Leukemia, Myelodysplasia, Transplantation

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

AML cells

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

 

 

Cancer patient receives therapy

Photo by Rhoda Baer

 

A new report highlights recent advances made in the fight against cancer but suggests the burden of cancer in the US is still on the rise.

The AACR Cancer Progress Report 2016 states that the number of cancer survivors in the US rose by 1 million from 2014 to 2016, reaching an estimated 15.5 million.

Meanwhile, the US Food and Drug Administration (FDA) approved new treatments for a range of cancers.

Between August 1, 2015, and July 31, 2016, the FDA approved 13 new anticancer therapies and new uses for 11 previously approved anticancer therapies.

Six of these drugs were approved to treat hematologic malignancies:

• Venetoclax for chronic lymphocytic leukemia
• Daratumumab for multiple myeloma
• Elotuzumab for multiple myeloma
• Ixazomib for multiple myeloma
• Obinutuzumab for follicular lymphoma
• Nivolumab for classical Hodgkin lymphoma.

The report notes that the use of immunotherapy, in particular, is on the rise. For example, on August 1, 2015, checkpoint inhibitors were approved for just 2 cancers—melanoma and lung cancer.

As of September 1, 2016, checkpoint inhibitors have been approved for 6 cancers—Hodgkin lymphoma, bladder cancer, head and neck cancer, kidney cancer, lung cancer, and melanoma.

“The promise of immunotherapy for cancer therapy has never been greater, and the opportunity to make significant progress in this critical area is real,” said Nancy E. Davidson, MD, president of the AACR and director of the University of Pittsburgh Cancer Institute in Pennsylvania.

“However, continued progress is going to require a sustained federal commitment to the research agenda. And in fact, if the necessary funding is provided, we will accelerate the pace of progress and, in turn, markedly reduce morbidity and mortality from cancer.”

Growing burden of cancer

The report emphasizes that although advances are being made against cancers, these diseases continue to exert an immense personal and economic toll, and the burden of cancer is expected to grow in the coming decades.

According to the report:

• More than 595,000 people in the US are projected to die from cancer in 2016
• Cancer is the number one cause of disease-related death among US children
• The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035
• It is estimated that the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs will rise to $156 billion in 2020.

The report states that the increasing economic and personal burden of cancer underscores the need for more research to develop new approaches to cancer prevention and treatment.

The report also highlights the recommendations of the National Cancer Moonshot Initiative Blue Ribbon Panel for accelerating the pace of progress in cancer research.

“Research has made tremendous advances against cancer,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, we need to accelerate the pace of progress because it is unacceptable that 1 American will die of cancer every minute of every day this year.”

Doctor and patient in hospital

Photo courtesy of CDC

New research suggests that many patients who die of cancer do not receive strong opioid medications in their last year of life, despite the fact that these drugs are the recommended treatment for cancer-related pain.

Researchers used UK Cancer Registry Data to study more than 6000 cancer patients who died over a 7-year period.

Less than half of these patients received prescriptions for strong opioid medications in their last year of life.

Among those patients who did receive such prescriptions, many received them late.

Lucy Ziegler, PhD, of the University of Leeds in the UK, and her colleagues conducted this study and reported the results in PAIN.

The study included 6080 cancer patients who died between 2005 and 2012.

About 76% (n=4610) of these patients had received one or more prescriptions for analgesics, including 48% (n=2919) who received a strong opioid and 28% (n=1691) who received a non-opioid or weak opioid. The remaining 24% (n=1470) did not receive any prescription analgesic.

The chance of receiving strong opioids was not affected by patients’ age or sex.

However, patients who died in a hospital were 60% less likely to have a prescription for strong opioids during the last year of life, when compared with those who died in hospice.

And patients who received chemotherapy in the last year of life were 30% more likely to receive a strong opioid than patients who did not receive chemotherapy.

Timing of therapy

Among the patients who did receive strong opioids, the median time between receiving the medication and death was 9 weeks. By 6 weeks before death, just 30% of patients had been prescribed a strong opioid.

The researchers noted that these figures don’t match up with previous studies reporting that severe pain can occur “much earlier in the cancer trajectory.”

Older patients were more likely to receive their strong opioid prescription late (defined as later than 9 weeks before death). After other factors were taken into account, patients age 60 or older were about 2 to 4 times more likely to be in the late-prescribing group, compared with those age 50 or younger.

Compared to patients who died in hospice, patients who died in a hospital were 40% more likely to receive a late prescription for a strong opioid. Patients who died in their own home were 2.6 times more likely to receive a late prescription, and patients who died in a care home were 2.8 times more likely to receive a late prescription.

Patients who had surgery were 40% more likely to receive a late prescription than patients who did not undergo surgery.

But patients who received chemotherapy and/or radiotherapy were 30% more likely to have received an early prescription for a strong opioid than patients who did not receive chemo/radiotherapy.

Dr Ziegler and her colleagues noted that this study had its limitations; in particular, the lack of data on pain severity.

Still, the researchers believe their results support the hypothesis of potential under-treatment of cancer pain and suggest that many more patients with advanced cancer and pain may benefit from a strong opioid analgesic.

Doctor and patient in hospital

Photo courtesy of CDC

New research suggests that many patients who die of cancer do not receive strong opioid medications in their last year of life, despite the fact that these drugs are the recommended treatment for cancer-related pain.

Researchers used UK Cancer Registry Data to study more than 6000 cancer patients who died over a 7-year period.

Less than half of these patients received prescriptions for strong opioid medications in their last year of life.

Among those patients who did receive such prescriptions, many received them late.

Lucy Ziegler, PhD, of the University of Leeds in the UK, and her colleagues conducted this study and reported the results in PAIN.

The study included 6080 cancer patients who died between 2005 and 2012.

About 76% (n=4610) of these patients had received one or more prescriptions for analgesics, including 48% (n=2919) who received a strong opioid and 28% (n=1691) who received a non-opioid or weak opioid. The remaining 24% (n=1470) did not receive any prescription analgesic.

The chance of receiving strong opioids was not affected by patients’ age or sex.

However, patients who died in a hospital were 60% less likely to have a prescription for strong opioids during the last year of life, when compared with those who died in hospice.

And patients who received chemotherapy in the last year of life were 30% more likely to receive a strong opioid than patients who did not receive chemotherapy.

Timing of therapy

Among the patients who did receive strong opioids, the median time between receiving the medication and death was 9 weeks. By 6 weeks before death, just 30% of patients had been prescribed a strong opioid.

The researchers noted that these figures don’t match up with previous studies reporting that severe pain can occur “much earlier in the cancer trajectory.”

Older patients were more likely to receive their strong opioid prescription late (defined as later than 9 weeks before death). After other factors were taken into account, patients age 60 or older were about 2 to 4 times more likely to be in the late-prescribing group, compared with those age 50 or younger.

Compared to patients who died in hospice, patients who died in a hospital were 40% more likely to receive a late prescription for a strong opioid. Patients who died in their own home were 2.6 times more likely to receive a late prescription, and patients who died in a care home were 2.8 times more likely to receive a late prescription.

Patients who had surgery were 40% more likely to receive a late prescription than patients who did not undergo surgery.

But patients who received chemotherapy and/or radiotherapy were 30% more likely to have received an early prescription for a strong opioid than patients who did not receive chemo/radiotherapy.

Dr Ziegler and her colleagues noted that this study had its limitations; in particular, the lack of data on pain severity.

Still, the researchers believe their results support the hypothesis of potential under-treatment of cancer pain and suggest that many more patients with advanced cancer and pain may benefit from a strong opioid analgesic.

Doctor and patient in hospital

Photo courtesy of CDC

New research suggests that many patients who die of cancer do not receive strong opioid medications in their last year of life, despite the fact that these drugs are the recommended treatment for cancer-related pain.

Researchers used UK Cancer Registry Data to study more than 6000 cancer patients who died over a 7-year period.

Less than half of these patients received prescriptions for strong opioid medications in their last year of life.

Among those patients who did receive such prescriptions, many received them late.

Lucy Ziegler, PhD, of the University of Leeds in the UK, and her colleagues conducted this study and reported the results in PAIN.

The study included 6080 cancer patients who died between 2005 and 2012.

About 76% (n=4610) of these patients had received one or more prescriptions for analgesics, including 48% (n=2919) who received a strong opioid and 28% (n=1691) who received a non-opioid or weak opioid. The remaining 24% (n=1470) did not receive any prescription analgesic.

The chance of receiving strong opioids was not affected by patients’ age or sex.

However, patients who died in a hospital were 60% less likely to have a prescription for strong opioids during the last year of life, when compared with those who died in hospice.

And patients who received chemotherapy in the last year of life were 30% more likely to receive a strong opioid than patients who did not receive chemotherapy.

Timing of therapy

Among the patients who did receive strong opioids, the median time between receiving the medication and death was 9 weeks. By 6 weeks before death, just 30% of patients had been prescribed a strong opioid.

The researchers noted that these figures don’t match up with previous studies reporting that severe pain can occur “much earlier in the cancer trajectory.”

Older patients were more likely to receive their strong opioid prescription late (defined as later than 9 weeks before death). After other factors were taken into account, patients age 60 or older were about 2 to 4 times more likely to be in the late-prescribing group, compared with those age 50 or younger.

Compared to patients who died in hospice, patients who died in a hospital were 40% more likely to receive a late prescription for a strong opioid. Patients who died in their own home were 2.6 times more likely to receive a late prescription, and patients who died in a care home were 2.8 times more likely to receive a late prescription.

Patients who had surgery were 40% more likely to receive a late prescription than patients who did not undergo surgery.

But patients who received chemotherapy and/or radiotherapy were 30% more likely to have received an early prescription for a strong opioid than patients who did not receive chemo/radiotherapy.

Dr Ziegler and her colleagues noted that this study had its limitations; in particular, the lack of data on pain severity.

Still, the researchers believe their results support the hypothesis of potential under-treatment of cancer pain and suggest that many more patients with advanced cancer and pain may benefit from a strong opioid analgesic.

B-cell precursor ALL

Image by Vashi Donsk

Adding rituximab to a chemotherapy regimen can improve event-free survival (EFS) in adults with newly diagnosed, CD20-positive acute lymphoblastic leukemia (ALL), according to the GRAALL-2005/R study.

The 2-year EFS was significantly higher for patients who received rituximab than for those who received chemotherapy alone.

However, there was no significant difference between the groups in 2-year overall survival.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, and his colleagues reported these results in NEJM. Results from this study were previously presented at the 2015 ASH Annual Meeting.

The study included 209 patients with newly diagnosed, Ph-negative, B-cell precursor ALL with 20% or more CD20-positive leukemic blasts.

The patients’ median age was 40.2 (range, 24.5–52.6), 13% had an ECOG performance status greater than 1, 6% had CNS involvement, and 21% had a white blood cell count of 30 x 10⁹/L or higher.

Half of the patients (n=104) were randomized to receive the GRAALL-2005 regimen, and the other half (n=105) were randomized to receive the same regimen plus rituximab. Details on the regimens are available in the supplementary material published with the NEJM paper.

Baseline patient characteristics were well-balanced between the treatment groups.

Results

At a median follow-up of 30 months, 101 patients (48%) had at least 1 event, including 44 (42%) in the rituximab group and 57 (55%) in the control group.

There were 17 induction failures (8 in the rituximab group and 9 in the control group), 57 relapses (22 and 35, respectively), and 27 deaths during remission (14 and 13, respectively). Two patients in the rituximab group were lost to follow-up during the first 12 months.

The 2-year EFS was significantly higher in the rituximab group than the control group—65% and 52%, respectively (hazard ratio [HR]=0.66, P=0.04).

However, the EFS benefit did not translate into a significant improvement in overall survival. The 2-year overall survival was 71% in the rituximab group and 64% in the control group (HR=0.70, P=0.10).

Similarly, the cumulative incidence of death during first remission was not significantly different between the treatment groups—12% for both (HR=0.98, P=0.96).

The researchers said the difference in EFS was mostly due to a lower incidence of relapse in the rituximab group. The 2-year incidence of relapse was 18% in the rituximab group and 32% in the control group (HR=0.52, P=0.02).

In a multivariate analysis, receiving the control treatment, older age, higher white blood cell count at baseline, and CNS involvement were all significantly associated with poor EFS.

There were 245 severe adverse events (AEs) reported in 124 patients—67 patients with 1 event, 26 with 2 events, 13 with 3 events, and 18 with 4 or more events.

The overall incidence of severe AEs did not differ significantly between the treatment groups—96% in the rituximab group and 92% in the control group.

Severe AEs included infection, laboratory abnormalities, allergic reactions, neurologic events, pulmonary events, coagulopathy, cardiac events, gastrointestinal events, and “other” events.

The only severe AE for which there was a significant difference between the treatment groups was allergic reactions. There were 2 severe allergic events in the rituximab group and 14 in the control group (P=0.002). Of these 16 events, all but 1 were due to asparaginase.

The researchers therefore theorized that rituximab might inhibit B-cell protection of antibodies against asparaginase, although they could not confirm this hypothesis.

B-cell precursor ALL

Image by Vashi Donsk

Adding rituximab to a chemotherapy regimen can improve event-free survival (EFS) in adults with newly diagnosed, CD20-positive acute lymphoblastic leukemia (ALL), according to the GRAALL-2005/R study.

The 2-year EFS was significantly higher for patients who received rituximab than for those who received chemotherapy alone.

However, there was no significant difference between the groups in 2-year overall survival.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, and his colleagues reported these results in NEJM. Results from this study were previously presented at the 2015 ASH Annual Meeting.

The study included 209 patients with newly diagnosed, Ph-negative, B-cell precursor ALL with 20% or more CD20-positive leukemic blasts.

The patients’ median age was 40.2 (range, 24.5–52.6), 13% had an ECOG performance status greater than 1, 6% had CNS involvement, and 21% had a white blood cell count of 30 x 10⁹/L or higher.

Half of the patients (n=104) were randomized to receive the GRAALL-2005 regimen, and the other half (n=105) were randomized to receive the same regimen plus rituximab. Details on the regimens are available in the supplementary material published with the NEJM paper.

Baseline patient characteristics were well-balanced between the treatment groups.

Results

At a median follow-up of 30 months, 101 patients (48%) had at least 1 event, including 44 (42%) in the rituximab group and 57 (55%) in the control group.

There were 17 induction failures (8 in the rituximab group and 9 in the control group), 57 relapses (22 and 35, respectively), and 27 deaths during remission (14 and 13, respectively). Two patients in the rituximab group were lost to follow-up during the first 12 months.

The 2-year EFS was significantly higher in the rituximab group than the control group—65% and 52%, respectively (hazard ratio [HR]=0.66, P=0.04).

However, the EFS benefit did not translate into a significant improvement in overall survival. The 2-year overall survival was 71% in the rituximab group and 64% in the control group (HR=0.70, P=0.10).

Similarly, the cumulative incidence of death during first remission was not significantly different between the treatment groups—12% for both (HR=0.98, P=0.96).

The researchers said the difference in EFS was mostly due to a lower incidence of relapse in the rituximab group. The 2-year incidence of relapse was 18% in the rituximab group and 32% in the control group (HR=0.52, P=0.02).

In a multivariate analysis, receiving the control treatment, older age, higher white blood cell count at baseline, and CNS involvement were all significantly associated with poor EFS.

There were 245 severe adverse events (AEs) reported in 124 patients—67 patients with 1 event, 26 with 2 events, 13 with 3 events, and 18 with 4 or more events.

The overall incidence of severe AEs did not differ significantly between the treatment groups—96% in the rituximab group and 92% in the control group.

Severe AEs included infection, laboratory abnormalities, allergic reactions, neurologic events, pulmonary events, coagulopathy, cardiac events, gastrointestinal events, and “other” events.

The only severe AE for which there was a significant difference between the treatment groups was allergic reactions. There were 2 severe allergic events in the rituximab group and 14 in the control group (P=0.002). Of these 16 events, all but 1 were due to asparaginase.

The researchers therefore theorized that rituximab might inhibit B-cell protection of antibodies against asparaginase, although they could not confirm this hypothesis.

B-cell precursor ALL

Image by Vashi Donsk

Adding rituximab to a chemotherapy regimen can improve event-free survival (EFS) in adults with newly diagnosed, CD20-positive acute lymphoblastic leukemia (ALL), according to the GRAALL-2005/R study.

The 2-year EFS was significantly higher for patients who received rituximab than for those who received chemotherapy alone.

However, there was no significant difference between the groups in 2-year overall survival.

Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, and his colleagues reported these results in NEJM. Results from this study were previously presented at the 2015 ASH Annual Meeting.

The study included 209 patients with newly diagnosed, Ph-negative, B-cell precursor ALL with 20% or more CD20-positive leukemic blasts.

The patients’ median age was 40.2 (range, 24.5–52.6), 13% had an ECOG performance status greater than 1, 6% had CNS involvement, and 21% had a white blood cell count of 30 x 10⁹/L or higher.

Half of the patients (n=104) were randomized to receive the GRAALL-2005 regimen, and the other half (n=105) were randomized to receive the same regimen plus rituximab. Details on the regimens are available in the supplementary material published with the NEJM paper.

Baseline patient characteristics were well-balanced between the treatment groups.

Results

At a median follow-up of 30 months, 101 patients (48%) had at least 1 event, including 44 (42%) in the rituximab group and 57 (55%) in the control group.

There were 17 induction failures (8 in the rituximab group and 9 in the control group), 57 relapses (22 and 35, respectively), and 27 deaths during remission (14 and 13, respectively). Two patients in the rituximab group were lost to follow-up during the first 12 months.

The 2-year EFS was significantly higher in the rituximab group than the control group—65% and 52%, respectively (hazard ratio [HR]=0.66, P=0.04).

However, the EFS benefit did not translate into a significant improvement in overall survival. The 2-year overall survival was 71% in the rituximab group and 64% in the control group (HR=0.70, P=0.10).

Similarly, the cumulative incidence of death during first remission was not significantly different between the treatment groups—12% for both (HR=0.98, P=0.96).

The researchers said the difference in EFS was mostly due to a lower incidence of relapse in the rituximab group. The 2-year incidence of relapse was 18% in the rituximab group and 32% in the control group (HR=0.52, P=0.02).

In a multivariate analysis, receiving the control treatment, older age, higher white blood cell count at baseline, and CNS involvement were all significantly associated with poor EFS.

There were 245 severe adverse events (AEs) reported in 124 patients—67 patients with 1 event, 26 with 2 events, 13 with 3 events, and 18 with 4 or more events.

The overall incidence of severe AEs did not differ significantly between the treatment groups—96% in the rituximab group and 92% in the control group.

Severe AEs included infection, laboratory abnormalities, allergic reactions, neurologic events, pulmonary events, coagulopathy, cardiac events, gastrointestinal events, and “other” events.

The only severe AE for which there was a significant difference between the treatment groups was allergic reactions. There were 2 severe allergic events in the rituximab group and 14 in the control group (P=0.002). Of these 16 events, all but 1 were due to asparaginase.

The researchers therefore theorized that rituximab might inhibit B-cell protection of antibodies against asparaginase, although they could not confirm this hypothesis.

Lab mouse

New research has revealed a potential treatment strategy for acute myeloid leukemia (AML) and other malignancies that show a preference for metabolizing fat over sugar.

The study suggests the protein prolyl hydroxylase 3 (PHD3) is a key regulator of fatty acid oxidation, and PHD3 expression is low in certain malignancies—particularly AML—but overexpressing PHD3 can have anticancer effects.

Researchers believe this finding might aid the development of therapies that work by starving tumors of their fuel.

“This really represents a new frontier in looking at the metabolism of cancer,” said study author Marcia Haigis, PhD, of Harvard Medical School in Boston, Massachusetts.

“Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy.”

Dr Haigis and her colleagues described the work in Molecular Cell.

The researchers knew that when cells run low on nutrients, they switch from sugar to fat as their fuel source to sustain function.

When cells have low energy, the protein AMPK targets the enzyme ACC to activate fat oxidation, which helps cells burn fats to make energy. However, when cells have enough resources, they seek to maintain energy balance.

Dr Haigis and her colleagues were searching for precisely how cells turn off fat oxidation and homed in on PHD3. Recent studies had suggested that PHD3 plays a part in cell metabolism, but,

until now, its precise role has remained unclear.

In a series of experiments, Dr Haigis’s team showed that PHD3 suppressed fat-burning by chemically modifying and activating ACC2—a version of the same enzyme responsible for keeping cellular fat-burning in check.

To determine PHD3’s role in cancer, the researchers combed through databases of all human cancers. The team theorized that sugar-craving malignancies would have high levels of PDH3, and cancers that relied on fat for their energy would have low levels.

The researchers found the lowest levels of PHD3 in AML, so they decided to examine the effects of restoring PHD3 in AML cells and a mouse model of the disease.

The experiments showed that restoring PHD3 expression reduces AML potency, and ACC2 is required for the inhibitory effects of PHD3. Overexpressing PHD3 limited fatty acid oxidation via regulation of ACC2, which decreased leukemia cell proliferation and enhanced survival in the mouse model of AML.

Dr Haigis noted that more basic research is needed before this work can move ahead to the clinic, as it’s still unclear why certain cancers depend on fat.

“What do fats provide to tumors that other fuels don’t?” Dr Haigis asked. “That’s one open question, and this is only the first chapter in the story.” 

Lab mouse

New research has revealed a potential treatment strategy for acute myeloid leukemia (AML) and other malignancies that show a preference for metabolizing fat over sugar.

The study suggests the protein prolyl hydroxylase 3 (PHD3) is a key regulator of fatty acid oxidation, and PHD3 expression is low in certain malignancies—particularly AML—but overexpressing PHD3 can have anticancer effects.

Researchers believe this finding might aid the development of therapies that work by starving tumors of their fuel.

“This really represents a new frontier in looking at the metabolism of cancer,” said study author Marcia Haigis, PhD, of Harvard Medical School in Boston, Massachusetts.

“Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy.”

Dr Haigis and her colleagues described the work in Molecular Cell.

The researchers knew that when cells run low on nutrients, they switch from sugar to fat as their fuel source to sustain function.

When cells have low energy, the protein AMPK targets the enzyme ACC to activate fat oxidation, which helps cells burn fats to make energy. However, when cells have enough resources, they seek to maintain energy balance.

Dr Haigis and her colleagues were searching for precisely how cells turn off fat oxidation and homed in on PHD3. Recent studies had suggested that PHD3 plays a part in cell metabolism, but,

until now, its precise role has remained unclear.

In a series of experiments, Dr Haigis’s team showed that PHD3 suppressed fat-burning by chemically modifying and activating ACC2—a version of the same enzyme responsible for keeping cellular fat-burning in check.

To determine PHD3’s role in cancer, the researchers combed through databases of all human cancers. The team theorized that sugar-craving malignancies would have high levels of PDH3, and cancers that relied on fat for their energy would have low levels.

The researchers found the lowest levels of PHD3 in AML, so they decided to examine the effects of restoring PHD3 in AML cells and a mouse model of the disease.

The experiments showed that restoring PHD3 expression reduces AML potency, and ACC2 is required for the inhibitory effects of PHD3. Overexpressing PHD3 limited fatty acid oxidation via regulation of ACC2, which decreased leukemia cell proliferation and enhanced survival in the mouse model of AML.

Dr Haigis noted that more basic research is needed before this work can move ahead to the clinic, as it’s still unclear why certain cancers depend on fat.

“What do fats provide to tumors that other fuels don’t?” Dr Haigis asked. “That’s one open question, and this is only the first chapter in the story.” 

Lab mouse

New research has revealed a potential treatment strategy for acute myeloid leukemia (AML) and other malignancies that show a preference for metabolizing fat over sugar.

The study suggests the protein prolyl hydroxylase 3 (PHD3) is a key regulator of fatty acid oxidation, and PHD3 expression is low in certain malignancies—particularly AML—but overexpressing PHD3 can have anticancer effects.

Researchers believe this finding might aid the development of therapies that work by starving tumors of their fuel.

“This really represents a new frontier in looking at the metabolism of cancer,” said study author Marcia Haigis, PhD, of Harvard Medical School in Boston, Massachusetts.

“Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy.”

Dr Haigis and her colleagues described the work in Molecular Cell.

The researchers knew that when cells run low on nutrients, they switch from sugar to fat as their fuel source to sustain function.

When cells have low energy, the protein AMPK targets the enzyme ACC to activate fat oxidation, which helps cells burn fats to make energy. However, when cells have enough resources, they seek to maintain energy balance.

Dr Haigis and her colleagues were searching for precisely how cells turn off fat oxidation and homed in on PHD3. Recent studies had suggested that PHD3 plays a part in cell metabolism, but,

until now, its precise role has remained unclear.

In a series of experiments, Dr Haigis’s team showed that PHD3 suppressed fat-burning by chemically modifying and activating ACC2—a version of the same enzyme responsible for keeping cellular fat-burning in check.

To determine PHD3’s role in cancer, the researchers combed through databases of all human cancers. The team theorized that sugar-craving malignancies would have high levels of PDH3, and cancers that relied on fat for their energy would have low levels.

The researchers found the lowest levels of PHD3 in AML, so they decided to examine the effects of restoring PHD3 in AML cells and a mouse model of the disease.

The experiments showed that restoring PHD3 expression reduces AML potency, and ACC2 is required for the inhibitory effects of PHD3. Overexpressing PHD3 limited fatty acid oxidation via regulation of ACC2, which decreased leukemia cell proliferation and enhanced survival in the mouse model of AML.

Dr Haigis noted that more basic research is needed before this work can move ahead to the clinic, as it’s still unclear why certain cancers depend on fat.

“What do fats provide to tumors that other fuels don’t?” Dr Haigis asked. “That’s one open question, and this is only the first chapter in the story.” 

Cancer patient

Photo by Bill Branson

Brain cancer has overtaken leukemia to become the deadliest childhood cancer in the US, according to a report from the US Centers for Disease Control and Prevention’s National Center for Health Statistics.

The report includes cancer mortality statistics from 1999 to 2014 pertaining to children and adolescents (ages 1 to 19).

In both 1999 and 2014, more than half of all cancer deaths in this population were attributable to leukemias or brain cancers.

In 1999, a greater percentage of deaths were attributed to leukemias than to brain cancers—29.7% and 23.7%, respectively.

But in 2014, brain cancer deaths exceeded leukemia deaths—29.9% and 24.9%, respectively.

The data also showed that, overall, cancer mortality has decreased among children and adolescents in the US.

The cancer death rate was 20% lower in 2014 than in 1999—2.28 deaths per 100,000 persons and 2.85 deaths per 100,000 persons, respectively.

Cancer death rates declined from 1999 to 2014 for all of the age groups studied (divided by 5-year increments) and for both sexes. However, cancer death rates were consistently higher for males than females.

In 2014, 54.8% of cancer deaths among children and adolescents were attributable to either leukemias or brain cancers.

The 2014 death rates by cancer site, from most common to least, were as follows:

• Brain cancers (29.9%)
• Leukemias (24.9%)
• Bone and articular cartilage cancers (10.1%)
• Cancers of the thyroid and other endocrine glands (9.0%)
• Mesothelial and soft tissue cancers (7.7%)
• Non-Hodgkin lymphomas (3.9%)
• Cancers of the liver and intrahepatic bile ducts (2.0%)
• Cancers of the kidney and renal pelvis (1.8%).

Data on the remaining cancer sites were not shown separately.

For more information, see the full report, “Declines in Cancer Death Rates Among Children and Adolescents in the United States, 1999–2014.”

Cancer patient

Photo by Bill Branson

Brain cancer has overtaken leukemia to become the deadliest childhood cancer in the US, according to a report from the US Centers for Disease Control and Prevention’s National Center for Health Statistics.

The report includes cancer mortality statistics from 1999 to 2014 pertaining to children and adolescents (ages 1 to 19).

In both 1999 and 2014, more than half of all cancer deaths in this population were attributable to leukemias or brain cancers.

In 1999, a greater percentage of deaths were attributed to leukemias than to brain cancers—29.7% and 23.7%, respectively.

But in 2014, brain cancer deaths exceeded leukemia deaths—29.9% and 24.9%, respectively.

The data also showed that, overall, cancer mortality has decreased among children and adolescents in the US.

The cancer death rate was 20% lower in 2014 than in 1999—2.28 deaths per 100,000 persons and 2.85 deaths per 100,000 persons, respectively.

Cancer death rates declined from 1999 to 2014 for all of the age groups studied (divided by 5-year increments) and for both sexes. However, cancer death rates were consistently higher for males than females.

In 2014, 54.8% of cancer deaths among children and adolescents were attributable to either leukemias or brain cancers.

The 2014 death rates by cancer site, from most common to least, were as follows:

• Brain cancers (29.9%)
• Leukemias (24.9%)
• Bone and articular cartilage cancers (10.1%)
• Cancers of the thyroid and other endocrine glands (9.0%)
• Mesothelial and soft tissue cancers (7.7%)
• Non-Hodgkin lymphomas (3.9%)
• Cancers of the liver and intrahepatic bile ducts (2.0%)
• Cancers of the kidney and renal pelvis (1.8%).

Data on the remaining cancer sites were not shown separately.

For more information, see the full report, “Declines in Cancer Death Rates Among Children and Adolescents in the United States, 1999–2014.”

Cancer patient

Photo by Bill Branson

Brain cancer has overtaken leukemia to become the deadliest childhood cancer in the US, according to a report from the US Centers for Disease Control and Prevention’s National Center for Health Statistics.

The report includes cancer mortality statistics from 1999 to 2014 pertaining to children and adolescents (ages 1 to 19).

In both 1999 and 2014, more than half of all cancer deaths in this population were attributable to leukemias or brain cancers.

In 1999, a greater percentage of deaths were attributed to leukemias than to brain cancers—29.7% and 23.7%, respectively.

But in 2014, brain cancer deaths exceeded leukemia deaths—29.9% and 24.9%, respectively.

The data also showed that, overall, cancer mortality has decreased among children and adolescents in the US.

The cancer death rate was 20% lower in 2014 than in 1999—2.28 deaths per 100,000 persons and 2.85 deaths per 100,000 persons, respectively.

Cancer death rates declined from 1999 to 2014 for all of the age groups studied (divided by 5-year increments) and for both sexes. However, cancer death rates were consistently higher for males than females.

In 2014, 54.8% of cancer deaths among children and adolescents were attributable to either leukemias or brain cancers.

The 2014 death rates by cancer site, from most common to least, were as follows:

• Brain cancers (29.9%)
• Leukemias (24.9%)
• Bone and articular cartilage cancers (10.1%)
• Cancers of the thyroid and other endocrine glands (9.0%)
• Mesothelial and soft tissue cancers (7.7%)
• Non-Hodgkin lymphomas (3.9%)
• Cancers of the liver and intrahepatic bile ducts (2.0%)
• Cancers of the kidney and renal pelvis (1.8%).

Data on the remaining cancer sites were not shown separately.

For more information, see the full report, “Declines in Cancer Death Rates Among Children and Adolescents in the United States, 1999–2014.”

Micrograph showing AML

Compounds that inhibit the metabolic enzyme dihydroorotate dehydrogenase (DHODH) may be effective in treating acute myeloid leukemia (AML), according to preclinical research.

Investigators found that inhibiting DHODH enables myeloid differentiation in AML cells.

In mouse models of AML, treatment with a DHODH inhibitor reduced leukemia burden, decreased leukemia-initiating cell activity, and improved survival.

David Scadden, MD, of Massachusetts General Hospital in Boston, and his colleagues conducted this research and reported the results in Cell.

The research began with the observation that HoxA9, which is normally downregulated during myeloid differentiation, is expressed in roughly 70% of AML patients.

Since no inhibitors of HoxA9 have been identified, Dr Scadden and his colleagues set out to identify compounds that could overcome the differentiation blockade characteristic of AML cells.

The investigators first set up a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to fluoresce if they reached maturity.

The team then screened more than 330,000 small molecules, looking for those that would cause the cells to fluoresce, indicating that the HoxA9-induced differentiation blockade had been overcome.

Only 12 compounds produced the desired result. Eleven of these compounds were found to act by suppressing DHODH, which was not previously known to have a role in myeloid differentiation.

Further experiments showed that DHODH inhibition could induce differentiation in both mouse and human AML cells.

The investigators then tested BRQ, a known DHODH inhibitor, in several mouse models of AML.

Treatment with BRQ led to differentiation, reduced leukemia burden, decreased activity of leukemia-initiating cells, and prolonged survival when compared to treatment with cytarabine and doxorubicin.

“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target because it can be complicated and imprecise,” Dr Scadden noted.

“We think that, with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified.”

Micrograph showing AML

Compounds that inhibit the metabolic enzyme dihydroorotate dehydrogenase (DHODH) may be effective in treating acute myeloid leukemia (AML), according to preclinical research.

Investigators found that inhibiting DHODH enables myeloid differentiation in AML cells.

In mouse models of AML, treatment with a DHODH inhibitor reduced leukemia burden, decreased leukemia-initiating cell activity, and improved survival.

David Scadden, MD, of Massachusetts General Hospital in Boston, and his colleagues conducted this research and reported the results in Cell.

The research began with the observation that HoxA9, which is normally downregulated during myeloid differentiation, is expressed in roughly 70% of AML patients.

Since no inhibitors of HoxA9 have been identified, Dr Scadden and his colleagues set out to identify compounds that could overcome the differentiation blockade characteristic of AML cells.

The investigators first set up a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to fluoresce if they reached maturity.

The team then screened more than 330,000 small molecules, looking for those that would cause the cells to fluoresce, indicating that the HoxA9-induced differentiation blockade had been overcome.

Only 12 compounds produced the desired result. Eleven of these compounds were found to act by suppressing DHODH, which was not previously known to have a role in myeloid differentiation.

Further experiments showed that DHODH inhibition could induce differentiation in both mouse and human AML cells.

The investigators then tested BRQ, a known DHODH inhibitor, in several mouse models of AML.

Treatment with BRQ led to differentiation, reduced leukemia burden, decreased activity of leukemia-initiating cells, and prolonged survival when compared to treatment with cytarabine and doxorubicin.

“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target because it can be complicated and imprecise,” Dr Scadden noted.

“We think that, with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified.”

Micrograph showing AML

Compounds that inhibit the metabolic enzyme dihydroorotate dehydrogenase (DHODH) may be effective in treating acute myeloid leukemia (AML), according to preclinical research.

Investigators found that inhibiting DHODH enables myeloid differentiation in AML cells.

In mouse models of AML, treatment with a DHODH inhibitor reduced leukemia burden, decreased leukemia-initiating cell activity, and improved survival.

David Scadden, MD, of Massachusetts General Hospital in Boston, and his colleagues conducted this research and reported the results in Cell.

The research began with the observation that HoxA9, which is normally downregulated during myeloid differentiation, is expressed in roughly 70% of AML patients.

Since no inhibitors of HoxA9 have been identified, Dr Scadden and his colleagues set out to identify compounds that could overcome the differentiation blockade characteristic of AML cells.

The investigators first set up a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to fluoresce if they reached maturity.

The team then screened more than 330,000 small molecules, looking for those that would cause the cells to fluoresce, indicating that the HoxA9-induced differentiation blockade had been overcome.

Only 12 compounds produced the desired result. Eleven of these compounds were found to act by suppressing DHODH, which was not previously known to have a role in myeloid differentiation.

Further experiments showed that DHODH inhibition could induce differentiation in both mouse and human AML cells.

The investigators then tested BRQ, a known DHODH inhibitor, in several mouse models of AML.

Treatment with BRQ led to differentiation, reduced leukemia burden, decreased activity of leukemia-initiating cells, and prolonged survival when compared to treatment with cytarabine and doxorubicin.

“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target because it can be complicated and imprecise,” Dr Scadden noted.

“We think that, with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified.”

CML cells

Image by Difu Wu

Two preclinical studies published in Cancer Discovery suggest that EZH2 inhibitors might enhance the efficacy of treatment with tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML).

One study showed that CML leukemic stem cells (LSCs) are dependent upon EZH2.

The other study revealed that epigenetic reprogramming sensitizes CML LSCs to combined treatment with an EZH2 inhibitor and a TKI.

EZH2 dependence

In the first study, in vitro experiments revealed that LSCs have an overabundance of EZH2. In fact, the researchers found that EZH2 helps LSCs survive and give rise to full-fledged CML cells.

Experiments in mice showed that inactivating EZH2 through gene-editing techniques caused LSCs to die, halting CML at its source.

“The stem cells’ dependence on EZH2 suggests they will be especially vulnerable to drugs that target the protein,” said study author Stuart Orkin, MD, of Boston Children’s Hospital in Massachusetts.

“Our findings suggest inhibition of EZH2 should be considered as a way to eradicate CML when used in combination with current targeted therapies. It offers a promising approach to shortening the duration of therapy in order to achieve a cure. If successful, the cost savings of such an approach could also be significant.”

Combination treatment

The second study supports the idea that combining EZH2 inhibitors and TKIs could benefit patients with CML.

Mary T. Scott, of the University of Glasgow in the UK, and her colleagues found that EZH2 and H3K27me3 reprogramming is important for LSC survival and renders the cells sensitive to combined treatment with an EZH2 inhibitor and a TKI.

The researchers treated CML CD34+ cells, normal CD34+ cells, and LSCs with the EZH2 inhibitor GSK343 and the TKI dasatinib, both alone and in combination. The team said that GSK343 selectively targeted the loss of H3K27me3 in the presence of dasatinib.

In addition, combination treatment led to a significant reduction in cell viability (even in “TKI-persistent” cells), an increase in apoptosis, and a reduction in colony-forming cell and granulocyte/erythroid/macrophage/megakaryocyte outputs, when compared to dasatinib alone.

The researchers also evaluated a TKI and an EZH2 inhibitor in a mouse model of CML. The mice received nilotinib and EPZ-6438, both alone and in combination, for either 14 days or 25 days.

After 14 days of treatment, mice that received the combination had significant reductions in levels of leukemic (Ph+) human CD45+ cells, CD45+CD34+ progenitor cells, and primitive CD45+CD34+CD38− stem cells in the bone marrow, when compared to mice that received nilotinib alone.

After 25 days of treatment, mice that received the combination had near-complete elimination of CD45+CD34+ progenitor cells and a greater than 70% reduction of CD45+CD34+CD38− cells, when compared to mice that received nilotinib alone.

The researchers said these results demonstrate a clear rationale for combining TKI treatment with an EZH2 inhibitor, as an EZH2 inhibitor can target primitive CML cells not eradicated by a TKI alone.

CML cells

Image by Difu Wu

Two preclinical studies published in Cancer Discovery suggest that EZH2 inhibitors might enhance the efficacy of treatment with tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML).

One study showed that CML leukemic stem cells (LSCs) are dependent upon EZH2.

The other study revealed that epigenetic reprogramming sensitizes CML LSCs to combined treatment with an EZH2 inhibitor and a TKI.

EZH2 dependence

In the first study, in vitro experiments revealed that LSCs have an overabundance of EZH2. In fact, the researchers found that EZH2 helps LSCs survive and give rise to full-fledged CML cells.

Experiments in mice showed that inactivating EZH2 through gene-editing techniques caused LSCs to die, halting CML at its source.

“The stem cells’ dependence on EZH2 suggests they will be especially vulnerable to drugs that target the protein,” said study author Stuart Orkin, MD, of Boston Children’s Hospital in Massachusetts.

“Our findings suggest inhibition of EZH2 should be considered as a way to eradicate CML when used in combination with current targeted therapies. It offers a promising approach to shortening the duration of therapy in order to achieve a cure. If successful, the cost savings of such an approach could also be significant.”

Combination treatment

The second study supports the idea that combining EZH2 inhibitors and TKIs could benefit patients with CML.

Mary T. Scott, of the University of Glasgow in the UK, and her colleagues found that EZH2 and H3K27me3 reprogramming is important for LSC survival and renders the cells sensitive to combined treatment with an EZH2 inhibitor and a TKI.

The researchers treated CML CD34+ cells, normal CD34+ cells, and LSCs with the EZH2 inhibitor GSK343 and the TKI dasatinib, both alone and in combination. The team said that GSK343 selectively targeted the loss of H3K27me3 in the presence of dasatinib.

In addition, combination treatment led to a significant reduction in cell viability (even in “TKI-persistent” cells), an increase in apoptosis, and a reduction in colony-forming cell and granulocyte/erythroid/macrophage/megakaryocyte outputs, when compared to dasatinib alone.

The researchers also evaluated a TKI and an EZH2 inhibitor in a mouse model of CML. The mice received nilotinib and EPZ-6438, both alone and in combination, for either 14 days or 25 days.

After 14 days of treatment, mice that received the combination had significant reductions in levels of leukemic (Ph+) human CD45+ cells, CD45+CD34+ progenitor cells, and primitive CD45+CD34+CD38− stem cells in the bone marrow, when compared to mice that received nilotinib alone.

After 25 days of treatment, mice that received the combination had near-complete elimination of CD45+CD34+ progenitor cells and a greater than 70% reduction of CD45+CD34+CD38− cells, when compared to mice that received nilotinib alone.

The researchers said these results demonstrate a clear rationale for combining TKI treatment with an EZH2 inhibitor, as an EZH2 inhibitor can target primitive CML cells not eradicated by a TKI alone.

CML cells

Image by Difu Wu

Two preclinical studies published in Cancer Discovery suggest that EZH2 inhibitors might enhance the efficacy of treatment with tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML).

One study showed that CML leukemic stem cells (LSCs) are dependent upon EZH2.

The other study revealed that epigenetic reprogramming sensitizes CML LSCs to combined treatment with an EZH2 inhibitor and a TKI.

EZH2 dependence

In the first study, in vitro experiments revealed that LSCs have an overabundance of EZH2. In fact, the researchers found that EZH2 helps LSCs survive and give rise to full-fledged CML cells.

Experiments in mice showed that inactivating EZH2 through gene-editing techniques caused LSCs to die, halting CML at its source.

“The stem cells’ dependence on EZH2 suggests they will be especially vulnerable to drugs that target the protein,” said study author Stuart Orkin, MD, of Boston Children’s Hospital in Massachusetts.

“Our findings suggest inhibition of EZH2 should be considered as a way to eradicate CML when used in combination with current targeted therapies. It offers a promising approach to shortening the duration of therapy in order to achieve a cure. If successful, the cost savings of such an approach could also be significant.”

Combination treatment

The second study supports the idea that combining EZH2 inhibitors and TKIs could benefit patients with CML.

Mary T. Scott, of the University of Glasgow in the UK, and her colleagues found that EZH2 and H3K27me3 reprogramming is important for LSC survival and renders the cells sensitive to combined treatment with an EZH2 inhibitor and a TKI.

The researchers treated CML CD34+ cells, normal CD34+ cells, and LSCs with the EZH2 inhibitor GSK343 and the TKI dasatinib, both alone and in combination. The team said that GSK343 selectively targeted the loss of H3K27me3 in the presence of dasatinib.

In addition, combination treatment led to a significant reduction in cell viability (even in “TKI-persistent” cells), an increase in apoptosis, and a reduction in colony-forming cell and granulocyte/erythroid/macrophage/megakaryocyte outputs, when compared to dasatinib alone.

The researchers also evaluated a TKI and an EZH2 inhibitor in a mouse model of CML. The mice received nilotinib and EPZ-6438, both alone and in combination, for either 14 days or 25 days.

After 14 days of treatment, mice that received the combination had significant reductions in levels of leukemic (Ph+) human CD45+ cells, CD45+CD34+ progenitor cells, and primitive CD45+CD34+CD38− stem cells in the bone marrow, when compared to mice that received nilotinib alone.

After 25 days of treatment, mice that received the combination had near-complete elimination of CD45+CD34+ progenitor cells and a greater than 70% reduction of CD45+CD34+CD38− cells, when compared to mice that received nilotinib alone.

The researchers said these results demonstrate a clear rationale for combining TKI treatment with an EZH2 inhibitor, as an EZH2 inhibitor can target primitive CML cells not eradicated by a TKI alone.

Doel nuclear power station

Photo by Rafaël Delaedt

Living near a certain type of nuclear facility may increase a child’s risk of developing acute leukemia, a new study suggests.

The research showed a 2- to 3-fold increased risk of acute leukemia among children living near 1 nuclear facility in Belgium—Mol-Dessel.

However, children who lived near the 3 other Belgian nuclear facilities studied—Doel, Fleurus, and Tihange—had no such increased risk.

Researchers said this study does not confirm a causal relationship between the Mol-Dessel facility and the increased risk of leukemia observed.

However, they did say the facility seems a plausible cause of the increased risk because the data showed significant associations between acute leukemia incidence and 3 surrogate measures of exposure—distance from the facility, prevailing winds, and simulated discharges of the radionuclide Ar-41.

An Van Nieuwenhuyse, MD, PhD, of the Scientific Institute of Public Health in Brussels, Belgium, and colleagues conducted this research and reported the results in the European Journal of Cancer Prevention.

Facilities

The study included 4 nuclear facilities in Belgium—Doel, Mol-Dessel, Fleurus, and Tihange. (The researchers also evaluated a fifth facility, Chooz, but they said it was not possible to draw conclusions regarding this site because the region around it is sparsely populated, which limits the number of cancer cases.)

Doel and Tihange are electricity-generating nuclear power plants that started up in 1975. The nuclear facility at Fleurus has produced radionuclides for medicine and industry since 1971.

The Mol-Dessel facility started up in 1956, and a combination of nuclear activities have taken place there, including scientific and technological research, applied research and metrology, operational waste management, the Belgian Underground Research Laboratory, and the production of fuel assemblies for pressurized-water reactors based on uranium oxide and mixed oxides.

Analysis

The researchers set out to determine whether there was an excess incidence of acute leukemia among children ages 0 to 14 who lived in the vicinity of the aforementioned nuclear facilities. The team analyzed data spanning the period from 2002 to 2008.

For all 4 facilities, the researchers used 2 different measures of surrogate exposure to radionuclide gaseous discharges—residential proximity to the nuclear site and prevailing wind directions.

For the Mol-Dessel site, the researchers also used estimated discharges of the radionuclide Ar-41 as a surrogate measure of exposure.

Results

The data did not show an increased incidence of acute leukemia among children living near the Doel, Tihange, or Fleurus facilities. However, children living within 15 km of the Mol-Dessel site had a significantly increased risk of acute leukemia.

In fact, the researchers said they observed statistically significant associations as a function of distance, prevailing winds, and simulated Ar-41 discharges, which suggests a potential link between acute leukemia incidence and the Mol-Dessel site.

The rate ratios for the Mol-Dessel facility, which were adjusted for age, sex, and socioeconomic status, were:

• 2.70 (95% CI: 1.15–6.33) for children living 0 to 5 km from the site (5 cases of acute leukemia)
• 1.82 (95% CI: 1.02–3.25) for children living 0 to 10 km from the site (11 cases of acute leukemia)
• 1.96 (95% CI: 1.19–3.22) for children living 0 to 15 km from the site (15 cases of acute leukemia)
• 1.09 (95% CI: 0.71–1.61) for children living 0 to 20 km from the site (21 cases of acute leukemia).

The 3 communities lying in the dominant wind direction of the Mol-Dessel nuclear site had rate ratios of 6.81 (95% CI: 2.28–20.32), 4.39 (95% CI: 1.46–13.17), and 3.74 (95% CI: 0.98–14.27).

The researchers calculated P values using Stone’s test, Bithell’s linear risk score test (LRS), and Bithell’s linear risk score test with corresponding ranks as a function of the different measures of surrogate exposure (LRS^r).

All 3 tests showed a significant association between acute leukemia incidence and proximity to the Mol-Dessel site (P<0.01 for all). However, only LRS and LRS^r showed a significant association for wind direction (P=0.01 and 0.03, respectively) and simulated radioactive discharges by Ar-41 (P<0.01 for both).

The researchers noted that, although these results suggest an association between acute childhood leukemia and the Mol-Dessel site, this study had limitations, and more research is needed.

Doel nuclear power station

Photo by Rafaël Delaedt

Living near a certain type of nuclear facility may increase a child’s risk of developing acute leukemia, a new study suggests.

The research showed a 2- to 3-fold increased risk of acute leukemia among children living near 1 nuclear facility in Belgium—Mol-Dessel.

However, children who lived near the 3 other Belgian nuclear facilities studied—Doel, Fleurus, and Tihange—had no such increased risk.

Researchers said this study does not confirm a causal relationship between the Mol-Dessel facility and the increased risk of leukemia observed.

However, they did say the facility seems a plausible cause of the increased risk because the data showed significant associations between acute leukemia incidence and 3 surrogate measures of exposure—distance from the facility, prevailing winds, and simulated discharges of the radionuclide Ar-41.

An Van Nieuwenhuyse, MD, PhD, of the Scientific Institute of Public Health in Brussels, Belgium, and colleagues conducted this research and reported the results in the European Journal of Cancer Prevention.

Facilities

The study included 4 nuclear facilities in Belgium—Doel, Mol-Dessel, Fleurus, and Tihange. (The researchers also evaluated a fifth facility, Chooz, but they said it was not possible to draw conclusions regarding this site because the region around it is sparsely populated, which limits the number of cancer cases.)

Doel and Tihange are electricity-generating nuclear power plants that started up in 1975. The nuclear facility at Fleurus has produced radionuclides for medicine and industry since 1971.

The Mol-Dessel facility started up in 1956, and a combination of nuclear activities have taken place there, including scientific and technological research, applied research and metrology, operational waste management, the Belgian Underground Research Laboratory, and the production of fuel assemblies for pressurized-water reactors based on uranium oxide and mixed oxides.

Analysis

The researchers set out to determine whether there was an excess incidence of acute leukemia among children ages 0 to 14 who lived in the vicinity of the aforementioned nuclear facilities. The team analyzed data spanning the period from 2002 to 2008.

For all 4 facilities, the researchers used 2 different measures of surrogate exposure to radionuclide gaseous discharges—residential proximity to the nuclear site and prevailing wind directions.

For the Mol-Dessel site, the researchers also used estimated discharges of the radionuclide Ar-41 as a surrogate measure of exposure.

Results

The data did not show an increased incidence of acute leukemia among children living near the Doel, Tihange, or Fleurus facilities. However, children living within 15 km of the Mol-Dessel site had a significantly increased risk of acute leukemia.

In fact, the researchers said they observed statistically significant associations as a function of distance, prevailing winds, and simulated Ar-41 discharges, which suggests a potential link between acute leukemia incidence and the Mol-Dessel site.

The rate ratios for the Mol-Dessel facility, which were adjusted for age, sex, and socioeconomic status, were:

• 2.70 (95% CI: 1.15–6.33) for children living 0 to 5 km from the site (5 cases of acute leukemia)
• 1.82 (95% CI: 1.02–3.25) for children living 0 to 10 km from the site (11 cases of acute leukemia)
• 1.96 (95% CI: 1.19–3.22) for children living 0 to 15 km from the site (15 cases of acute leukemia)
• 1.09 (95% CI: 0.71–1.61) for children living 0 to 20 km from the site (21 cases of acute leukemia).

The 3 communities lying in the dominant wind direction of the Mol-Dessel nuclear site had rate ratios of 6.81 (95% CI: 2.28–20.32), 4.39 (95% CI: 1.46–13.17), and 3.74 (95% CI: 0.98–14.27).

The researchers calculated P values using Stone’s test, Bithell’s linear risk score test (LRS), and Bithell’s linear risk score test with corresponding ranks as a function of the different measures of surrogate exposure (LRS^r).

All 3 tests showed a significant association between acute leukemia incidence and proximity to the Mol-Dessel site (P<0.01 for all). However, only LRS and LRS^r showed a significant association for wind direction (P=0.01 and 0.03, respectively) and simulated radioactive discharges by Ar-41 (P<0.01 for both).

The researchers noted that, although these results suggest an association between acute childhood leukemia and the Mol-Dessel site, this study had limitations, and more research is needed.

Doel nuclear power station

Photo by Rafaël Delaedt

Living near a certain type of nuclear facility may increase a child’s risk of developing acute leukemia, a new study suggests.

The research showed a 2- to 3-fold increased risk of acute leukemia among children living near 1 nuclear facility in Belgium—Mol-Dessel.

However, children who lived near the 3 other Belgian nuclear facilities studied—Doel, Fleurus, and Tihange—had no such increased risk.

Researchers said this study does not confirm a causal relationship between the Mol-Dessel facility and the increased risk of leukemia observed.

However, they did say the facility seems a plausible cause of the increased risk because the data showed significant associations between acute leukemia incidence and 3 surrogate measures of exposure—distance from the facility, prevailing winds, and simulated discharges of the radionuclide Ar-41.

An Van Nieuwenhuyse, MD, PhD, of the Scientific Institute of Public Health in Brussels, Belgium, and colleagues conducted this research and reported the results in the European Journal of Cancer Prevention.

Facilities

The study included 4 nuclear facilities in Belgium—Doel, Mol-Dessel, Fleurus, and Tihange. (The researchers also evaluated a fifth facility, Chooz, but they said it was not possible to draw conclusions regarding this site because the region around it is sparsely populated, which limits the number of cancer cases.)

Doel and Tihange are electricity-generating nuclear power plants that started up in 1975. The nuclear facility at Fleurus has produced radionuclides for medicine and industry since 1971.

The Mol-Dessel facility started up in 1956, and a combination of nuclear activities have taken place there, including scientific and technological research, applied research and metrology, operational waste management, the Belgian Underground Research Laboratory, and the production of fuel assemblies for pressurized-water reactors based on uranium oxide and mixed oxides.

Analysis

The researchers set out to determine whether there was an excess incidence of acute leukemia among children ages 0 to 14 who lived in the vicinity of the aforementioned nuclear facilities. The team analyzed data spanning the period from 2002 to 2008.

For all 4 facilities, the researchers used 2 different measures of surrogate exposure to radionuclide gaseous discharges—residential proximity to the nuclear site and prevailing wind directions.

For the Mol-Dessel site, the researchers also used estimated discharges of the radionuclide Ar-41 as a surrogate measure of exposure.

Results

The data did not show an increased incidence of acute leukemia among children living near the Doel, Tihange, or Fleurus facilities. However, children living within 15 km of the Mol-Dessel site had a significantly increased risk of acute leukemia.

In fact, the researchers said they observed statistically significant associations as a function of distance, prevailing winds, and simulated Ar-41 discharges, which suggests a potential link between acute leukemia incidence and the Mol-Dessel site.

The rate ratios for the Mol-Dessel facility, which were adjusted for age, sex, and socioeconomic status, were:

• 2.70 (95% CI: 1.15–6.33) for children living 0 to 5 km from the site (5 cases of acute leukemia)
• 1.82 (95% CI: 1.02–3.25) for children living 0 to 10 km from the site (11 cases of acute leukemia)
• 1.96 (95% CI: 1.19–3.22) for children living 0 to 15 km from the site (15 cases of acute leukemia)
• 1.09 (95% CI: 0.71–1.61) for children living 0 to 20 km from the site (21 cases of acute leukemia).

The 3 communities lying in the dominant wind direction of the Mol-Dessel nuclear site had rate ratios of 6.81 (95% CI: 2.28–20.32), 4.39 (95% CI: 1.46–13.17), and 3.74 (95% CI: 0.98–14.27).

The researchers calculated P values using Stone’s test, Bithell’s linear risk score test (LRS), and Bithell’s linear risk score test with corresponding ranks as a function of the different measures of surrogate exposure (LRS^r).

All 3 tests showed a significant association between acute leukemia incidence and proximity to the Mol-Dessel site (P<0.01 for all). However, only LRS and LRS^r showed a significant association for wind direction (P=0.01 and 0.03, respectively) and simulated radioactive discharges by Ar-41 (P<0.01 for both).

The researchers noted that, although these results suggest an association between acute childhood leukemia and the Mol-Dessel site, this study had limitations, and more research is needed.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.