabled via genome editing, leukemia cells died due to necroptosis after SMAC mimetics had been administered. If necroptotic genes were disabled, apoptosis led to cell death.

Only the simultaneous deactivation of apoptotic and necroptotic genes resulted in the complete resistance of leukemic cells to SMAC mimetics.

Therefore, the researchers concluded that simultaneous activation of apoptosis and necroptosis is responsible for the strong anti-leukemic effect of SMAC mimetics.

“SMAC mimetics have great potential to eliminate leukemia cells in patients that aren’t sensitive to established chemotherapeutic drugs,” Dr Bornhauser said. “They are effectively a double-edged sword. They kill cells that block apoptosis through necroptosis.”

The researchers are now looking for suitable biomarkers to identify patients who might benefit from treatment with SMAC mimetics in clinical trials.

Micrograph showing ALL

Patients with high-risk, relapsed/refractory acute lymphoblastic leukemia (ALL) may be sensitive to treatment with SMAC mimetics, according to researchers.

One SMAC mimetic in particular, birinapant, demonstrated varied activity in samples from ALL patients, but samples from patients with resistant disease were the most sensitive to the drug.

Birinapant also had “marked antileukemic effects” in some mice with ALL.

The researchers found this antileukemic activity was dependent on simultaneous activation of apoptosis and necroptosis.

The team reported these findings in Science Translational Medicine.

“Our research reveals that an alternative cell-death program, necroptosis, can be activated in human ALL cells,” said study author Beat Bornhauser, PhD, of the Children’s Hospital Zurich in Switzerland.

“This enables leukemia cells that barely respond to existing chemotherapeutic drugs to be killed off.”

In vitro and in vivo activity

The researchers tested the efficacy of SMAC mimetics in a set of 51 patient-derived B-cell precursor ALL xenografts, which was enriched for samples from relapsed and drug-resistant disease.

The response to birinapant varied greatly, but samples from high-risk or relapsed patients tended to be highly sensitive to the drug.

The researchers observed similar response profiles with the SMAC mimetic LCL161, although this drug proved less potent than birinapant.

The team also evaluated the antileukemic activity of SMAC mimetics in mouse models of ALL.

Birinapant delayed disease progression and induced complete responses in sensitive ALL cases. LCL161, on the other hand, did not display any in vivo activity.

Determining the mechanism of activity

The researchers used CRISPR-Cas9 to determine how SMAC mimetics fight ALL, and they discovered that the drugs trigger both apoptosis and necroptosis.

If the genes responsible for apoptosis were disabled via genome editing, leukemia cells died due to necroptosis after SMAC mimetics had been administered. If necroptotic genes were disabled, apoptosis led to cell death.

Only the simultaneous deactivation of apoptotic and necroptotic genes resulted in the complete resistance of leukemic cells to SMAC mimetics.

Therefore, the researchers concluded that simultaneous activation of apoptosis and necroptosis is responsible for the strong anti-leukemic effect of SMAC mimetics.

“SMAC mimetics have great potential to eliminate leukemia cells in patients that aren’t sensitive to established chemotherapeutic drugs,” Dr Bornhauser said. “They are effectively a double-edged sword. They kill cells that block apoptosis through necroptosis.”

The researchers are now looking for suitable biomarkers to identify patients who might benefit from treatment with SMAC mimetics in clinical trials.

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

SAN FRANCISCO—A new study has shown that hydroxyurea (HU) can improve lung function in young patients with sickle cell disease (SCD).

“Persons with sickle cell disease experience an annual decline in lung function that starts in childhood,” said study investigator Anya McLaren, MD, of The Hospital for Sick Children in Toronto, Ontario, Canada.

“This study is the first of its kind to look at the effect of hydroxyurea on lung function. We found that hydroxyurea improves annual pulmonary function decline in children with sickle cell disease by more than one-third.”

The study was presented at the ATS 2016 International Conference as abstract 7225.

For this study, Dr McLaren and her colleagues evaluated the effects of HU in 94 SCD patients. The patients’ average age at baseline was 11 (range, 6 to 20), 96% of patients had HbSS genotype, and 47% were male.

The patients were followed for 4 years after HU initiation. The investigators assessed lung function before and after HU initiation in a few ways.

They used the forced expiratory volume (FEV) test, which measures how much air a person can exhale during a forced breath. The amount of air can be measured during the first second of the forced breath (FEV1) and at later time points.

Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test. If the FEV1/FVC ratio is less than 80%, it indicates that an obstructive defect is present.

The investigators also assessed FEF25-75, or the forced expiratory flow at 25%–75% of FVC. This measurement helps determine if there is an obstruction in the airway.

In addition, the team measured total lung capacity.

Results

The investigators found no significant change in total lung capacity, FVC, or FEV1/FVC predicted measurements after patients began receiving HU.

However, there were significant improvements in both FEV1 and FEF25-75 after treatment.

The annual rate of decline in predicted FEV1 and FEF25-75 before patients started HU was -1.98%/year (95% CI -2.57 to -1.39) and -3.59%/year (95% CI -4.43 to -2.75), respectively.

After HU treatment began, there was a significant (P<0.05) improvement in the annual decline, to -1.28%/year (95% CI -1.79 to -0.76) and -2.88%/year (95% CI -3.49 to -2.28), respectively.

The investigators noted that changes in FEV1 and FEF25-75 were independent of a patient’s age at baseline and the time from HU therapy initiation.

Dr McLaren pointed out that HU is underused in SCD patients, likely because clinicians are concerned about patient non-compliance and afraid of potential side effects, particularly carcinogenesis. But some of those fears may be unfounded, she said.

“Long-term observational studies suggest beneficial effects [of HU] without excessive damage to bone marrow, deleterious effects on growth and development, altered fertility, accumulation of mutations, or increased carcinogenicity,” Dr McLaren said.

“Evidence that lung function may be better preserved while on hydroxyurea may encourage compliance and adherence to this medication for patients with sickle cell disease. In combination with the established safety data, it hopefully will promote physician recommendations for hydroxyurea initiation and encouragement of compliance.”

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

SAN FRANCISCO—A new study has shown that hydroxyurea (HU) can improve lung function in young patients with sickle cell disease (SCD).

“Persons with sickle cell disease experience an annual decline in lung function that starts in childhood,” said study investigator Anya McLaren, MD, of The Hospital for Sick Children in Toronto, Ontario, Canada.

“This study is the first of its kind to look at the effect of hydroxyurea on lung function. We found that hydroxyurea improves annual pulmonary function decline in children with sickle cell disease by more than one-third.”

The study was presented at the ATS 2016 International Conference as abstract 7225.

For this study, Dr McLaren and her colleagues evaluated the effects of HU in 94 SCD patients. The patients’ average age at baseline was 11 (range, 6 to 20), 96% of patients had HbSS genotype, and 47% were male.

The patients were followed for 4 years after HU initiation. The investigators assessed lung function before and after HU initiation in a few ways.

They used the forced expiratory volume (FEV) test, which measures how much air a person can exhale during a forced breath. The amount of air can be measured during the first second of the forced breath (FEV1) and at later time points.

Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test. If the FEV1/FVC ratio is less than 80%, it indicates that an obstructive defect is present.

The investigators also assessed FEF25-75, or the forced expiratory flow at 25%–75% of FVC. This measurement helps determine if there is an obstruction in the airway.

In addition, the team measured total lung capacity.

Results

The investigators found no significant change in total lung capacity, FVC, or FEV1/FVC predicted measurements after patients began receiving HU.

However, there were significant improvements in both FEV1 and FEF25-75 after treatment.

The annual rate of decline in predicted FEV1 and FEF25-75 before patients started HU was -1.98%/year (95% CI -2.57 to -1.39) and -3.59%/year (95% CI -4.43 to -2.75), respectively.

After HU treatment began, there was a significant (P<0.05) improvement in the annual decline, to -1.28%/year (95% CI -1.79 to -0.76) and -2.88%/year (95% CI -3.49 to -2.28), respectively.

The investigators noted that changes in FEV1 and FEF25-75 were independent of a patient’s age at baseline and the time from HU therapy initiation.

Dr McLaren pointed out that HU is underused in SCD patients, likely because clinicians are concerned about patient non-compliance and afraid of potential side effects, particularly carcinogenesis. But some of those fears may be unfounded, she said.

“Long-term observational studies suggest beneficial effects [of HU] without excessive damage to bone marrow, deleterious effects on growth and development, altered fertility, accumulation of mutations, or increased carcinogenicity,” Dr McLaren said.

“Evidence that lung function may be better preserved while on hydroxyurea may encourage compliance and adherence to this medication for patients with sickle cell disease. In combination with the established safety data, it hopefully will promote physician recommendations for hydroxyurea initiation and encouragement of compliance.”

Doctor examines SCD patient

Photo courtesy of St. Jude

Children’s Research Hospital

SAN FRANCISCO—A new study has shown that hydroxyurea (HU) can improve lung function in young patients with sickle cell disease (SCD).

“Persons with sickle cell disease experience an annual decline in lung function that starts in childhood,” said study investigator Anya McLaren, MD, of The Hospital for Sick Children in Toronto, Ontario, Canada.

“This study is the first of its kind to look at the effect of hydroxyurea on lung function. We found that hydroxyurea improves annual pulmonary function decline in children with sickle cell disease by more than one-third.”

The study was presented at the ATS 2016 International Conference as abstract 7225.

For this study, Dr McLaren and her colleagues evaluated the effects of HU in 94 SCD patients. The patients’ average age at baseline was 11 (range, 6 to 20), 96% of patients had HbSS genotype, and 47% were male.

The patients were followed for 4 years after HU initiation. The investigators assessed lung function before and after HU initiation in a few ways.

They used the forced expiratory volume (FEV) test, which measures how much air a person can exhale during a forced breath. The amount of air can be measured during the first second of the forced breath (FEV1) and at later time points.

Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test. If the FEV1/FVC ratio is less than 80%, it indicates that an obstructive defect is present.

The investigators also assessed FEF25-75, or the forced expiratory flow at 25%–75% of FVC. This measurement helps determine if there is an obstruction in the airway.

In addition, the team measured total lung capacity.

Results

The investigators found no significant change in total lung capacity, FVC, or FEV1/FVC predicted measurements after patients began receiving HU.

However, there were significant improvements in both FEV1 and FEF25-75 after treatment.

The annual rate of decline in predicted FEV1 and FEF25-75 before patients started HU was -1.98%/year (95% CI -2.57 to -1.39) and -3.59%/year (95% CI -4.43 to -2.75), respectively.

After HU treatment began, there was a significant (P<0.05) improvement in the annual decline, to -1.28%/year (95% CI -1.79 to -0.76) and -2.88%/year (95% CI -3.49 to -2.28), respectively.

The investigators noted that changes in FEV1 and FEF25-75 were independent of a patient’s age at baseline and the time from HU therapy initiation.

Dr McLaren pointed out that HU is underused in SCD patients, likely because clinicians are concerned about patient non-compliance and afraid of potential side effects, particularly carcinogenesis. But some of those fears may be unfounded, she said.

“Long-term observational studies suggest beneficial effects [of HU] without excessive damage to bone marrow, deleterious effects on growth and development, altered fertility, accumulation of mutations, or increased carcinogenicity,” Dr McLaren said.

“Evidence that lung function may be better preserved while on hydroxyurea may encourage compliance and adherence to this medication for patients with sickle cell disease. In combination with the established safety data, it hopefully will promote physician recommendations for hydroxyurea initiation and encouragement of compliance.”

Hematopoietic stem cells

in the bone marrow

Scientists believe they have come one step closer to creating hematopoietic stem cells (HSCs) that are just like the real thing.

“Our work focuses on finding a way to generate a supply of these life-saving hematopoietic stem cells in the lab so that they are a perfect match to the patient in need of a transplant,” said Hanna Mikkola, MD, PhD, of the University of California, Los Angeles.

“One big challenge is that when we try to create hematopoietic stem cells from pluripotent stem cells in the lab, they don’t acquire the same abilities of the real hematopoietic stem cells found in the body.”

Dr Mikkola and her colleagues described their attempts to overcome this challenge in Nature Cell Biology.

The researchers tried to create HSCs from pluripotent stem cells, but when they compared the lab-created cells to HSCs found in the body, they found that HOXA genes weren’t activated in the lab-created cells.

The team also discovered that HOXA genes help HSCs maintain their stem-cell attributes, such as the ability to self-renew.

“Without the ability to self-renew, hematopoietic stem cells cannot be used for transplantation therapies,” said Vincenzo Calvanese, PhD, an assistant project scientist in Dr Mikkola’s lab.

“Our findings show that the activation of HOXA genes can be used as a marker for hematopoietic stem cells that have acquired the capacity to renew themselves.”

The researchers’ next challenge was to pinpoint the naturally occurring process that activates HOXA genes so they could try to replicate the process in the lab.

They found that mimicking the effects of retinoic acid acts like a switch that turns on the HOXA genes during HSC development.

“Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Diana Dou, a graduate student in Dr Mikkola’s lab.

“This is an important step forward as we work to develop hematopoietic stem cells for transplantation therapies for life-threatening blood diseases.”

The researchers’ next step will be to refine the process they’ve developed in order to produce lab-created HSCs that have—and maintain—all the functions of human HSCs.

Hematopoietic stem cells

in the bone marrow

Scientists believe they have come one step closer to creating hematopoietic stem cells (HSCs) that are just like the real thing.

“Our work focuses on finding a way to generate a supply of these life-saving hematopoietic stem cells in the lab so that they are a perfect match to the patient in need of a transplant,” said Hanna Mikkola, MD, PhD, of the University of California, Los Angeles.

“One big challenge is that when we try to create hematopoietic stem cells from pluripotent stem cells in the lab, they don’t acquire the same abilities of the real hematopoietic stem cells found in the body.”

Dr Mikkola and her colleagues described their attempts to overcome this challenge in Nature Cell Biology.

The researchers tried to create HSCs from pluripotent stem cells, but when they compared the lab-created cells to HSCs found in the body, they found that HOXA genes weren’t activated in the lab-created cells.

The team also discovered that HOXA genes help HSCs maintain their stem-cell attributes, such as the ability to self-renew.

“Without the ability to self-renew, hematopoietic stem cells cannot be used for transplantation therapies,” said Vincenzo Calvanese, PhD, an assistant project scientist in Dr Mikkola’s lab.

“Our findings show that the activation of HOXA genes can be used as a marker for hematopoietic stem cells that have acquired the capacity to renew themselves.”

The researchers’ next challenge was to pinpoint the naturally occurring process that activates HOXA genes so they could try to replicate the process in the lab.

They found that mimicking the effects of retinoic acid acts like a switch that turns on the HOXA genes during HSC development.

“Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Diana Dou, a graduate student in Dr Mikkola’s lab.

“This is an important step forward as we work to develop hematopoietic stem cells for transplantation therapies for life-threatening blood diseases.”

The researchers’ next step will be to refine the process they’ve developed in order to produce lab-created HSCs that have—and maintain—all the functions of human HSCs.

Hematopoietic stem cells

in the bone marrow

Scientists believe they have come one step closer to creating hematopoietic stem cells (HSCs) that are just like the real thing.

“Our work focuses on finding a way to generate a supply of these life-saving hematopoietic stem cells in the lab so that they are a perfect match to the patient in need of a transplant,” said Hanna Mikkola, MD, PhD, of the University of California, Los Angeles.

“One big challenge is that when we try to create hematopoietic stem cells from pluripotent stem cells in the lab, they don’t acquire the same abilities of the real hematopoietic stem cells found in the body.”

Dr Mikkola and her colleagues described their attempts to overcome this challenge in Nature Cell Biology.

The researchers tried to create HSCs from pluripotent stem cells, but when they compared the lab-created cells to HSCs found in the body, they found that HOXA genes weren’t activated in the lab-created cells.

The team also discovered that HOXA genes help HSCs maintain their stem-cell attributes, such as the ability to self-renew.

“Without the ability to self-renew, hematopoietic stem cells cannot be used for transplantation therapies,” said Vincenzo Calvanese, PhD, an assistant project scientist in Dr Mikkola’s lab.

“Our findings show that the activation of HOXA genes can be used as a marker for hematopoietic stem cells that have acquired the capacity to renew themselves.”

The researchers’ next challenge was to pinpoint the naturally occurring process that activates HOXA genes so they could try to replicate the process in the lab.

They found that mimicking the effects of retinoic acid acts like a switch that turns on the HOXA genes during HSC development.

“Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Diana Dou, a graduate student in Dr Mikkola’s lab.

“This is an important step forward as we work to develop hematopoietic stem cells for transplantation therapies for life-threatening blood diseases.”

The researchers’ next step will be to refine the process they’ve developed in order to produce lab-created HSCs that have—and maintain—all the functions of human HSCs.

Smiling baby

Photo by Petr Kratochvil

Giving very preterm infants high-dose recombinant human erythropoietin (EPO) at birth does not improve neurodevelopmental outcomes at 2 years, according to a study published in JAMA.

Researchers found no significant differences between infants who received EPO and those who did not when it came to cognitive development, motor development, cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

Giancarlo Natalucci, MD, of the University of Zurich in Switzerland, and his colleagues conducted this study in 448 preterm infants who were born between 26 weeks’ gestation and 31 weeks 6 days’ gestation.

The subjects’ average gestational age was 29 weeks, and their average birth weight was 1210 g (2.7 lbs).

The infants were randomized to receive high-dose EPO (n=228) or placebo (saline, n=220) intravenously within 3 hours of birth, at 12 to 18 hours, and at 36 to 42 hours after birth.

Neurodevelopmental outcome data were available for 81% of the infants (n=365) at an average age of 23.6 months.

Cognitive development, as assessed with the Mental Development Index (MDI), was not significantly different between the EPO group and the placebo group. In an intent-to-treat analysis, the mean MDI was 93.5 in the EPO group and 94.5 in the placebo group (P=0.056). In the per-protocol analysis, the mean MDI was 93.9 and 94.5, respectively (P=0.70).

The researchers also found no significant differences between the treatment groups for secondary outcomes such as motor development, cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

The team assessed motor development using the psychomotor development index (PDI). In the intent-to-treat analysis, the mean PDI was 89.5 in the EPO group and 92.1 in the placebo group (P=0.15). In the per-protocol analysis, the mean PDI was 89.2 and 92.8, respectively (P=0.06).

In the intent-to-treat analysis, the incidence of cerebral palsy was 4% in the EPO group and 5% in the placebo group (P>0.99). In the per-protocol analysis, it was 5% for both groups (P=0.41).

In the intent-to-treat analysis, severe hearing impairment occurred in 1 EPO-treated patient and no placebo-treated patients (P>0.99). Severe visual impairment occurred in 2 and 0, respectively (P=0.50). The incidences were the same in the per-protocol analysis.

And there were no significant differences between the treatment groups (per-protocol or intent-to-treat) when it came to growth parameters such as head circumference, weight, or length.

The researchers said these results suggest that EPO may not have a neuroprotective role in very preterm infants, but follow-up is required to assess cognitive and physical problems that may not become evident until later in life.

Smiling baby

Photo by Petr Kratochvil

Giving very preterm infants high-dose recombinant human erythropoietin (EPO) at birth does not improve neurodevelopmental outcomes at 2 years, according to a study published in JAMA.

Researchers found no significant differences between infants who received EPO and those who did not when it came to cognitive development, motor development, cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

Giancarlo Natalucci, MD, of the University of Zurich in Switzerland, and his colleagues conducted this study in 448 preterm infants who were born between 26 weeks’ gestation and 31 weeks 6 days’ gestation.

The subjects’ average gestational age was 29 weeks, and their average birth weight was 1210 g (2.7 lbs).

The infants were randomized to receive high-dose EPO (n=228) or placebo (saline, n=220) intravenously within 3 hours of birth, at 12 to 18 hours, and at 36 to 42 hours after birth.

Neurodevelopmental outcome data were available for 81% of the infants (n=365) at an average age of 23.6 months.

Cognitive development, as assessed with the Mental Development Index (MDI), was not significantly different between the EPO group and the placebo group. In an intent-to-treat analysis, the mean MDI was 93.5 in the EPO group and 94.5 in the placebo group (P=0.056). In the per-protocol analysis, the mean MDI was 93.9 and 94.5, respectively (P=0.70).

The researchers also found no significant differences between the treatment groups for secondary outcomes such as motor development, cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

The team assessed motor development using the psychomotor development index (PDI). In the intent-to-treat analysis, the mean PDI was 89.5 in the EPO group and 92.1 in the placebo group (P=0.15). In the per-protocol analysis, the mean PDI was 89.2 and 92.8, respectively (P=0.06).

In the intent-to-treat analysis, the incidence of cerebral palsy was 4% in the EPO group and 5% in the placebo group (P>0.99). In the per-protocol analysis, it was 5% for both groups (P=0.41).

In the intent-to-treat analysis, severe hearing impairment occurred in 1 EPO-treated patient and no placebo-treated patients (P>0.99). Severe visual impairment occurred in 2 and 0, respectively (P=0.50). The incidences were the same in the per-protocol analysis.

And there were no significant differences between the treatment groups (per-protocol or intent-to-treat) when it came to growth parameters such as head circumference, weight, or length.

The researchers said these results suggest that EPO may not have a neuroprotective role in very preterm infants, but follow-up is required to assess cognitive and physical problems that may not become evident until later in life.

Smiling baby

Photo by Petr Kratochvil

Giving very preterm infants high-dose recombinant human erythropoietin (EPO) at birth does not improve neurodevelopmental outcomes at 2 years, according to a study published in JAMA.

Researchers found no significant differences between infants who received EPO and those who did not when it came to cognitive development, motor development, cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

Giancarlo Natalucci, MD, of the University of Zurich in Switzerland, and his colleagues conducted this study in 448 preterm infants who were born between 26 weeks’ gestation and 31 weeks 6 days’ gestation.

The subjects’ average gestational age was 29 weeks, and their average birth weight was 1210 g (2.7 lbs).

The infants were randomized to receive high-dose EPO (n=228) or placebo (saline, n=220) intravenously within 3 hours of birth, at 12 to 18 hours, and at 36 to 42 hours after birth.

Neurodevelopmental outcome data were available for 81% of the infants (n=365) at an average age of 23.6 months.

Cognitive development, as assessed with the Mental Development Index (MDI), was not significantly different between the EPO group and the placebo group. In an intent-to-treat analysis, the mean MDI was 93.5 in the EPO group and 94.5 in the placebo group (P=0.056). In the per-protocol analysis, the mean MDI was 93.9 and 94.5, respectively (P=0.70).

The researchers also found no significant differences between the treatment groups for secondary outcomes such as motor development, cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

The team assessed motor development using the psychomotor development index (PDI). In the intent-to-treat analysis, the mean PDI was 89.5 in the EPO group and 92.1 in the placebo group (P=0.15). In the per-protocol analysis, the mean PDI was 89.2 and 92.8, respectively (P=0.06).

In the intent-to-treat analysis, the incidence of cerebral palsy was 4% in the EPO group and 5% in the placebo group (P>0.99). In the per-protocol analysis, it was 5% for both groups (P=0.41).

In the intent-to-treat analysis, severe hearing impairment occurred in 1 EPO-treated patient and no placebo-treated patients (P>0.99). Severe visual impairment occurred in 2 and 0, respectively (P=0.50). The incidences were the same in the per-protocol analysis.

And there were no significant differences between the treatment groups (per-protocol or intent-to-treat) when it came to growth parameters such as head circumference, weight, or length.

The researchers said these results suggest that EPO may not have a neuroprotective role in very preterm infants, but follow-up is required to assess cognitive and physical problems that may not become evident until later in life.

Lab mice

Photo by Aaron Logan

Researchers say they have discovered a method for expanding natural killer T cells (NKTs) that ensures their persistence, thereby making NKTs more attractive as chimeric antigen receptor (CAR) carriers for cancer immunotherapy.

When transduced with a CD19-specific CAR, the researchers’ persistent NKTs produced sustained tumor regression in a mouse model of B-cell lymphoma.

The team described this work in the Journal of Clinical Investigation.

“NKT technology is quite powerful and offers a significant potential for treatment of cancer,” said study author Leonid Metelitsa, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“But for it to be most effective, we have to find the best way to expand the cells ex vivo while preserving their ability to persist once delivered back to patients. If they can persist in the body for a long time, they have much longer therapeutic activity, and this is essential for fighting cancer.”

Molecule affects persistence

The researchers noted that central memory T cells are known for their ability to proliferate and persist, and these cells are characterized by expression of the surface molecule CD62L.

In this study, the team found that NKT cells freshly derived from blood did not express CD62L, or it was expressed at a very low level. However, after the researchers expanded NKT cells, they found that CD62L was expressed at higher levels.

“We consistently identified a subset of cells present at very high numbers after the first 12 days of expansion, and critical to this subset of cells was the presence of CD62L,” Dr Metelitsa said. “In fact, they became the majority of the new cells.”

In addition, Dr Metelitsa said that CD62L-positive NKT cells were responsible for further propagation of NKTs in culture, which is important for achieving large numbers of cells. However, extensive culture led to the eventual decline of CD62L expression in NKTs.

To test the role of CD62L in NKT-cell persistence, the researchers delivered CD62L-positive and CD62L-negative NKTs to immune-deficient NSG mice. They found that CD62L-positive NKTs persisted 5 times longer than CD62L-negative NKTs.

CAR-NKTs fight lymphoma

Next, the researchers transduced CD62L-positive and CD62L-negative NKTs with a CD19-specific CAR and delivered these cells to mice with B-cell lymphoma.

The team found that both CD62L-positve and CD62L-negative CAR-NKTs prolonged the survival of mice, when compared to controls (P<0.001).

However, only the CD62L-positive CAR-NKTs induced sustained tumor regression. Seven of 9 mice that received CD62L-positive CAR-NKTs lived, and 5 were tumor-free for at least 3 months. But all 10 mice that received CD62L-negative CAR-NKTs ultimately succumbed to tumor progression (P<0.001).

Costimulation improves NKTs/CAR-NKTs

The researchers then turned their focus to costimulation of NKTs in order to maintain the subset with a high percentage of CD62L-positive cells in prolonged culture. Costimulation involves the interaction of receptors on NKTs with activating molecules on an antigen-presenting cell to increase the NKTs’ immune functions.

“We have known that costimulation is an important part of immune response and immunotherapy, but, in this case, we did not know which costimulatory molecules would be important for the expansion and persistence of CD62L-positive NKT cells,” said Gengwen Tian, MD, of the Baylor College of Medicine.

After testing more than 100 combinations, the researchers discovered that combining an antigen-presenting molecule—CD1d—with 3 costimulatory molecules—CD86, 4-1BBL, and OX40L—induced prolonged persistence and better therapeutic activity of NKTs and CAR-NKTs in mouse models.

“When we developed an antigen-presenting cell clone that expressed CD1d with all of these costimulatory molecules at certain levels, NKT cells maintained a high percentage of CD62L even in a prolonged culture,” Dr Metelitsa said.

The researchers conducted in vivo testing of CAR-NKT cells that were expanded with the original method or with the costimulation method. And they found that costimulated cells had significantly higher therapeutic activity in mouse models of neuroblastoma and lymphoma.

“Our goal now is to optimize our NKT cell expansion protocol so that we can obtain FDA approval to initiate clinical trials,” Dr Metelitsa said.

Lab mice

Photo by Aaron Logan

Researchers say they have discovered a method for expanding natural killer T cells (NKTs) that ensures their persistence, thereby making NKTs more attractive as chimeric antigen receptor (CAR) carriers for cancer immunotherapy.

When transduced with a CD19-specific CAR, the researchers’ persistent NKTs produced sustained tumor regression in a mouse model of B-cell lymphoma.

The team described this work in the Journal of Clinical Investigation.

“NKT technology is quite powerful and offers a significant potential for treatment of cancer,” said study author Leonid Metelitsa, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“But for it to be most effective, we have to find the best way to expand the cells ex vivo while preserving their ability to persist once delivered back to patients. If they can persist in the body for a long time, they have much longer therapeutic activity, and this is essential for fighting cancer.”

Molecule affects persistence

The researchers noted that central memory T cells are known for their ability to proliferate and persist, and these cells are characterized by expression of the surface molecule CD62L.

In this study, the team found that NKT cells freshly derived from blood did not express CD62L, or it was expressed at a very low level. However, after the researchers expanded NKT cells, they found that CD62L was expressed at higher levels.

“We consistently identified a subset of cells present at very high numbers after the first 12 days of expansion, and critical to this subset of cells was the presence of CD62L,” Dr Metelitsa said. “In fact, they became the majority of the new cells.”

In addition, Dr Metelitsa said that CD62L-positive NKT cells were responsible for further propagation of NKTs in culture, which is important for achieving large numbers of cells. However, extensive culture led to the eventual decline of CD62L expression in NKTs.

To test the role of CD62L in NKT-cell persistence, the researchers delivered CD62L-positive and CD62L-negative NKTs to immune-deficient NSG mice. They found that CD62L-positive NKTs persisted 5 times longer than CD62L-negative NKTs.

CAR-NKTs fight lymphoma

Next, the researchers transduced CD62L-positive and CD62L-negative NKTs with a CD19-specific CAR and delivered these cells to mice with B-cell lymphoma.

The team found that both CD62L-positve and CD62L-negative CAR-NKTs prolonged the survival of mice, when compared to controls (P<0.001).

However, only the CD62L-positive CAR-NKTs induced sustained tumor regression. Seven of 9 mice that received CD62L-positive CAR-NKTs lived, and 5 were tumor-free for at least 3 months. But all 10 mice that received CD62L-negative CAR-NKTs ultimately succumbed to tumor progression (P<0.001).

Costimulation improves NKTs/CAR-NKTs

The researchers then turned their focus to costimulation of NKTs in order to maintain the subset with a high percentage of CD62L-positive cells in prolonged culture. Costimulation involves the interaction of receptors on NKTs with activating molecules on an antigen-presenting cell to increase the NKTs’ immune functions.

“We have known that costimulation is an important part of immune response and immunotherapy, but, in this case, we did not know which costimulatory molecules would be important for the expansion and persistence of CD62L-positive NKT cells,” said Gengwen Tian, MD, of the Baylor College of Medicine.

After testing more than 100 combinations, the researchers discovered that combining an antigen-presenting molecule—CD1d—with 3 costimulatory molecules—CD86, 4-1BBL, and OX40L—induced prolonged persistence and better therapeutic activity of NKTs and CAR-NKTs in mouse models.

“When we developed an antigen-presenting cell clone that expressed CD1d with all of these costimulatory molecules at certain levels, NKT cells maintained a high percentage of CD62L even in a prolonged culture,” Dr Metelitsa said.

The researchers conducted in vivo testing of CAR-NKT cells that were expanded with the original method or with the costimulation method. And they found that costimulated cells had significantly higher therapeutic activity in mouse models of neuroblastoma and lymphoma.

“Our goal now is to optimize our NKT cell expansion protocol so that we can obtain FDA approval to initiate clinical trials,” Dr Metelitsa said.

Lab mice

Photo by Aaron Logan

Researchers say they have discovered a method for expanding natural killer T cells (NKTs) that ensures their persistence, thereby making NKTs more attractive as chimeric antigen receptor (CAR) carriers for cancer immunotherapy.

When transduced with a CD19-specific CAR, the researchers’ persistent NKTs produced sustained tumor regression in a mouse model of B-cell lymphoma.

The team described this work in the Journal of Clinical Investigation.

“NKT technology is quite powerful and offers a significant potential for treatment of cancer,” said study author Leonid Metelitsa, MD, PhD, of Baylor College of Medicine in Houston, Texas.

“But for it to be most effective, we have to find the best way to expand the cells ex vivo while preserving their ability to persist once delivered back to patients. If they can persist in the body for a long time, they have much longer therapeutic activity, and this is essential for fighting cancer.”

Molecule affects persistence

The researchers noted that central memory T cells are known for their ability to proliferate and persist, and these cells are characterized by expression of the surface molecule CD62L.

In this study, the team found that NKT cells freshly derived from blood did not express CD62L, or it was expressed at a very low level. However, after the researchers expanded NKT cells, they found that CD62L was expressed at higher levels.

“We consistently identified a subset of cells present at very high numbers after the first 12 days of expansion, and critical to this subset of cells was the presence of CD62L,” Dr Metelitsa said. “In fact, they became the majority of the new cells.”

In addition, Dr Metelitsa said that CD62L-positive NKT cells were responsible for further propagation of NKTs in culture, which is important for achieving large numbers of cells. However, extensive culture led to the eventual decline of CD62L expression in NKTs.

To test the role of CD62L in NKT-cell persistence, the researchers delivered CD62L-positive and CD62L-negative NKTs to immune-deficient NSG mice. They found that CD62L-positive NKTs persisted 5 times longer than CD62L-negative NKTs.

CAR-NKTs fight lymphoma

Next, the researchers transduced CD62L-positive and CD62L-negative NKTs with a CD19-specific CAR and delivered these cells to mice with B-cell lymphoma.

The team found that both CD62L-positve and CD62L-negative CAR-NKTs prolonged the survival of mice, when compared to controls (P<0.001).

However, only the CD62L-positive CAR-NKTs induced sustained tumor regression. Seven of 9 mice that received CD62L-positive CAR-NKTs lived, and 5 were tumor-free for at least 3 months. But all 10 mice that received CD62L-negative CAR-NKTs ultimately succumbed to tumor progression (P<0.001).

Costimulation improves NKTs/CAR-NKTs

The researchers then turned their focus to costimulation of NKTs in order to maintain the subset with a high percentage of CD62L-positive cells in prolonged culture. Costimulation involves the interaction of receptors on NKTs with activating molecules on an antigen-presenting cell to increase the NKTs’ immune functions.

“We have known that costimulation is an important part of immune response and immunotherapy, but, in this case, we did not know which costimulatory molecules would be important for the expansion and persistence of CD62L-positive NKT cells,” said Gengwen Tian, MD, of the Baylor College of Medicine.

After testing more than 100 combinations, the researchers discovered that combining an antigen-presenting molecule—CD1d—with 3 costimulatory molecules—CD86, 4-1BBL, and OX40L—induced prolonged persistence and better therapeutic activity of NKTs and CAR-NKTs in mouse models.

“When we developed an antigen-presenting cell clone that expressed CD1d with all of these costimulatory molecules at certain levels, NKT cells maintained a high percentage of CD62L even in a prolonged culture,” Dr Metelitsa said.

The researchers conducted in vivo testing of CAR-NKT cells that were expanded with the original method or with the costimulation method. And they found that costimulated cells had significantly higher therapeutic activity in mouse models of neuroblastoma and lymphoma.

“Our goal now is to optimize our NKT cell expansion protocol so that we can obtain FDA approval to initiate clinical trials,” Dr Metelitsa said.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

A new study suggests that cancer patients with HIV are less likely to receive cancer treatment, regardless of insurance status and comorbidities.

Patients with HIV were less likely than their HIV-free peers to receive treatment for Hodgkin lymphoma, diffuse large B-cell lymphoma, and 7 solid tumor malignancies.

Gita Suneja, MD, of the University of Utah in Salt Lake City, and her colleagues reported these findings in Cancer.

The team used the National Cancer Data Base to study non-elderly US adults diagnosed with 10 common cancers from 2003 to 2011. There were a total of 10,265 HIV-infected patients and 2,219,232 HIV-free patients.

The researchers examined associations between HIV status and lack of cancer treatment, taking into account insurance status and comorbidities.

The results showed a lack of treatment among HIV patients for all of the cancers studied except anal cancer (relative risk [RR]=1.20, P=0.333).

So HIV-infected patients were more likely to lack cancer treatment for:

• Hodgkin lymphoma (RR=1.92, P<0.001)
• Diffuse large B-cell lymphoma (RR=1.82, P<0.001)
• Head and neck cancer (RR=1.48, P=0.013)
• Upper gastrointestinal tract cancer (RR=2.62, P<0.001)
• Colorectal cancer (RR=1.70, P=0.006)
• Lung cancer (RR=2.46, P<0.001)
• Breast cancer (RR=2.14, P=0.015)
• Cervical cancer (RR=2.81, P<0.001)
• Prostate cancer (RR=2.16, P<0.001).

The researchers said factors that predicted a lack of cancer treatment among HIV-infected individuals varied between those with solid tumors and those with lymphomas.

Advanced stage at the time of cancer diagnosis (stage IV vs stage I) meant HIV patients with solid tumors were less likely to receive cancer treatment, but lymphoma patients were more likely to receive cancer treatment.

Having a higher modified Charlson-Deyo comorbidity score (1 or 2+ vs 0) predicted a lack of cancer treatment for HIV-infected patients with lymphoma but not those with solid tumors.

And older age (45-64 vs 18-44) was associated with a lack of treatment for HIV-infected patients regardless of cancer type, but this was only significant for lymphoma patients.

For the entire cohort, black race (vs white) and a lack of private insurance (Medicaid, Medicare, uninsured, or unknown insurance status) were significant predictors for a lack of cancer treatment among HIV patients.

Still, the researchers noted that, even among privately insured patients, HIV-infected individuals were less likely to receive cancer treatment.

Dr Suneja and her colleagues said several factors may contribute to these findings. For one, HIV-infected patients have historically been excluded from cancer clinical trials, thereby limiting the applicability of trial results for this population.

In addition, cancer treatment guidelines specific to HIV-infected patients are not available for most cancer types. And clinicians may lack experience treating HIV-infected patients with cancer.

Furthermore, the psychosocial and economic challenges associated with the dual management of cancer and HIV treatment may make adherence to treatment a challenge.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

A new study suggests that cancer patients with HIV are less likely to receive cancer treatment, regardless of insurance status and comorbidities.

Patients with HIV were less likely than their HIV-free peers to receive treatment for Hodgkin lymphoma, diffuse large B-cell lymphoma, and 7 solid tumor malignancies.

Gita Suneja, MD, of the University of Utah in Salt Lake City, and her colleagues reported these findings in Cancer.

The team used the National Cancer Data Base to study non-elderly US adults diagnosed with 10 common cancers from 2003 to 2011. There were a total of 10,265 HIV-infected patients and 2,219,232 HIV-free patients.

The researchers examined associations between HIV status and lack of cancer treatment, taking into account insurance status and comorbidities.

The results showed a lack of treatment among HIV patients for all of the cancers studied except anal cancer (relative risk [RR]=1.20, P=0.333).

So HIV-infected patients were more likely to lack cancer treatment for:

• Hodgkin lymphoma (RR=1.92, P<0.001)
• Diffuse large B-cell lymphoma (RR=1.82, P<0.001)
• Head and neck cancer (RR=1.48, P=0.013)
• Upper gastrointestinal tract cancer (RR=2.62, P<0.001)
• Colorectal cancer (RR=1.70, P=0.006)
• Lung cancer (RR=2.46, P<0.001)
• Breast cancer (RR=2.14, P=0.015)
• Cervical cancer (RR=2.81, P<0.001)
• Prostate cancer (RR=2.16, P<0.001).

The researchers said factors that predicted a lack of cancer treatment among HIV-infected individuals varied between those with solid tumors and those with lymphomas.

Advanced stage at the time of cancer diagnosis (stage IV vs stage I) meant HIV patients with solid tumors were less likely to receive cancer treatment, but lymphoma patients were more likely to receive cancer treatment.

Having a higher modified Charlson-Deyo comorbidity score (1 or 2+ vs 0) predicted a lack of cancer treatment for HIV-infected patients with lymphoma but not those with solid tumors.

And older age (45-64 vs 18-44) was associated with a lack of treatment for HIV-infected patients regardless of cancer type, but this was only significant for lymphoma patients.

For the entire cohort, black race (vs white) and a lack of private insurance (Medicaid, Medicare, uninsured, or unknown insurance status) were significant predictors for a lack of cancer treatment among HIV patients.

Still, the researchers noted that, even among privately insured patients, HIV-infected individuals were less likely to receive cancer treatment.

Dr Suneja and her colleagues said several factors may contribute to these findings. For one, HIV-infected patients have historically been excluded from cancer clinical trials, thereby limiting the applicability of trial results for this population.

In addition, cancer treatment guidelines specific to HIV-infected patients are not available for most cancer types. And clinicians may lack experience treating HIV-infected patients with cancer.

Furthermore, the psychosocial and economic challenges associated with the dual management of cancer and HIV treatment may make adherence to treatment a challenge.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

A new study suggests that cancer patients with HIV are less likely to receive cancer treatment, regardless of insurance status and comorbidities.

Patients with HIV were less likely than their HIV-free peers to receive treatment for Hodgkin lymphoma, diffuse large B-cell lymphoma, and 7 solid tumor malignancies.

Gita Suneja, MD, of the University of Utah in Salt Lake City, and her colleagues reported these findings in Cancer.

The team used the National Cancer Data Base to study non-elderly US adults diagnosed with 10 common cancers from 2003 to 2011. There were a total of 10,265 HIV-infected patients and 2,219,232 HIV-free patients.

The researchers examined associations between HIV status and lack of cancer treatment, taking into account insurance status and comorbidities.

The results showed a lack of treatment among HIV patients for all of the cancers studied except anal cancer (relative risk [RR]=1.20, P=0.333).

So HIV-infected patients were more likely to lack cancer treatment for:

• Hodgkin lymphoma (RR=1.92, P<0.001)
• Diffuse large B-cell lymphoma (RR=1.82, P<0.001)
• Head and neck cancer (RR=1.48, P=0.013)
• Upper gastrointestinal tract cancer (RR=2.62, P<0.001)
• Colorectal cancer (RR=1.70, P=0.006)
• Lung cancer (RR=2.46, P<0.001)
• Breast cancer (RR=2.14, P=0.015)
• Cervical cancer (RR=2.81, P<0.001)
• Prostate cancer (RR=2.16, P<0.001).

The researchers said factors that predicted a lack of cancer treatment among HIV-infected individuals varied between those with solid tumors and those with lymphomas.

Advanced stage at the time of cancer diagnosis (stage IV vs stage I) meant HIV patients with solid tumors were less likely to receive cancer treatment, but lymphoma patients were more likely to receive cancer treatment.

Having a higher modified Charlson-Deyo comorbidity score (1 or 2+ vs 0) predicted a lack of cancer treatment for HIV-infected patients with lymphoma but not those with solid tumors.

And older age (45-64 vs 18-44) was associated with a lack of treatment for HIV-infected patients regardless of cancer type, but this was only significant for lymphoma patients.

For the entire cohort, black race (vs white) and a lack of private insurance (Medicaid, Medicare, uninsured, or unknown insurance status) were significant predictors for a lack of cancer treatment among HIV patients.

Still, the researchers noted that, even among privately insured patients, HIV-infected individuals were less likely to receive cancer treatment.

Dr Suneja and her colleagues said several factors may contribute to these findings. For one, HIV-infected patients have historically been excluded from cancer clinical trials, thereby limiting the applicability of trial results for this population.

In addition, cancer treatment guidelines specific to HIV-infected patients are not available for most cancer types. And clinicians may lack experience treating HIV-infected patients with cancer.

Furthermore, the psychosocial and economic challenges associated with the dual management of cancer and HIV treatment may make adherence to treatment a challenge.

Nivolumab (Opdivo)

Photo courtesy of Business Wire

The US Food and Drug Administration (FDA) has granted accelerated approval for the PD-1 inhibitor nivolumab (Opdivo) to treat classical Hodgkin lymphoma (cHL).

The drug is approved to treat patients with relapsed or refractory cHL who have received an autologous hematopoietic stem cell transplant (HSCT) and post-transplant brentuximab vedotin.

Nivolumab received accelerated approval because it has not yet shown a clinical benefit in these patients. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of nivolumab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted nivolumab breakthrough therapy designation, priority review status, and orphan drug designation.

Dosing and precautions

The recommended dose and schedule of nivolumab for cHL patients is 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.

The FDA added a new “Warning and Precaution” to the label for nivolumab, regarding complications of allogeneic HSCT after nivolumab.

Transplant-related deaths have occurred. So the FDA said healthcare professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.

The FDA has required the manufacturer of nivolumab, Bristol-Myers Squibb, to further study the safety of allogeneic HSCT after nivolumab.

Full prescribing information for the drug is available here.

Trials of nivolumab

The FDA granted nivolumab accelerated approval in cHL patients based on the results of 2 single-arm, multicenter trials—the phase 1 Checkmate 039 trial (presented at ICML last year) and the phase 2 CheckMate 205 trial (to be presented at ASCO 2016).

Efficacy

Thus far, researchers have evaluated the efficacy of nivolumab in 95 cHL patients from both trials. All of these patients previously received an autologous HSCT and post-transplant brentuximab vedotin. They received a median of 5 prior systemic regimens (range, 3 to 15).

The patients received a median of 17 doses of nivolumab (range, 3 to 48). The overall response rate was 65%, and the complete response rate was 7%.

The median time to response was 2.1 months (range, 0.7 to 5.7), and the estimated median duration of response was 8.7 months (range, 0+ to 23.1+).

Safety

Researchers evaluated the safety of nivolumab in 263 patients with relapsed or refractory cHL. Ninety-eight percent of these patients had received an autologous HSCT.  The patients received a median of 10 doses of nivolumab (range, 1 to 48) at the approved dose and schedule.

The most common (≥20%) adverse events (AEs) of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea.

Additional common (≥10%) AEs included rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis.

Serious AEs were reported in 21% of patients. The most common, reported in 1% to 3% of patients, were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, and rash.

Nivolumab (Opdivo)

Photo courtesy of Business Wire

The US Food and Drug Administration (FDA) has granted accelerated approval for the PD-1 inhibitor nivolumab (Opdivo) to treat classical Hodgkin lymphoma (cHL).

The drug is approved to treat patients with relapsed or refractory cHL who have received an autologous hematopoietic stem cell transplant (HSCT) and post-transplant brentuximab vedotin.

Nivolumab received accelerated approval because it has not yet shown a clinical benefit in these patients. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of nivolumab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted nivolumab breakthrough therapy designation, priority review status, and orphan drug designation.

Dosing and precautions

The recommended dose and schedule of nivolumab for cHL patients is 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.

The FDA added a new “Warning and Precaution” to the label for nivolumab, regarding complications of allogeneic HSCT after nivolumab.

Transplant-related deaths have occurred. So the FDA said healthcare professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.

The FDA has required the manufacturer of nivolumab, Bristol-Myers Squibb, to further study the safety of allogeneic HSCT after nivolumab.

Full prescribing information for the drug is available here.

Trials of nivolumab

The FDA granted nivolumab accelerated approval in cHL patients based on the results of 2 single-arm, multicenter trials—the phase 1 Checkmate 039 trial (presented at ICML last year) and the phase 2 CheckMate 205 trial (to be presented at ASCO 2016).

Efficacy

Thus far, researchers have evaluated the efficacy of nivolumab in 95 cHL patients from both trials. All of these patients previously received an autologous HSCT and post-transplant brentuximab vedotin. They received a median of 5 prior systemic regimens (range, 3 to 15).

The patients received a median of 17 doses of nivolumab (range, 3 to 48). The overall response rate was 65%, and the complete response rate was 7%.

The median time to response was 2.1 months (range, 0.7 to 5.7), and the estimated median duration of response was 8.7 months (range, 0+ to 23.1+).

Safety

Researchers evaluated the safety of nivolumab in 263 patients with relapsed or refractory cHL. Ninety-eight percent of these patients had received an autologous HSCT.  The patients received a median of 10 doses of nivolumab (range, 1 to 48) at the approved dose and schedule.

The most common (≥20%) adverse events (AEs) of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea.

Additional common (≥10%) AEs included rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis.

Serious AEs were reported in 21% of patients. The most common, reported in 1% to 3% of patients, were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, and rash.

Nivolumab (Opdivo)

Photo courtesy of Business Wire

The US Food and Drug Administration (FDA) has granted accelerated approval for the PD-1 inhibitor nivolumab (Opdivo) to treat classical Hodgkin lymphoma (cHL).

The drug is approved to treat patients with relapsed or refractory cHL who have received an autologous hematopoietic stem cell transplant (HSCT) and post-transplant brentuximab vedotin.

Nivolumab received accelerated approval because it has not yet shown a clinical benefit in these patients. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of nivolumab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted nivolumab breakthrough therapy designation, priority review status, and orphan drug designation.

Dosing and precautions

The recommended dose and schedule of nivolumab for cHL patients is 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity.

The FDA added a new “Warning and Precaution” to the label for nivolumab, regarding complications of allogeneic HSCT after nivolumab.

Transplant-related deaths have occurred. So the FDA said healthcare professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.

The FDA has required the manufacturer of nivolumab, Bristol-Myers Squibb, to further study the safety of allogeneic HSCT after nivolumab.

Full prescribing information for the drug is available here.

Trials of nivolumab

The FDA granted nivolumab accelerated approval in cHL patients based on the results of 2 single-arm, multicenter trials—the phase 1 Checkmate 039 trial (presented at ICML last year) and the phase 2 CheckMate 205 trial (to be presented at ASCO 2016).

Efficacy

Thus far, researchers have evaluated the efficacy of nivolumab in 95 cHL patients from both trials. All of these patients previously received an autologous HSCT and post-transplant brentuximab vedotin. They received a median of 5 prior systemic regimens (range, 3 to 15).

The patients received a median of 17 doses of nivolumab (range, 3 to 48). The overall response rate was 65%, and the complete response rate was 7%.

The median time to response was 2.1 months (range, 0.7 to 5.7), and the estimated median duration of response was 8.7 months (range, 0+ to 23.1+).

Safety

Researchers evaluated the safety of nivolumab in 263 patients with relapsed or refractory cHL. Ninety-eight percent of these patients had received an autologous HSCT.  The patients received a median of 10 doses of nivolumab (range, 1 to 48) at the approved dose and schedule.

The most common (≥20%) adverse events (AEs) of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea.

Additional common (≥10%) AEs included rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis.

Serious AEs were reported in 21% of patients. The most common, reported in 1% to 3% of patients, were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, and rash.

Human Tregs

Image by Kathryn T. Iacono

A new approach to cancer immunotherapy may avoid some of the shortcomings associated with other methods, according to researchers.

The group found that eliminating a key protein in regulatory T cells (Tregs) makes them so unstable that they become effector T cells (Teff) and begin to attack the cancer.

And this conversion from Treg to Teff occurs only in the inflammatory conditions that prevail within many tumors.

As a result, Tregs embedded in normal tissue throughout the body continue to have a restraining effect on their local Teffs, protecting healthy organs and tissues from attack.

The researchers said this raises the prospect of therapies that concentrate the immune system’s firepower on tumors without producing residual damage and harmful side effects.

“Many current approaches to immunotherapy involve depleting or blocking Tregs in order to shift the balance toward Teff cells,” said Harvey Cantor, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“This, however, runs the risk of triggering an autoimmune response in which the Teff cells attack normal as well as malignant tissue. The key to our approach is that it singles out the Tregs inside a tumor for conversion, leaving Tregs elsewhere in the body unchanged.”

Dr Cantor and his colleagues described the approach in PNAS.

The study builds on research published last year in Science. That study showed that Tregs maintain their immune-suppressive properties under inflammatory conditions as long as they have high enough levels of a protein called Helios. Depriving Tregs of sufficient Helios caused them to lose that stability and turn into Teff cells.

The new study explored whether this convertibility could be harnessed for therapeutic purposes in cancers.

The first set of experiments involved mice engineered to lack Helios in their Tregs. When the animals were injected with melanoma or colon cancer cells, they developed tumors far more slowly than animals with normal Tregs.

“Inspection of the animals’ tumor tissue showed an unstable set of T regulatory cells, many of which had converted into Teffs,” said Hye-Jung Kim, PhD, also of the Dana-Farber Cancer Institute.

The researchers then explored whether stanching Helios production in tumor-dwelling Tregs could have the same effect. They tested several antibodies that bind to key receptors on Tregs and cause a downturn in Helios production.

The team chose an antibody that worked well, DTA-1, and tested it in mice with Treg-laden tumors. When they analyzed the tumor tissue, it was clear that DTA-1 had triggered conversion of Tregs to Teffs.

“This represents a next stage in cancer immunotherapy,” Dr Cantor said. “We now have a very specific, targeted way of inducing a T-effector-cell attack on cancer while lowering the risk of adverse effects on healthy tissue. The next step will be to organize a clinical trial using this approach in patients.”

Human Tregs

Image by Kathryn T. Iacono

A new approach to cancer immunotherapy may avoid some of the shortcomings associated with other methods, according to researchers.

The group found that eliminating a key protein in regulatory T cells (Tregs) makes them so unstable that they become effector T cells (Teff) and begin to attack the cancer.

And this conversion from Treg to Teff occurs only in the inflammatory conditions that prevail within many tumors.

As a result, Tregs embedded in normal tissue throughout the body continue to have a restraining effect on their local Teffs, protecting healthy organs and tissues from attack.

The researchers said this raises the prospect of therapies that concentrate the immune system’s firepower on tumors without producing residual damage and harmful side effects.

“Many current approaches to immunotherapy involve depleting or blocking Tregs in order to shift the balance toward Teff cells,” said Harvey Cantor, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“This, however, runs the risk of triggering an autoimmune response in which the Teff cells attack normal as well as malignant tissue. The key to our approach is that it singles out the Tregs inside a tumor for conversion, leaving Tregs elsewhere in the body unchanged.”

Dr Cantor and his colleagues described the approach in PNAS.

The study builds on research published last year in Science. That study showed that Tregs maintain their immune-suppressive properties under inflammatory conditions as long as they have high enough levels of a protein called Helios. Depriving Tregs of sufficient Helios caused them to lose that stability and turn into Teff cells.

The new study explored whether this convertibility could be harnessed for therapeutic purposes in cancers.

The first set of experiments involved mice engineered to lack Helios in their Tregs. When the animals were injected with melanoma or colon cancer cells, they developed tumors far more slowly than animals with normal Tregs.

“Inspection of the animals’ tumor tissue showed an unstable set of T regulatory cells, many of which had converted into Teffs,” said Hye-Jung Kim, PhD, also of the Dana-Farber Cancer Institute.

The researchers then explored whether stanching Helios production in tumor-dwelling Tregs could have the same effect. They tested several antibodies that bind to key receptors on Tregs and cause a downturn in Helios production.

The team chose an antibody that worked well, DTA-1, and tested it in mice with Treg-laden tumors. When they analyzed the tumor tissue, it was clear that DTA-1 had triggered conversion of Tregs to Teffs.

“This represents a next stage in cancer immunotherapy,” Dr Cantor said. “We now have a very specific, targeted way of inducing a T-effector-cell attack on cancer while lowering the risk of adverse effects on healthy tissue. The next step will be to organize a clinical trial using this approach in patients.”

Human Tregs

Image by Kathryn T. Iacono

A new approach to cancer immunotherapy may avoid some of the shortcomings associated with other methods, according to researchers.

The group found that eliminating a key protein in regulatory T cells (Tregs) makes them so unstable that they become effector T cells (Teff) and begin to attack the cancer.

And this conversion from Treg to Teff occurs only in the inflammatory conditions that prevail within many tumors.

As a result, Tregs embedded in normal tissue throughout the body continue to have a restraining effect on their local Teffs, protecting healthy organs and tissues from attack.

The researchers said this raises the prospect of therapies that concentrate the immune system’s firepower on tumors without producing residual damage and harmful side effects.

“Many current approaches to immunotherapy involve depleting or blocking Tregs in order to shift the balance toward Teff cells,” said Harvey Cantor, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“This, however, runs the risk of triggering an autoimmune response in which the Teff cells attack normal as well as malignant tissue. The key to our approach is that it singles out the Tregs inside a tumor for conversion, leaving Tregs elsewhere in the body unchanged.”

Dr Cantor and his colleagues described the approach in PNAS.

The study builds on research published last year in Science. That study showed that Tregs maintain their immune-suppressive properties under inflammatory conditions as long as they have high enough levels of a protein called Helios. Depriving Tregs of sufficient Helios caused them to lose that stability and turn into Teff cells.

The new study explored whether this convertibility could be harnessed for therapeutic purposes in cancers.

The first set of experiments involved mice engineered to lack Helios in their Tregs. When the animals were injected with melanoma or colon cancer cells, they developed tumors far more slowly than animals with normal Tregs.

“Inspection of the animals’ tumor tissue showed an unstable set of T regulatory cells, many of which had converted into Teffs,” said Hye-Jung Kim, PhD, also of the Dana-Farber Cancer Institute.

The researchers then explored whether stanching Helios production in tumor-dwelling Tregs could have the same effect. They tested several antibodies that bind to key receptors on Tregs and cause a downturn in Helios production.

The team chose an antibody that worked well, DTA-1, and tested it in mice with Treg-laden tumors. When they analyzed the tumor tissue, it was clear that DTA-1 had triggered conversion of Tregs to Teffs.

“This represents a next stage in cancer immunotherapy,” Dr Cantor said. “We now have a very specific, targeted way of inducing a T-effector-cell attack on cancer while lowering the risk of adverse effects on healthy tissue. The next step will be to organize a clinical trial using this approach in patients.”

Marathon runners

Photo by K. Johansson

Being physically active during leisure time may lower a person’s risk of certain cancers, according to a new study.

A high level of physical activity was associated with a 20% lower risk of myeloid leukemia, a 17% lower risk of myeloma, a 9% lower risk of non-Hodgkin lymphoma, and a 7% lower risk of cancer in general.

On the other hand, a high level of physical activity was also associated with a higher risk of malignant melanoma and prostate cancer.

Steven C. Moore, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues reported these findings in JAMA Internal Medicine.

The researchers pooled data from 12 US and European study cohorts with self-reported physical activity (1987-2004). And they analyzed associations between physical activity and 26 types of cancer.

The study included 1.4 million participants, and 186,932 cancers were identified during a median of 11 years of follow-up.

Compared with the lowest level of leisure-time physical activity (10th percentile), the highest level of activity (90th percentile) had strong inverse associations (a 20% or greater reduction in risk) for 7 cancer types:

• Myeloid leukemia (hazard ratio [HR]=0.80 [95% CI, 0.70-0.92])
• Esophageal adenocarcinoma (HR=0.58 [95% CI, 0.37-0.89])
• Liver cancer (HR=0.73 [95% CI, 0.55-0.98])
• Lung cancer (HR=0.74 [95% CI, 0.71-0.77])
• Kidney cancer (HR=0.77 [95% CI, 0.70-0.85])
• Gastric cardia (HR=0.78 [95% CI, 0.64-0.95])
• Endometrial cancer (HR=0.79 [95% CI, 0.68-0.92]).

There were moderate inverse associations (a 10% to 20% reduction in risk) between the highest level of activity and 6 cancers:

• Myeloma (HR=0.83 [95% CI, 0.72-0.95])
• Colon cancer (HR=0.84 [95% CI, 0.77-0.91])
• Head and neck cancer (HR=0.85 [95% CI, 0.78-0.93])
• Rectal cancer (HR=0.87 [95% CI, 0.80-0.95])
• Bladder cancer (HR=0.87 [95% CI, 0.82-0.92])
• Breast cancer (HR=0.90 [95% CI, 0.87-0.93]).

And there were suggestive inverse associations between the highest level of activity and 3 cancers:

• Non-Hodgkin lymphoma (HR=0.91 [95% CI, 0.83-1.00])
• Gallbladder cancer (HR=0.72 [95% CI, 0.51-1.01])
• Small intestine cancer (HR=0.78 [95% CI, 0.60-1.00]).

However, the highest level of activity was also associated with an increased risk of prostate cancer (HR=1.05 [95% CI, 1.03-1.08]) and malignant melanoma (HR=1.27 [95% CI, 1.16-1.40]).

The researchers said the main limitation of this study is that they cannot fully exclude the possibility that diet, smoking, and other factors may have affected these results. Also, the study used self-reported physical activity, which can mean errors in recall.

Still, the team said these findings support promoting physical activity as a key component of population-wide cancer prevention and control efforts.

Marathon runners

Photo by K. Johansson

Being physically active during leisure time may lower a person’s risk of certain cancers, according to a new study.

A high level of physical activity was associated with a 20% lower risk of myeloid leukemia, a 17% lower risk of myeloma, a 9% lower risk of non-Hodgkin lymphoma, and a 7% lower risk of cancer in general.

On the other hand, a high level of physical activity was also associated with a higher risk of malignant melanoma and prostate cancer.

Steven C. Moore, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues reported these findings in JAMA Internal Medicine.

The researchers pooled data from 12 US and European study cohorts with self-reported physical activity (1987-2004). And they analyzed associations between physical activity and 26 types of cancer.

The study included 1.4 million participants, and 186,932 cancers were identified during a median of 11 years of follow-up.

Compared with the lowest level of leisure-time physical activity (10th percentile), the highest level of activity (90th percentile) had strong inverse associations (a 20% or greater reduction in risk) for 7 cancer types:

• Myeloid leukemia (hazard ratio [HR]=0.80 [95% CI, 0.70-0.92])
• Esophageal adenocarcinoma (HR=0.58 [95% CI, 0.37-0.89])
• Liver cancer (HR=0.73 [95% CI, 0.55-0.98])
• Lung cancer (HR=0.74 [95% CI, 0.71-0.77])
• Kidney cancer (HR=0.77 [95% CI, 0.70-0.85])
• Gastric cardia (HR=0.78 [95% CI, 0.64-0.95])
• Endometrial cancer (HR=0.79 [95% CI, 0.68-0.92]).

There were moderate inverse associations (a 10% to 20% reduction in risk) between the highest level of activity and 6 cancers:

• Myeloma (HR=0.83 [95% CI, 0.72-0.95])
• Colon cancer (HR=0.84 [95% CI, 0.77-0.91])
• Head and neck cancer (HR=0.85 [95% CI, 0.78-0.93])
• Rectal cancer (HR=0.87 [95% CI, 0.80-0.95])
• Bladder cancer (HR=0.87 [95% CI, 0.82-0.92])
• Breast cancer (HR=0.90 [95% CI, 0.87-0.93]).

And there were suggestive inverse associations between the highest level of activity and 3 cancers:

• Non-Hodgkin lymphoma (HR=0.91 [95% CI, 0.83-1.00])
• Gallbladder cancer (HR=0.72 [95% CI, 0.51-1.01])
• Small intestine cancer (HR=0.78 [95% CI, 0.60-1.00]).

However, the highest level of activity was also associated with an increased risk of prostate cancer (HR=1.05 [95% CI, 1.03-1.08]) and malignant melanoma (HR=1.27 [95% CI, 1.16-1.40]).

The researchers said the main limitation of this study is that they cannot fully exclude the possibility that diet, smoking, and other factors may have affected these results. Also, the study used self-reported physical activity, which can mean errors in recall.

Still, the team said these findings support promoting physical activity as a key component of population-wide cancer prevention and control efforts.

Marathon runners

Photo by K. Johansson

Being physically active during leisure time may lower a person’s risk of certain cancers, according to a new study.

A high level of physical activity was associated with a 20% lower risk of myeloid leukemia, a 17% lower risk of myeloma, a 9% lower risk of non-Hodgkin lymphoma, and a 7% lower risk of cancer in general.

On the other hand, a high level of physical activity was also associated with a higher risk of malignant melanoma and prostate cancer.

Steven C. Moore, PhD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues reported these findings in JAMA Internal Medicine.

The researchers pooled data from 12 US and European study cohorts with self-reported physical activity (1987-2004). And they analyzed associations between physical activity and 26 types of cancer.

The study included 1.4 million participants, and 186,932 cancers were identified during a median of 11 years of follow-up.

Compared with the lowest level of leisure-time physical activity (10th percentile), the highest level of activity (90th percentile) had strong inverse associations (a 20% or greater reduction in risk) for 7 cancer types:

• Myeloid leukemia (hazard ratio [HR]=0.80 [95% CI, 0.70-0.92])
• Esophageal adenocarcinoma (HR=0.58 [95% CI, 0.37-0.89])
• Liver cancer (HR=0.73 [95% CI, 0.55-0.98])
• Lung cancer (HR=0.74 [95% CI, 0.71-0.77])
• Kidney cancer (HR=0.77 [95% CI, 0.70-0.85])
• Gastric cardia (HR=0.78 [95% CI, 0.64-0.95])
• Endometrial cancer (HR=0.79 [95% CI, 0.68-0.92]).

There were moderate inverse associations (a 10% to 20% reduction in risk) between the highest level of activity and 6 cancers:

• Myeloma (HR=0.83 [95% CI, 0.72-0.95])
• Colon cancer (HR=0.84 [95% CI, 0.77-0.91])
• Head and neck cancer (HR=0.85 [95% CI, 0.78-0.93])
• Rectal cancer (HR=0.87 [95% CI, 0.80-0.95])
• Bladder cancer (HR=0.87 [95% CI, 0.82-0.92])
• Breast cancer (HR=0.90 [95% CI, 0.87-0.93]).

And there were suggestive inverse associations between the highest level of activity and 3 cancers:

• Non-Hodgkin lymphoma (HR=0.91 [95% CI, 0.83-1.00])
• Gallbladder cancer (HR=0.72 [95% CI, 0.51-1.01])
• Small intestine cancer (HR=0.78 [95% CI, 0.60-1.00]).

However, the highest level of activity was also associated with an increased risk of prostate cancer (HR=1.05 [95% CI, 1.03-1.08]) and malignant melanoma (HR=1.27 [95% CI, 1.16-1.40]).

The researchers said the main limitation of this study is that they cannot fully exclude the possibility that diet, smoking, and other factors may have affected these results. Also, the study used self-reported physical activity, which can mean errors in recall.

Still, the team said these findings support promoting physical activity as a key component of population-wide cancer prevention and control efforts.