Leukemia, Myelodysplasia, Transplantation

The Brazilain wasp

Polybia paulista

Photo by Mario Palma/

São Paulo State University

The wasp Polybia paulista protects itself from predators by producing venom known to contain a cancer-fighting toxin.

A study published in Biophysical Journal helps explain how the venom’s toxin, MP1 (Polybia-MP1), selectively kills cancer cells without harming normal cells.

MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating holes that facilitate the escape of molecules crucial for cell function.

“Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs,” said study author Paul Beales, PhD, of the University of Leeds in the UK.

MP1 is known to act against microbial pathogens by disrupting the bacterial cell membrane. The peptide has shown promise for treating cancers, as it can inhibit the growth of prostate and bladder cancer cells, as well as multi-drug resistant leukemic cells.

However, it has not been clear how MP1 selectively destroys cancer cells without harming normal cells. Dr Beales and his colleagues thought an explanation might lie in the unique properties of cancer cell membranes.

In healthy cell membranes, the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are located in the inner membrane leaflet facing the inside of the cell. But in cancer cells, PS and PE are embedded in the outer membrane leaflet facing the cell surroundings.

The researchers tested their theory by creating model membranes, some of which contained PE and/or PS, and exposing them to MP1. They used a wide range of imaging and biophysical techniques to characterize MP1’s destructive effects on the membranes.

The team found that PS increased the binding of MP1 to the membrane by a factor of 7 to 8. On the other hand, PE enhanced MP1’s ability to quickly disrupt the membrane, increasing the size of holes by a factor of 20 to 30.

“Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells,” said study author João Ruggiero Neto, of São Paulo State University in Brazil.

“The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising.”

In future studies, the researchers plan to alter MP1’s amino acid sequence to examine how the peptide’s structure relates to its function and further improve the peptide’s selectivity and potency for clinical purposes.

“Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine,” Dr Beales said.

“As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that.”

The Brazilain wasp

Polybia paulista

Photo by Mario Palma/

São Paulo State University

The wasp Polybia paulista protects itself from predators by producing venom known to contain a cancer-fighting toxin.

A study published in Biophysical Journal helps explain how the venom’s toxin, MP1 (Polybia-MP1), selectively kills cancer cells without harming normal cells.

MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating holes that facilitate the escape of molecules crucial for cell function.

“Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs,” said study author Paul Beales, PhD, of the University of Leeds in the UK.

MP1 is known to act against microbial pathogens by disrupting the bacterial cell membrane. The peptide has shown promise for treating cancers, as it can inhibit the growth of prostate and bladder cancer cells, as well as multi-drug resistant leukemic cells.

However, it has not been clear how MP1 selectively destroys cancer cells without harming normal cells. Dr Beales and his colleagues thought an explanation might lie in the unique properties of cancer cell membranes.

In healthy cell membranes, the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are located in the inner membrane leaflet facing the inside of the cell. But in cancer cells, PS and PE are embedded in the outer membrane leaflet facing the cell surroundings.

The researchers tested their theory by creating model membranes, some of which contained PE and/or PS, and exposing them to MP1. They used a wide range of imaging and biophysical techniques to characterize MP1’s destructive effects on the membranes.

The team found that PS increased the binding of MP1 to the membrane by a factor of 7 to 8. On the other hand, PE enhanced MP1’s ability to quickly disrupt the membrane, increasing the size of holes by a factor of 20 to 30.

“Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells,” said study author João Ruggiero Neto, of São Paulo State University in Brazil.

“The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising.”

In future studies, the researchers plan to alter MP1’s amino acid sequence to examine how the peptide’s structure relates to its function and further improve the peptide’s selectivity and potency for clinical purposes.

“Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine,” Dr Beales said.

“As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that.”

The Brazilain wasp

Polybia paulista

Photo by Mario Palma/

São Paulo State University

The wasp Polybia paulista protects itself from predators by producing venom known to contain a cancer-fighting toxin.

A study published in Biophysical Journal helps explain how the venom’s toxin, MP1 (Polybia-MP1), selectively kills cancer cells without harming normal cells.

MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating holes that facilitate the escape of molecules crucial for cell function.

“Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs,” said study author Paul Beales, PhD, of the University of Leeds in the UK.

MP1 is known to act against microbial pathogens by disrupting the bacterial cell membrane. The peptide has shown promise for treating cancers, as it can inhibit the growth of prostate and bladder cancer cells, as well as multi-drug resistant leukemic cells.

However, it has not been clear how MP1 selectively destroys cancer cells without harming normal cells. Dr Beales and his colleagues thought an explanation might lie in the unique properties of cancer cell membranes.

In healthy cell membranes, the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are located in the inner membrane leaflet facing the inside of the cell. But in cancer cells, PS and PE are embedded in the outer membrane leaflet facing the cell surroundings.

The researchers tested their theory by creating model membranes, some of which contained PE and/or PS, and exposing them to MP1. They used a wide range of imaging and biophysical techniques to characterize MP1’s destructive effects on the membranes.

The team found that PS increased the binding of MP1 to the membrane by a factor of 7 to 8. On the other hand, PE enhanced MP1’s ability to quickly disrupt the membrane, increasing the size of holes by a factor of 20 to 30.

“Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells,” said study author João Ruggiero Neto, of São Paulo State University in Brazil.

“The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising.”

In future studies, the researchers plan to alter MP1’s amino acid sequence to examine how the peptide’s structure relates to its function and further improve the peptide’s selectivity and potency for clinical purposes.

“Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine,” Dr Beales said.

“As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

Drs Michelle Churchman

and Charles Mullighan

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Retinoids and FAK inhibitors may override resistance to tyrosine kinase inhibitors (TKIs) in IKZF1-mutated, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to preclinical research published in Cancer Cell.

Experiments showed that, in Ph+ ALL, IKZF1 mutations prompt changes that reduce responsiveness to TKIs. But combining a TKI with a retinoid or FAK inhibitor can overcome this problem.

“The research shows why, in this era of targeted therapies, Ph+ ALL patients who also have IKZF1 mutations fare so poorly,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The insight also led us to a promising new treatment strategy.”

To conduct this research, Dr Mullighan and his colleagues began with mouse models of IKZF1-mutated Ph+ ALL, with and without mutations in the ARF gene. ARF encodes a tumor suppressor protein and is altered in about half of Ph+ ALL cases.

With these models, the researchers showed that the addition of IKZF1 mutations, particularly in combination with ARF mutations, was a central event in driving ALL.

In pre-B cells with BCR-ABL1, IKZF1 mutations induced a stem cell-like phenotype, increased stromal bone marrow adhesion, and reduced responsiveness to the TKI dasatinib.

When the researchers investigated the increased adhesion of mutated cells, they found overexpression of FAK and other molecules implicated in leukemic and stem cell adherence. This led the researchers to speculate that FAK inhibitors might prove useful against IKZF1-mutated Ph+ ALL.

But the team also found, through a screen of 483 compounds, that retinoids can reverse the effects of IKZF1 mutations. The antineoplastic agent bexarotene and 4 nuclear hormone receptor effectors—carbacyclin, all-trans retinoic acid (ATRA), 9-cis RA, and 13-cis RA—proved particularly effective.

The drugs worked, in part, by inducing expression of wild-type IKZF1. But they also worked in other ways to reverse the stem-cell phenotype, halt cell proliferation, and promote differentiation of altered cells.

The researchers then tested bexarotene and dasatinib, alone and in combination, in mice transplanted with ARF^-/- BCR-ABL1 pre-B cells, with or without IK6 expression. Bexarotene alone produced “significant benefit without detectable toxicity.”

Dasatinib alone increased survival, but dasatinib and bexarotene in combination resulted in a greater survival advantage. The combination nearly doubled the survival time of mice with IK6 tumors, when compared to dasatinib alone.

The researchers also established xenografts of Ph+ ALL that recapitulate a range of IKZF1 genotypes. They administered dasatinib plus bexarotene, ATRA, or the FAK inhibitors PF-562271, NVPTAE226, or PF-573228 ex vivo and observed “significant potentiation of cell killing.”

The team is currently investigating how to incorporate retinoids or FAK inhibitors into the existing treatment of IKZF1-mutated Ph+ ALL.

Drs Michelle Churchman

and Charles Mullighan

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Retinoids and FAK inhibitors may override resistance to tyrosine kinase inhibitors (TKIs) in IKZF1-mutated, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to preclinical research published in Cancer Cell.

Experiments showed that, in Ph+ ALL, IKZF1 mutations prompt changes that reduce responsiveness to TKIs. But combining a TKI with a retinoid or FAK inhibitor can overcome this problem.

“The research shows why, in this era of targeted therapies, Ph+ ALL patients who also have IKZF1 mutations fare so poorly,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The insight also led us to a promising new treatment strategy.”

To conduct this research, Dr Mullighan and his colleagues began with mouse models of IKZF1-mutated Ph+ ALL, with and without mutations in the ARF gene. ARF encodes a tumor suppressor protein and is altered in about half of Ph+ ALL cases.

With these models, the researchers showed that the addition of IKZF1 mutations, particularly in combination with ARF mutations, was a central event in driving ALL.

In pre-B cells with BCR-ABL1, IKZF1 mutations induced a stem cell-like phenotype, increased stromal bone marrow adhesion, and reduced responsiveness to the TKI dasatinib.

When the researchers investigated the increased adhesion of mutated cells, they found overexpression of FAK and other molecules implicated in leukemic and stem cell adherence. This led the researchers to speculate that FAK inhibitors might prove useful against IKZF1-mutated Ph+ ALL.

But the team also found, through a screen of 483 compounds, that retinoids can reverse the effects of IKZF1 mutations. The antineoplastic agent bexarotene and 4 nuclear hormone receptor effectors—carbacyclin, all-trans retinoic acid (ATRA), 9-cis RA, and 13-cis RA—proved particularly effective.

The drugs worked, in part, by inducing expression of wild-type IKZF1. But they also worked in other ways to reverse the stem-cell phenotype, halt cell proliferation, and promote differentiation of altered cells.

The researchers then tested bexarotene and dasatinib, alone and in combination, in mice transplanted with ARF^-/- BCR-ABL1 pre-B cells, with or without IK6 expression. Bexarotene alone produced “significant benefit without detectable toxicity.”

Dasatinib alone increased survival, but dasatinib and bexarotene in combination resulted in a greater survival advantage. The combination nearly doubled the survival time of mice with IK6 tumors, when compared to dasatinib alone.

The researchers also established xenografts of Ph+ ALL that recapitulate a range of IKZF1 genotypes. They administered dasatinib plus bexarotene, ATRA, or the FAK inhibitors PF-562271, NVPTAE226, or PF-573228 ex vivo and observed “significant potentiation of cell killing.”

The team is currently investigating how to incorporate retinoids or FAK inhibitors into the existing treatment of IKZF1-mutated Ph+ ALL.

Drs Michelle Churchman

and Charles Mullighan

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Retinoids and FAK inhibitors may override resistance to tyrosine kinase inhibitors (TKIs) in IKZF1-mutated, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to preclinical research published in Cancer Cell.

Experiments showed that, in Ph+ ALL, IKZF1 mutations prompt changes that reduce responsiveness to TKIs. But combining a TKI with a retinoid or FAK inhibitor can overcome this problem.

“The research shows why, in this era of targeted therapies, Ph+ ALL patients who also have IKZF1 mutations fare so poorly,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The insight also led us to a promising new treatment strategy.”

To conduct this research, Dr Mullighan and his colleagues began with mouse models of IKZF1-mutated Ph+ ALL, with and without mutations in the ARF gene. ARF encodes a tumor suppressor protein and is altered in about half of Ph+ ALL cases.

With these models, the researchers showed that the addition of IKZF1 mutations, particularly in combination with ARF mutations, was a central event in driving ALL.

In pre-B cells with BCR-ABL1, IKZF1 mutations induced a stem cell-like phenotype, increased stromal bone marrow adhesion, and reduced responsiveness to the TKI dasatinib.

When the researchers investigated the increased adhesion of mutated cells, they found overexpression of FAK and other molecules implicated in leukemic and stem cell adherence. This led the researchers to speculate that FAK inhibitors might prove useful against IKZF1-mutated Ph+ ALL.

But the team also found, through a screen of 483 compounds, that retinoids can reverse the effects of IKZF1 mutations. The antineoplastic agent bexarotene and 4 nuclear hormone receptor effectors—carbacyclin, all-trans retinoic acid (ATRA), 9-cis RA, and 13-cis RA—proved particularly effective.

The drugs worked, in part, by inducing expression of wild-type IKZF1. But they also worked in other ways to reverse the stem-cell phenotype, halt cell proliferation, and promote differentiation of altered cells.

The researchers then tested bexarotene and dasatinib, alone and in combination, in mice transplanted with ARF^-/- BCR-ABL1 pre-B cells, with or without IK6 expression. Bexarotene alone produced “significant benefit without detectable toxicity.”

Dasatinib alone increased survival, but dasatinib and bexarotene in combination resulted in a greater survival advantage. The combination nearly doubled the survival time of mice with IK6 tumors, when compared to dasatinib alone.

The researchers also established xenografts of Ph+ ALL that recapitulate a range of IKZF1 genotypes. They administered dasatinib plus bexarotene, ATRA, or the FAK inhibitors PF-562271, NVPTAE226, or PF-573228 ex vivo and observed “significant potentiation of cell killing.”

The team is currently investigating how to incorporate retinoids or FAK inhibitors into the existing treatment of IKZF1-mutated Ph+ ALL.

Micrograph showing CML

Preclinical research has revealed nutrients that support the activity of chronic myelogenous leukemia (CML) stem cells and suggests these nutrients may be promising targets for CML therapy.

Investigators discovered that CML stem cells accumulate high levels of certain dipeptide species, and these dipeptides act as nutrients for the cells.

When the team inhibited dipeptide uptake, they observed decreased CML stem cell activity.

Combining agents that inhibit dipeptide uptake with tyrosine kinase inhibitors (TKIs) proved more effective against CML than TKI treatment alone, both in vitro and in vivo.

Kazuhito Naka, PhD, of Hiroshima University in Japan, and his colleagues conducted this research and disclosed the results in Nature Communications.

The team began by analyzing CML stem cells isolated from a mouse model of the disease. They found that CML stem cells accumulate significantly higher levels of certain dipeptide species—such as Ala-Leu, Asp-Leu, Ser-Tyr, and Thr-Val—than normal hematopoietic stem cells.

Additional investigation revealed that CML stem cells take up dipeptides via the Slc15A2 transporter. And once internalized, the dipeptides act as nutrients and play a role in CML stem cell maintenance.

The dipeptides activate amino-acid signaling via a pathway involving p38MAPK and Smad3, and this promotes CML stem cell maintenance.

To build upon these findings, the investigators assessed the effects of cefadroxil, which inhibits Slc15A2-mediated nutrient signaling, in combination with imatinib as CML treatment.

In murine CML stem cell cultures, the 2 drugs in combination reduced colony formation more effectively than imatinib alone.

In vivo, mice with CML responded to imatinib alone but eventually experienced disease recurrence. And cefadroxil alone promoted disease development. But when cefadroxil was given in combination with imatinib, disease recurrence was significantly lower than in mice that received imatinib alone.

The investigators then showed that cefadroxil decreases the number of CML stem cells in CML-affected mice. And cefadroxil combined with imatinib reduces CML stem cell numbers more effectively than imatinib alone.

In serial transplantation experiments, CML stem cells isolated from cefadroxil-treated mice completely lost their ability to drive BCR-ABL1+ disease in new recipients. These animals survived for more than 90 days, whereas mice that received CML stem cells from vehicle-treated mice developed BCR-ABL1+ disease and died before 80 days.

The investigators also tested cefadroxil in stem cells derived from humans with chronic CML. Cefadroxil suppressed the colony-forming capacity of all 3 samples tested. And combining cefadroxil with imatinib or dasatinib reduced colony formation more effectively than either TKI alone.

Lastly, the team decided to test 3 clinical-grade p38MAPK inhibitors that are already approved for use in the US—Ly2228820 (ralimetinib), VX-702, and BIRB796 (doramapimod). When cultured with CML stem cells, each of these drugs significantly decreased colony formation.

In addition, Ly2228820 combined with dasatinib delayed CML onset in mice and improved their survival when compared with dasatinib alone.

These results suggest p38MAPK inhibitors and cefadroxil may be useful additions to TKI therapy in CML, the investigators said.

“Our proposed approach of using inhibitors to shut down a key nutrient uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Dr Naka said. “It will open up a novel avenue for curative CML therapy.”

Micrograph showing CML

Preclinical research has revealed nutrients that support the activity of chronic myelogenous leukemia (CML) stem cells and suggests these nutrients may be promising targets for CML therapy.

Investigators discovered that CML stem cells accumulate high levels of certain dipeptide species, and these dipeptides act as nutrients for the cells.

When the team inhibited dipeptide uptake, they observed decreased CML stem cell activity.

Combining agents that inhibit dipeptide uptake with tyrosine kinase inhibitors (TKIs) proved more effective against CML than TKI treatment alone, both in vitro and in vivo.

Kazuhito Naka, PhD, of Hiroshima University in Japan, and his colleagues conducted this research and disclosed the results in Nature Communications.

The team began by analyzing CML stem cells isolated from a mouse model of the disease. They found that CML stem cells accumulate significantly higher levels of certain dipeptide species—such as Ala-Leu, Asp-Leu, Ser-Tyr, and Thr-Val—than normal hematopoietic stem cells.

Additional investigation revealed that CML stem cells take up dipeptides via the Slc15A2 transporter. And once internalized, the dipeptides act as nutrients and play a role in CML stem cell maintenance.

The dipeptides activate amino-acid signaling via a pathway involving p38MAPK and Smad3, and this promotes CML stem cell maintenance.

To build upon these findings, the investigators assessed the effects of cefadroxil, which inhibits Slc15A2-mediated nutrient signaling, in combination with imatinib as CML treatment.

In murine CML stem cell cultures, the 2 drugs in combination reduced colony formation more effectively than imatinib alone.

In vivo, mice with CML responded to imatinib alone but eventually experienced disease recurrence. And cefadroxil alone promoted disease development. But when cefadroxil was given in combination with imatinib, disease recurrence was significantly lower than in mice that received imatinib alone.

The investigators then showed that cefadroxil decreases the number of CML stem cells in CML-affected mice. And cefadroxil combined with imatinib reduces CML stem cell numbers more effectively than imatinib alone.

In serial transplantation experiments, CML stem cells isolated from cefadroxil-treated mice completely lost their ability to drive BCR-ABL1+ disease in new recipients. These animals survived for more than 90 days, whereas mice that received CML stem cells from vehicle-treated mice developed BCR-ABL1+ disease and died before 80 days.

The investigators also tested cefadroxil in stem cells derived from humans with chronic CML. Cefadroxil suppressed the colony-forming capacity of all 3 samples tested. And combining cefadroxil with imatinib or dasatinib reduced colony formation more effectively than either TKI alone.

Lastly, the team decided to test 3 clinical-grade p38MAPK inhibitors that are already approved for use in the US—Ly2228820 (ralimetinib), VX-702, and BIRB796 (doramapimod). When cultured with CML stem cells, each of these drugs significantly decreased colony formation.

In addition, Ly2228820 combined with dasatinib delayed CML onset in mice and improved their survival when compared with dasatinib alone.

These results suggest p38MAPK inhibitors and cefadroxil may be useful additions to TKI therapy in CML, the investigators said.

“Our proposed approach of using inhibitors to shut down a key nutrient uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Dr Naka said. “It will open up a novel avenue for curative CML therapy.”

Micrograph showing CML

Preclinical research has revealed nutrients that support the activity of chronic myelogenous leukemia (CML) stem cells and suggests these nutrients may be promising targets for CML therapy.

Investigators discovered that CML stem cells accumulate high levels of certain dipeptide species, and these dipeptides act as nutrients for the cells.

When the team inhibited dipeptide uptake, they observed decreased CML stem cell activity.

Combining agents that inhibit dipeptide uptake with tyrosine kinase inhibitors (TKIs) proved more effective against CML than TKI treatment alone, both in vitro and in vivo.

Kazuhito Naka, PhD, of Hiroshima University in Japan, and his colleagues conducted this research and disclosed the results in Nature Communications.

The team began by analyzing CML stem cells isolated from a mouse model of the disease. They found that CML stem cells accumulate significantly higher levels of certain dipeptide species—such as Ala-Leu, Asp-Leu, Ser-Tyr, and Thr-Val—than normal hematopoietic stem cells.

Additional investigation revealed that CML stem cells take up dipeptides via the Slc15A2 transporter. And once internalized, the dipeptides act as nutrients and play a role in CML stem cell maintenance.

The dipeptides activate amino-acid signaling via a pathway involving p38MAPK and Smad3, and this promotes CML stem cell maintenance.

To build upon these findings, the investigators assessed the effects of cefadroxil, which inhibits Slc15A2-mediated nutrient signaling, in combination with imatinib as CML treatment.

In murine CML stem cell cultures, the 2 drugs in combination reduced colony formation more effectively than imatinib alone.

In vivo, mice with CML responded to imatinib alone but eventually experienced disease recurrence. And cefadroxil alone promoted disease development. But when cefadroxil was given in combination with imatinib, disease recurrence was significantly lower than in mice that received imatinib alone.

The investigators then showed that cefadroxil decreases the number of CML stem cells in CML-affected mice. And cefadroxil combined with imatinib reduces CML stem cell numbers more effectively than imatinib alone.

In serial transplantation experiments, CML stem cells isolated from cefadroxil-treated mice completely lost their ability to drive BCR-ABL1+ disease in new recipients. These animals survived for more than 90 days, whereas mice that received CML stem cells from vehicle-treated mice developed BCR-ABL1+ disease and died before 80 days.

The investigators also tested cefadroxil in stem cells derived from humans with chronic CML. Cefadroxil suppressed the colony-forming capacity of all 3 samples tested. And combining cefadroxil with imatinib or dasatinib reduced colony formation more effectively than either TKI alone.

Lastly, the team decided to test 3 clinical-grade p38MAPK inhibitors that are already approved for use in the US—Ly2228820 (ralimetinib), VX-702, and BIRB796 (doramapimod). When cultured with CML stem cells, each of these drugs significantly decreased colony formation.

In addition, Ly2228820 combined with dasatinib delayed CML onset in mice and improved their survival when compared with dasatinib alone.

These results suggest p38MAPK inhibitors and cefadroxil may be useful additions to TKI therapy in CML, the investigators said.

“Our proposed approach of using inhibitors to shut down a key nutrient uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML,” Dr Naka said. “It will open up a novel avenue for curative CML therapy.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.

The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases

seem to open the door to viral infections.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.

“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”

Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.

The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.

MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.

If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.

“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”

Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.

Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.

So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.

When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.

“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.

“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”

Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.

“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.

Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.

“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.

The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases

seem to open the door to viral infections.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.

“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”

Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.

The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.

MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.

If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.

“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”

Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.

Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.

So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.

When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.

“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.

“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”

Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.

“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.

Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.

“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.

The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases

seem to open the door to viral infections.

“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.

“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”

Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.

The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.

MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.

If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.

“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”

Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.

Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.

So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.

When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.

“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.

“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”

Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.

“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”

The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.

Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.

“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”

Patient consults pharmacist

Photo by Rhoda Baer

A new study suggests that seniors with cancer may be taking complementary or alternative medicines (CAMs) without their oncologists’ knowledge.

In this single-center study, 27% of senior cancer patients took CAMs at some point during their cancer care.

CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.

Polypharmacy and certain comorbidities were linked to CAM use as well.

Researchers reported these findings in the Journal of Geriatric Oncology.

“Currently, few oncologists are aware of the alternative medicines their patients take,” said study author Ginah Nightingale, PharmD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

“Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic, and not relevant to their cancer care; because they think their doctor will disapprove; or because the doctor doesn’t specifically ask.”

To quantify CAM use in older cancer patients treated at their institution, Dr Nightingale and her colleagues surveyed patients who came to the Senior Adult Oncology Center at Thomas Jefferson University.

In a single visit, patients were seen by a medical oncologist, geriatrician, clinical pharmacist, social worker, and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications they actively used were reviewed and recorded.

A total of 234 patients were included in the final analysis. Their mean age was 79.9 (range, 61–98). Most (87%) had solid tumor malignancies, were Caucasian (74%), and were female (64%).

In all, 26.5% of patients (n=62) had taken at least 1 CAM during their cancer care, with 19.2% taking 1 CAM, 6.4% taking 2, 0.4% taking 3, and 0.4% taking 4 or more CAMs. The highest number of CAMs taken was 10.

CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.

Comorbidities significantly associated with CAM use were vision impairment (P=0.048) and urologic comorbidities (P=0.021). Polypharmacy (concurrent use of 5 or more medications) was significantly associated with CAM use as well (P=0.045).

Some of the commonly used CAMs were mega-dose vitamins or minerals, as well as treatments for macular degeneration, stomach probiotics, and joint health.

The researchers did not examine the potential adverse effects of these medications, but Dr Nightingale said some are known to have a biochemical effect on the body and other drugs.

“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” she added. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”

Patient consults pharmacist

Photo by Rhoda Baer

A new study suggests that seniors with cancer may be taking complementary or alternative medicines (CAMs) without their oncologists’ knowledge.

In this single-center study, 27% of senior cancer patients took CAMs at some point during their cancer care.

CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.

Polypharmacy and certain comorbidities were linked to CAM use as well.

Researchers reported these findings in the Journal of Geriatric Oncology.

“Currently, few oncologists are aware of the alternative medicines their patients take,” said study author Ginah Nightingale, PharmD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

“Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic, and not relevant to their cancer care; because they think their doctor will disapprove; or because the doctor doesn’t specifically ask.”

To quantify CAM use in older cancer patients treated at their institution, Dr Nightingale and her colleagues surveyed patients who came to the Senior Adult Oncology Center at Thomas Jefferson University.

In a single visit, patients were seen by a medical oncologist, geriatrician, clinical pharmacist, social worker, and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications they actively used were reviewed and recorded.

A total of 234 patients were included in the final analysis. Their mean age was 79.9 (range, 61–98). Most (87%) had solid tumor malignancies, were Caucasian (74%), and were female (64%).

In all, 26.5% of patients (n=62) had taken at least 1 CAM during their cancer care, with 19.2% taking 1 CAM, 6.4% taking 2, 0.4% taking 3, and 0.4% taking 4 or more CAMs. The highest number of CAMs taken was 10.

CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.

Comorbidities significantly associated with CAM use were vision impairment (P=0.048) and urologic comorbidities (P=0.021). Polypharmacy (concurrent use of 5 or more medications) was significantly associated with CAM use as well (P=0.045).

Some of the commonly used CAMs were mega-dose vitamins or minerals, as well as treatments for macular degeneration, stomach probiotics, and joint health.

The researchers did not examine the potential adverse effects of these medications, but Dr Nightingale said some are known to have a biochemical effect on the body and other drugs.

“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” she added. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”

Patient consults pharmacist

Photo by Rhoda Baer

A new study suggests that seniors with cancer may be taking complementary or alternative medicines (CAMs) without their oncologists’ knowledge.

In this single-center study, 27% of senior cancer patients took CAMs at some point during their cancer care.

CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.

Polypharmacy and certain comorbidities were linked to CAM use as well.

Researchers reported these findings in the Journal of Geriatric Oncology.

“Currently, few oncologists are aware of the alternative medicines their patients take,” said study author Ginah Nightingale, PharmD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

“Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic, and not relevant to their cancer care; because they think their doctor will disapprove; or because the doctor doesn’t specifically ask.”

To quantify CAM use in older cancer patients treated at their institution, Dr Nightingale and her colleagues surveyed patients who came to the Senior Adult Oncology Center at Thomas Jefferson University.

In a single visit, patients were seen by a medical oncologist, geriatrician, clinical pharmacist, social worker, and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications they actively used were reviewed and recorded.

A total of 234 patients were included in the final analysis. Their mean age was 79.9 (range, 61–98). Most (87%) had solid tumor malignancies, were Caucasian (74%), and were female (64%).

In all, 26.5% of patients (n=62) had taken at least 1 CAM during their cancer care, with 19.2% taking 1 CAM, 6.4% taking 2, 0.4% taking 3, and 0.4% taking 4 or more CAMs. The highest number of CAMs taken was 10.

CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.

Comorbidities significantly associated with CAM use were vision impairment (P=0.048) and urologic comorbidities (P=0.021). Polypharmacy (concurrent use of 5 or more medications) was significantly associated with CAM use as well (P=0.045).

Some of the commonly used CAMs were mega-dose vitamins or minerals, as well as treatments for macular degeneration, stomach probiotics, and joint health.

The researchers did not examine the potential adverse effects of these medications, but Dr Nightingale said some are known to have a biochemical effect on the body and other drugs.

“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” she added. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”

AML in the bone marrow

Mutations that persist after initial chemotherapy may confer an increased risk of relapse and poor survival in patients with acute myeloid leukemia (AML), according to research published in JAMA.

Investigators found that patients who still had leukemia-specific mutations 30 days after they began chemotherapy had significantly shorter event-free and overall survival than patients whose bone marrow was free of these mutations.

These findings suggest genetic profiling of AML and other cancers may be more effective if it is focused less on the specific set of mutations present in a patient’s tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

“If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient’s leukemia and determine whether that patient has responded to the chemotherapy, without having to wait for the cancer to recur,” said study author Jeffery M. Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”

To investigate the utility of this approach, Dr Klco and his colleagues conducted a retrospective study of AML patients. The team began with bone marrow samples from 71 AML patients treated with standard induction chemotherapy.

The investigators first sequenced these samples, which were obtained at the time of diagnosis, to see if the presence of mutations correlated with the outcome of chemotherapy. They found that mutations were no more informative than standard methods used to predict patient outcomes.

So the team sequenced samples obtained from 50 AML patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when the patients were in remission. Twenty-five of the 50 patients were from the first cohort of 71 patients, and 25 were new cases.

Analyzing these samples, the investigators found that 24 patients (48%) had persistent mutations in at least 5% of bone marrow cells after chemotherapy, even though, by standard clinical measures, they were in remission.

These patients had inferior event-free and overall survival when compared to the patients whose mutations had been cleared by initial chemotherapy.

The median event-free survival was 6 months and 17.9 months in patients with and without mutations, respectively (P<0.001). And the median overall survival was 10.5 months and 42 months, respectively (P=0.004).

The investigators noted that only a subset of the persistent mutations were in recurrently mutated AML genes (NPM1, FLT3, DNMT3A, etc.).

“These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse,” said study author Timothy J. Ley, MD, of the Washington University School of Medicine in St. Louis, Missouri.

“But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML patients.”

AML in the bone marrow

Mutations that persist after initial chemotherapy may confer an increased risk of relapse and poor survival in patients with acute myeloid leukemia (AML), according to research published in JAMA.

Investigators found that patients who still had leukemia-specific mutations 30 days after they began chemotherapy had significantly shorter event-free and overall survival than patients whose bone marrow was free of these mutations.

These findings suggest genetic profiling of AML and other cancers may be more effective if it is focused less on the specific set of mutations present in a patient’s tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

“If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient’s leukemia and determine whether that patient has responded to the chemotherapy, without having to wait for the cancer to recur,” said study author Jeffery M. Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”

To investigate the utility of this approach, Dr Klco and his colleagues conducted a retrospective study of AML patients. The team began with bone marrow samples from 71 AML patients treated with standard induction chemotherapy.

The investigators first sequenced these samples, which were obtained at the time of diagnosis, to see if the presence of mutations correlated with the outcome of chemotherapy. They found that mutations were no more informative than standard methods used to predict patient outcomes.

So the team sequenced samples obtained from 50 AML patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when the patients were in remission. Twenty-five of the 50 patients were from the first cohort of 71 patients, and 25 were new cases.

Analyzing these samples, the investigators found that 24 patients (48%) had persistent mutations in at least 5% of bone marrow cells after chemotherapy, even though, by standard clinical measures, they were in remission.

These patients had inferior event-free and overall survival when compared to the patients whose mutations had been cleared by initial chemotherapy.

The median event-free survival was 6 months and 17.9 months in patients with and without mutations, respectively (P<0.001). And the median overall survival was 10.5 months and 42 months, respectively (P=0.004).

The investigators noted that only a subset of the persistent mutations were in recurrently mutated AML genes (NPM1, FLT3, DNMT3A, etc.).

“These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse,” said study author Timothy J. Ley, MD, of the Washington University School of Medicine in St. Louis, Missouri.

“But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML patients.”

AML in the bone marrow

Mutations that persist after initial chemotherapy may confer an increased risk of relapse and poor survival in patients with acute myeloid leukemia (AML), according to research published in JAMA.

Investigators found that patients who still had leukemia-specific mutations 30 days after they began chemotherapy had significantly shorter event-free and overall survival than patients whose bone marrow was free of these mutations.

These findings suggest genetic profiling of AML and other cancers may be more effective if it is focused less on the specific set of mutations present in a patient’s tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

“If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient’s leukemia and determine whether that patient has responded to the chemotherapy, without having to wait for the cancer to recur,” said study author Jeffery M. Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”

To investigate the utility of this approach, Dr Klco and his colleagues conducted a retrospective study of AML patients. The team began with bone marrow samples from 71 AML patients treated with standard induction chemotherapy.

The investigators first sequenced these samples, which were obtained at the time of diagnosis, to see if the presence of mutations correlated with the outcome of chemotherapy. They found that mutations were no more informative than standard methods used to predict patient outcomes.

So the team sequenced samples obtained from 50 AML patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when the patients were in remission. Twenty-five of the 50 patients were from the first cohort of 71 patients, and 25 were new cases.

Analyzing these samples, the investigators found that 24 patients (48%) had persistent mutations in at least 5% of bone marrow cells after chemotherapy, even though, by standard clinical measures, they were in remission.

These patients had inferior event-free and overall survival when compared to the patients whose mutations had been cleared by initial chemotherapy.

The median event-free survival was 6 months and 17.9 months in patients with and without mutations, respectively (P<0.001). And the median overall survival was 10.5 months and 42 months, respectively (P=0.004).

The investigators noted that only a subset of the persistent mutations were in recurrently mutated AML genes (NPM1, FLT3, DNMT3A, etc.).

“These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse,” said study author Timothy J. Ley, MD, of the Washington University School of Medicine in St. Louis, Missouri.

“But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML patients.”

Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.

About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.

©Christian Jasiuk/Thinkstockphotos.com

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).

Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.

Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.

The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).

Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).

The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.

Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.

About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.

©Christian Jasiuk/Thinkstockphotos.com

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).

Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.

Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.

The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).

Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).

The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.

Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.

About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.

©Christian Jasiuk/Thinkstockphotos.com

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).

Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.

Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.

The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).

Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).

The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.

Lab mice

Photo by Aaron Logan

New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.

Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.

The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.

Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.

Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.

“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.

Experiments with JQ1

To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.

The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.

“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.

Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.

“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.

To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.

After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.

Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.

Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.

Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.

Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.

Lab mice

Photo by Aaron Logan

New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.

Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.

The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.

Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.

Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.

“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.

Experiments with JQ1

To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.

The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.

“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.

Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.

“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.

To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.

After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.

Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.

Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.

Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.

Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.

Lab mice

Photo by Aaron Logan

New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.

Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.

The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.

Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.

Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.

“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.

Experiments with JQ1

To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.

The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.

“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.

Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.

“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.

To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.

After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.

Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.

Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.

Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.

Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.

Clinical outcomes were significantly worse among younger patients with secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) compared with de novo disease, suggesting the presence of distinct AML subtypes, in a study published online Aug. 24 in Journal of Clinical Oncology.

The Armed Forces Institute of Pathology/Wikimedia Commons/Public Domain

In the Danish population-based study, patients under age 60 with de novo AML had a 3-year survival rate of 52%, compared with 35% for AML secondary to myelodysplastic syndrome (MDS-sAML), 19% for AML secondary to chronic myelomonocytic leukemia or myeloproliferative neoplasia (non-MDS-sAML), and 27% for tAML.

Non-MDS-sAML was associated with poorer outcomes at any age, but patients older than 60 years with MDS-sAML and tAML had outcomes similar to those of de novo AML, Dr. Lene Sofie Granfeldt Ostgard and associates reported (J Clin Oncol. 2015 Aug 24. doi:10.1200/JCO.2014.60.0890).

The cohort study evaluated records of 3,055 patients diagnosed with AML from 2000 to 2013. Overall, 73.6% had de novo AML, 19.8% had sAML (11.5% MDS, 8.3% non-MDS), and 6.6% had tAML. The researchers focused on the 1,567 patients (51.3%) who underwent curative intent therapy. Patients with sAML were less likely to receive intensive therapy than were patients with tAML or de novo AML. Patients who underwent intensive treatment had superior survival rates compared with patients within the same subgroup who did not undergo treatment.

Contrary to previous reports, the investigators did not observe an increase in the incidence of AML, sAML, or tAML over the 14-year study period. They did, however, find that clinical trial accrual rates for patients with sAML and tAML increased significantly over that period, which may account for reports of a temporal increase in tAML.

Adverse-risk cytogenetics were most prevalent in patients with tAML, likely because of clonal selection of chemotherapy-resistant p53-mutated cells. Patients with non-MDS-sAML had a higher frequency of aberrant karyotypes, though not classified as adverse, which the authors speculate may explain the worse outcomes observed in this group.

“Given the extremely poor prognosis associated with an antecedent diagnosis of CMML [chronic myelomonocytic leukemia] or MPN [myeloproliferative neoplasia], these entities should be considered separately from prior MDS when investigating outcomes and new treatment strategies in patients with sAML,” wrote Dr. Ostgard of Aarhus University Hospital, Denmark, and colleagues.

The presence of MDS-sAML and tAML was associated with worse survival, but the association was weaker in older patients and those with adverse cytogenetics, suggesting the relative effect of MDS or prior chemotherapy is small in patients with an already poor prognosis.

Dr. Ostgard reported consulting or advisory roles with Bristol-Myers Squibb and Abbvie. Several of her coauthors reported ties to industry sources.