Leukemia, Myelodysplasia, Transplantation

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Micrograph showing CLL

CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).

Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.

The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.

William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).

This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.

The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.

Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.

Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.

The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.

The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.

Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.

The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.

The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.

“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.

“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”

Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.

Micrograph showing CLL

CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).

Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.

The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.

William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).

This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.

The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.

Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.

Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.

The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.

The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.

Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.

The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.

The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.

“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.

“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”

Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.

Micrograph showing CLL

CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).

Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.

The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.

William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).

This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.

The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.

Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.

Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.

The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.

The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.

Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.

The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.

The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.

“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.

“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”

Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.

Image by Lance Liotta

New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).

Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.

In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.

“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.

“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”

Dr Tenen and his colleagues reported these findings in Nature Communications.

The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.

Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.

Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.

The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.

SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.

The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.

Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.

Image by Lance Liotta

New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).

Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.

In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.

“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.

“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”

Dr Tenen and his colleagues reported these findings in Nature Communications.

The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.

Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.

Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.

The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.

SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.

The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.

Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.

Image by Lance Liotta

New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).

Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.

In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.

“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.

“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”

Dr Tenen and his colleagues reported these findings in Nature Communications.

The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.

Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.

Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.

The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.

SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.

The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.

Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.

Photo by Bill Branson

A new checklist could improve education for parents and other caregivers of children newly diagnosed with cancer, according to a group of nurses.

The checklist is divided into topics that should be taught according to their level of urgency.

The list includes subjects that should be discussed prior to patients’ initial hospital discharge and topics that can be covered later, either within the first month of the patients’ cancer diagnosis or before patients complete therapy.

Cheryl Rodgers, PhD, RN, and her colleagues provided details on this checklist in the Journal of Pediatric Oncology Nursing.

A team of 19 nurses and 2 parent advocates from the Children’s Oncology Group developed the checklist based on existing education checklists, expert recommendations, and team-based activities and discussions.

The checklist is divided into primary, secondary, and tertiary topics.

Primary topics are those that should be discussed with caregivers before they leave the hospital the first time. Examples include home medication dose and frequency, who and when to call for help, preventing infection, and treatment side effects to know before the next appointment.

Secondary topics are those that can be covered during the first month after a child’s cancer diagnosis. Examples include an explanation of what cancer is, an overview of chemotherapy, and more details on the side effects of cancer treatment.

Tertiary topics can be discussed before the child finishes cancer treatment. Examples include details on tests and procedures, risky behaviors to avoid, coping skills, and insurance issues.

Dr Rodgers and her colleagues said this checklist provides nurses with a clear outline of topics that should be discussed with caregivers immediately and topics that can be safely deferred. This could prevent information overload and help caregivers remember the most important information.

Photo by Bill Branson

A new checklist could improve education for parents and other caregivers of children newly diagnosed with cancer, according to a group of nurses.

The checklist is divided into topics that should be taught according to their level of urgency.

The list includes subjects that should be discussed prior to patients’ initial hospital discharge and topics that can be covered later, either within the first month of the patients’ cancer diagnosis or before patients complete therapy.

Cheryl Rodgers, PhD, RN, and her colleagues provided details on this checklist in the Journal of Pediatric Oncology Nursing.

A team of 19 nurses and 2 parent advocates from the Children’s Oncology Group developed the checklist based on existing education checklists, expert recommendations, and team-based activities and discussions.

The checklist is divided into primary, secondary, and tertiary topics.

Primary topics are those that should be discussed with caregivers before they leave the hospital the first time. Examples include home medication dose and frequency, who and when to call for help, preventing infection, and treatment side effects to know before the next appointment.

Secondary topics are those that can be covered during the first month after a child’s cancer diagnosis. Examples include an explanation of what cancer is, an overview of chemotherapy, and more details on the side effects of cancer treatment.

Tertiary topics can be discussed before the child finishes cancer treatment. Examples include details on tests and procedures, risky behaviors to avoid, coping skills, and insurance issues.

Dr Rodgers and her colleagues said this checklist provides nurses with a clear outline of topics that should be discussed with caregivers immediately and topics that can be safely deferred. This could prevent information overload and help caregivers remember the most important information.

Photo by Bill Branson

A new checklist could improve education for parents and other caregivers of children newly diagnosed with cancer, according to a group of nurses.

The checklist is divided into topics that should be taught according to their level of urgency.

The list includes subjects that should be discussed prior to patients’ initial hospital discharge and topics that can be covered later, either within the first month of the patients’ cancer diagnosis or before patients complete therapy.

Cheryl Rodgers, PhD, RN, and her colleagues provided details on this checklist in the Journal of Pediatric Oncology Nursing.

A team of 19 nurses and 2 parent advocates from the Children’s Oncology Group developed the checklist based on existing education checklists, expert recommendations, and team-based activities and discussions.

The checklist is divided into primary, secondary, and tertiary topics.

Primary topics are those that should be discussed with caregivers before they leave the hospital the first time. Examples include home medication dose and frequency, who and when to call for help, preventing infection, and treatment side effects to know before the next appointment.

Secondary topics are those that can be covered during the first month after a child’s cancer diagnosis. Examples include an explanation of what cancer is, an overview of chemotherapy, and more details on the side effects of cancer treatment.

Tertiary topics can be discussed before the child finishes cancer treatment. Examples include details on tests and procedures, risky behaviors to avoid, coping skills, and insurance issues.

Dr Rodgers and her colleagues said this checklist provides nurses with a clear outline of topics that should be discussed with caregivers immediately and topics that can be safely deferred. This could prevent information overload and help caregivers remember the most important information.

Micrograph showing ALL

The US Food and Drug Administration (FDA) has granted orphan drug designation to LBS-007 as a treatment for acute lymphoblastic leukemia (ALL).

LBS-007 is a non-ATP cell-cycle inhibitor targeting a range of cancers.

LBS-007 functions by blocking the kinase activity of CDC7, a key regulator of the cancer cell cycle.

Inhibiting CDC7 stops the proliferation of tumor cells and results in cell death.

Lin BioScience, Inc., the company developing LBS-007, said the drug has demonstrated “very potent activity” against leukemia and solid tumors in preclinical studies.

The company is expected to launch a phase 1 trial of LBS-007 in drug-resistant and refractory acute leukemia in the fourth quarter of 2018.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing ALL

The US Food and Drug Administration (FDA) has granted orphan drug designation to LBS-007 as a treatment for acute lymphoblastic leukemia (ALL).

LBS-007 is a non-ATP cell-cycle inhibitor targeting a range of cancers.

LBS-007 functions by blocking the kinase activity of CDC7, a key regulator of the cancer cell cycle.

Inhibiting CDC7 stops the proliferation of tumor cells and results in cell death.

Lin BioScience, Inc., the company developing LBS-007, said the drug has demonstrated “very potent activity” against leukemia and solid tumors in preclinical studies.

The company is expected to launch a phase 1 trial of LBS-007 in drug-resistant and refractory acute leukemia in the fourth quarter of 2018.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing ALL

The US Food and Drug Administration (FDA) has granted orphan drug designation to LBS-007 as a treatment for acute lymphoblastic leukemia (ALL).

LBS-007 is a non-ATP cell-cycle inhibitor targeting a range of cancers.

LBS-007 functions by blocking the kinase activity of CDC7, a key regulator of the cancer cell cycle.

Inhibiting CDC7 stops the proliferation of tumor cells and results in cell death.

Lin BioScience, Inc., the company developing LBS-007, said the drug has demonstrated “very potent activity” against leukemia and solid tumors in preclinical studies.

The company is expected to launch a phase 1 trial of LBS-007 in drug-resistant and refractory acute leukemia in the fourth quarter of 2018.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Bill Branson

The European Commission has authorized use of gemtuzumab ozogamicin (GO, Mylotarg™) as a treatment for patients with acute myeloid leukemia (AML).

GO is now approved for use in combination with daunorubicin and cytarabine to treat patients age 15 and older who have previously untreated, de novo, CD33-positive AML, not including acute promyelocytic leukemia.

GO is an antibody-drug conjugate composed of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90% of AML patients.

When GO binds to the CD33 antigen on the cell surface, it is absorbed into the cell, and calicheamicin is released, causing cell death.

Previous rejection

The European Commission’s approval of GO follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). In February, the CHMP recommended that GO receive marketing authorization for the aforementioned indication.

However, the CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.

The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.

The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.

Phase 3 trial

The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.

ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.

Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m² on days 1 to 3) and cytarabine (200 mg/m² on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m² (up to a maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.

Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m² on day 1 of first consolidation course; 60 mg/m² on days 1 and 2 of second consolidation course) and cytarabine (1 g/m² every 12 hours on days 1 to 4) with or without GO at 3 mg/m² (up to a maximum of 1 vial) on day 1 according to their initial randomization.

Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.

Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.

The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).

There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been released).

All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.

 

Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.

Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).

Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.

Photo by Bill Branson

The European Commission has authorized use of gemtuzumab ozogamicin (GO, Mylotarg™) as a treatment for patients with acute myeloid leukemia (AML).

GO is now approved for use in combination with daunorubicin and cytarabine to treat patients age 15 and older who have previously untreated, de novo, CD33-positive AML, not including acute promyelocytic leukemia.

GO is an antibody-drug conjugate composed of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90% of AML patients.

When GO binds to the CD33 antigen on the cell surface, it is absorbed into the cell, and calicheamicin is released, causing cell death.

Previous rejection

The European Commission’s approval of GO follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). In February, the CHMP recommended that GO receive marketing authorization for the aforementioned indication.

However, the CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.

The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.

The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.

Phase 3 trial

The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.

ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.

Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m² on days 1 to 3) and cytarabine (200 mg/m² on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m² (up to a maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.

Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m² on day 1 of first consolidation course; 60 mg/m² on days 1 and 2 of second consolidation course) and cytarabine (1 g/m² every 12 hours on days 1 to 4) with or without GO at 3 mg/m² (up to a maximum of 1 vial) on day 1 according to their initial randomization.

Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.

Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.

The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).

There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been released).

All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.

 

Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.

Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).

Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.

Photo by Bill Branson

The European Commission has authorized use of gemtuzumab ozogamicin (GO, Mylotarg™) as a treatment for patients with acute myeloid leukemia (AML).

GO is now approved for use in combination with daunorubicin and cytarabine to treat patients age 15 and older who have previously untreated, de novo, CD33-positive AML, not including acute promyelocytic leukemia.

GO is an antibody-drug conjugate composed of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90% of AML patients.

When GO binds to the CD33 antigen on the cell surface, it is absorbed into the cell, and calicheamicin is released, causing cell death.

Previous rejection

The European Commission’s approval of GO follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). In February, the CHMP recommended that GO receive marketing authorization for the aforementioned indication.

However, the CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.

The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.

The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.

Phase 3 trial

The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.

ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.

Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m² on days 1 to 3) and cytarabine (200 mg/m² on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m² (up to a maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.

Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m² on day 1 of first consolidation course; 60 mg/m² on days 1 and 2 of second consolidation course) and cytarabine (1 g/m² every 12 hours on days 1 to 4) with or without GO at 3 mg/m² (up to a maximum of 1 vial) on day 1 according to their initial randomization.

Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.

Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.

The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).

There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been released).

All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.

 

Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.

Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).

Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Photo courtesy of CDC

New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.

The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.

After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.

Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.

The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.

The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).

Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.

Intervention

The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.

Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.

Results

The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.

After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).

Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).

In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.

Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.

All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.

The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.

Photo courtesy of CDC

New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.

The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.

After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.

Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.

The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.

The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).

Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.

Intervention

The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.

Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.

Results

The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.

After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).

Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).

In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.

Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.

All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.

The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.

Photo courtesy of CDC

New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.

The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.

After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.

Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.

The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.

The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).

Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.

Intervention

The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.

Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.

Results

The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.

After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).

Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).

In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.

Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.

All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.

The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Research Hospital/Seth Dixon

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“The pattern of IKZF1 variants was surprising because many of the variants were in regions of the gene that are rarely mutated in leukemic cells,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

Research Hospital/Seth Dixon

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“The pattern of IKZF1 variants was surprising because many of the variants were in regions of the gene that are rarely mutated in leukemic cells,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”

Research Hospital/Seth Dixon

Germline variants in IKZF1 can predispose carriers to acute lymphoblastic leukemia (ALL), according to a study published in Cancer Cell.

The research began with the discovery of an IKZF1 variant in 3 generations of a German family affected by pediatric ALL.

Researchers then analyzed data from nearly 5000 children with ALL and identified 27 additional germline variants in IKZF1.

These variants were present in 0.9% of the patients analyzed, and most of the patients with the variants had B-cell ALL.

“This finding adds to the growing body of evidence that, while germline variations still account for a small percentage of pediatric ALL cases overall, more children than previously recognized inherit a predisposition to develop ALL,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

In the Cancer Cell paper, Dr Mullighan and his colleagues report the discovery of a germline deletion variant in IKZF1 (c.del556 or D186fs), which was present in 3 generations of a family.

Two of the 6 family members with this variant had developed B-ALL as children and died. The remaining 4 subjects are apparently healthy, despite having reduced numbers of B cells.

To build upon this discovery, the researchers performed targeted sequencing of IKZF1 in 4963 children with ALL.

This revealed 27 additional IKZF1 variants in 43 patients, most of whom had B-ALL. (One patient had T-cell ALL, and, for 8 patients, their subtype was unknown.)

The researchers noted that the variants were distributed across the gene.

“The pattern of IKZF1 variants was surprising because many of the variants were in regions of the gene that are rarely mutated in leukemic cells,” said study author Jun J. Yang, PhD, of St. Jude. “These regions of the gene have not been well characterized.”

The researchers also found that 22 of the 28 IKZF1 variants adversely affect gene function, while the remaining 6 variants appear to be benign.

The team said the deleterious variants impair DNA binding and regulation of transcriptional targets, induce aberrant leukemic cell adhesion, and reduce ALL cells’ sensitivity to treatment with dasatinib and dexamethasone.

The researchers identified the most deleterious variants as 5 that are located outside of the zinc-finger domains (M31V, M347V, R423C, A434G, and L449F), 2 variants affecting the N-terminal DNA-binding domain (R162P and H163Y), 2 truncating nonsense variants (M306* and C394*), and the frameshift variant discovered in the German family (D186fs).

“This [research] will expand the number of genes to consider when screening for predisposition to leukemia, particularly B-ALL,” said study author Kim Nichols, of St. Jude.

“And while not everyone carrying a germline IKZF1 variant will develop leukemia, these results will help us educate families about the potential risk of leukemia.”