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Genome-editing approach could treat SCD
and a sickled one
Image by Betty Pace
CRISPR-Cas9-mediated genome editing might be a feasible approach for treating sickle cell disease (SCD), according to a group of researchers.
The team used CRISPR to edit hematopoietic stem and progenitor cells (HSPCs) from patients with SCD, which resulted in the production of red blood cells (RBCs) that had enough fetal hemoglobin to be healthy.
The researchers believe this approach might prove effective in treating beta-thalassemia as well.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin,” said study author Mitchell J. Weiss, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia . . . . We have found a way to use CRISPR gene editing to produce similar benefits.”
Dr Weiss and his colleagues described this method in Nature Medicine.
The researchers noted that SCD and beta-thalassemia become symptomatic when fetal gamma-globin expression from 2 genes, HBG1 and HBG2, decreases and the expression of adult beta-globin increases, which shifts RBC hemoglobin from the fetal form to the adult form.
Reversing this shift can raise levels of fetal hemoglobin and ameliorate the symptoms of beta-thalassemia or SCD.
The team also pointed out that, in people with a benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH), mutations attenuate gamma-globin-to-beta-globin switching, which causes high levels of fetal hemoglobin expression throughout the patients’ lives.
So the researchers set out to mimic this phenomenon in HSPCs from patients with SCD.
The team performed CRISPR–Cas9-mediated genome editing of the HSPCs to mutate a 13-nt sequence present in the promoters of the HBG1 and HBG2 genes.
In this way, they were able to recapitulate a naturally occurring HPFH-associated mutation, so the HSPCs produced RBCs with increased fetal hemoglobin levels.
“Our work has identified a potential DNA target for genome-editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia,” Dr Weiss said.
“We have been able to snip that DNA target using CRISPR, remove a short segment in a ‘control section’ of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”
Recently, scientists have used several genome-editing approaches to manipulate HSPCs for the possible treatment of SCD and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching.
“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system,” Dr Weiss said.
He and his colleagues noted that, at this stage, it is still too early to begin clinical trials of their approach. The researchers want to refine the genome-editing process and perform other experiments to minimize potentially harmful off-target mutations before clinical trials are considered.
In addition, they said it will be important to compare the different genome-editing approaches head-to-head to determine which is safest and most effective. 
and a sickled one
Image by Betty Pace
CRISPR-Cas9-mediated genome editing might be a feasible approach for treating sickle cell disease (SCD), according to a group of researchers.
The team used CRISPR to edit hematopoietic stem and progenitor cells (HSPCs) from patients with SCD, which resulted in the production of red blood cells (RBCs) that had enough fetal hemoglobin to be healthy.
The researchers believe this approach might prove effective in treating beta-thalassemia as well.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin,” said study author Mitchell J. Weiss, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia . . . . We have found a way to use CRISPR gene editing to produce similar benefits.”
Dr Weiss and his colleagues described this method in Nature Medicine.
The researchers noted that SCD and beta-thalassemia become symptomatic when fetal gamma-globin expression from 2 genes, HBG1 and HBG2, decreases and the expression of adult beta-globin increases, which shifts RBC hemoglobin from the fetal form to the adult form.
Reversing this shift can raise levels of fetal hemoglobin and ameliorate the symptoms of beta-thalassemia or SCD.
The team also pointed out that, in people with a benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH), mutations attenuate gamma-globin-to-beta-globin switching, which causes high levels of fetal hemoglobin expression throughout the patients’ lives.
So the researchers set out to mimic this phenomenon in HSPCs from patients with SCD.
The team performed CRISPR–Cas9-mediated genome editing of the HSPCs to mutate a 13-nt sequence present in the promoters of the HBG1 and HBG2 genes.
In this way, they were able to recapitulate a naturally occurring HPFH-associated mutation, so the HSPCs produced RBCs with increased fetal hemoglobin levels.
“Our work has identified a potential DNA target for genome-editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia,” Dr Weiss said.
“We have been able to snip that DNA target using CRISPR, remove a short segment in a ‘control section’ of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”
Recently, scientists have used several genome-editing approaches to manipulate HSPCs for the possible treatment of SCD and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching.
“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system,” Dr Weiss said.
He and his colleagues noted that, at this stage, it is still too early to begin clinical trials of their approach. The researchers want to refine the genome-editing process and perform other experiments to minimize potentially harmful off-target mutations before clinical trials are considered.
In addition, they said it will be important to compare the different genome-editing approaches head-to-head to determine which is safest and most effective.
and a sickled one
Image by Betty Pace
CRISPR-Cas9-mediated genome editing might be a feasible approach for treating sickle cell disease (SCD), according to a group of researchers.
The team used CRISPR to edit hematopoietic stem and progenitor cells (HSPCs) from patients with SCD, which resulted in the production of red blood cells (RBCs) that had enough fetal hemoglobin to be healthy.
The researchers believe this approach might prove effective in treating beta-thalassemia as well.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin,” said study author Mitchell J. Weiss, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia . . . . We have found a way to use CRISPR gene editing to produce similar benefits.”
Dr Weiss and his colleagues described this method in Nature Medicine.
The researchers noted that SCD and beta-thalassemia become symptomatic when fetal gamma-globin expression from 2 genes, HBG1 and HBG2, decreases and the expression of adult beta-globin increases, which shifts RBC hemoglobin from the fetal form to the adult form.
Reversing this shift can raise levels of fetal hemoglobin and ameliorate the symptoms of beta-thalassemia or SCD.
The team also pointed out that, in people with a benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH), mutations attenuate gamma-globin-to-beta-globin switching, which causes high levels of fetal hemoglobin expression throughout the patients’ lives.
So the researchers set out to mimic this phenomenon in HSPCs from patients with SCD.
The team performed CRISPR–Cas9-mediated genome editing of the HSPCs to mutate a 13-nt sequence present in the promoters of the HBG1 and HBG2 genes.
In this way, they were able to recapitulate a naturally occurring HPFH-associated mutation, so the HSPCs produced RBCs with increased fetal hemoglobin levels.
“Our work has identified a potential DNA target for genome-editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia,” Dr Weiss said.
“We have been able to snip that DNA target using CRISPR, remove a short segment in a ‘control section’ of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”
Recently, scientists have used several genome-editing approaches to manipulate HSPCs for the possible treatment of SCD and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching.
“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system,” Dr Weiss said.
He and his colleagues noted that, at this stage, it is still too early to begin clinical trials of their approach. The researchers want to refine the genome-editing process and perform other experiments to minimize potentially harmful off-target mutations before clinical trials are considered.
In addition, they said it will be important to compare the different genome-editing approaches head-to-head to determine which is safest and most effective.
Drug no longer in development for DLBCL, other cancers
ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.
In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.
Now, ProNAi has said it does not plan to resume development of the drug.
“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.
About PNT2258
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.
ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.
“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.
The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.
ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).
Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.
PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.
“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.
PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m2 through 150 mg/m2.
A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.
Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.
ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.
In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.
Now, ProNAi has said it does not plan to resume development of the drug.
“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.
About PNT2258
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.
ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.
“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.
The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.
ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).
Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.
PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.
“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.
PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m2 through 150 mg/m2.
A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.
Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.
ProNAi Therapeutics recently announced its decision to stop development of PNT2258, a drug designed to treat cancers characterized by overexpression of BCL2.
In June, the company suspended development of PNT2258, closing enrollment in a phase 2 trial of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and a phase 2 trial of patients with Richter’s transformation.
Now, ProNAi has said it does not plan to resume development of the drug.
“[N]o further investment in PNT2258 or the underlying DNAi platform by ProNAi is contemplated, and the company subsequently has closed its research facility based in Plymouth, Michigan, which supported these programs,” the company said in a statement.
About PNT2258
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles.
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
Last March, PNT2258 was granted orphan drug designation from the US Food and Drug Administration for the treatment of DLBCL.
ProNAi initially suspended the development of PNT2258 in June, following a review of interim data from the phase 2 Wolverine trial. The company said the drug produced “modest efficacy” in this trial, but it seemed the data were not “robust enough” to justify continued development of PNT2258.
“We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform,” Nick Glover, president and CEO of ProNAi, said at the time.
The Wolverine trial was designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 patients with relapsed/refractory DLBCL.
ProNAi reported interim safety and efficacy data as of April 25, 2016, for the first 37 subjects enrolled. The response rate was 8.1% overall (n=37) and 15.8% in the response-evaluable subgroup (n=19).
Subjects were considered response-evaluable if they met the amended eligibility criteria—a performance status of 0 to 1, 1 to 3 prior systemic treatment regimens, and receipt of at least 8 doses of PNT2258 within 35 days of starting therapy.
PNT2258 was also being evaluated in patients with Richter’s transformation in the phase 2 Brighton study. In June, ProNAi said it had enrolled 5 subjects in this study, and 4 had discontinued. No responses were observed.
“On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects,” Barbara Klencke, chief development officer of ProNAi, said at the time.
PNT2258 was evaluated in 2 prior studies as well. In a phase 1 study (NCT01191775), PNT2258 was given to 22 subjects with advanced solid tumors. The drug was considered well tolerated at doses ranging from 1 mg/m2 through 150 mg/m2.
A pilot study of PNT2258 (NCT01733238) enrolled 13 subjects with relapsed/refractory B-cell non-Hodgkin lymphoma. Responses were observed in subjects with DLBCL and those with follicular lymphoma.
Six subjects were progression-free at 12 months, and progression-free survival extended to 2 years and beyond in 4 subjects. The majority of the adverse events were grade 1 or 2.
Pulmonary complications affect cancer survivors long-term
Photo by Bill Branson
A new study suggests that survivors of childhood cancer may be plagued by pulmonary complications related to treatment well into their adult lives.
The research indicated that the cumulative incidence of pulmonary complications continues to increase up to 25 years from a patient’s initial cancer diagnosis.
In addition, platinum-based chemotherapy and higher doses of radiation were linked to an increased risk of death from pulmonary causes.
Andrew C. Dietz, MD, of Children’s Hospital Los Angeles in California, and his colleagues reported these findings in Cancer.
The researchers analyzed data from 20,690 five-year cancer survivors who participated in the Childhood Cancer Survivor Study to determine the incidence of death from pulmonary causes.
The team also assessed the incidence of various pulmonary complications in 14,316 of those cancer survivors (who completed a baseline survey and/or 1 of 2 follow-up surveys years later), comparing the results to those seen in a control group of 4027 cancer survivor siblings.
About 34% of the 14,316 cancer survivors had been diagnosed with acute leukemia, and about 21% were diagnosed with Hodgkin or non-Hodgkin lymphoma.
The cancer survivors’ median age at diagnosis was 7 (range, 0-21), and their median age at evaluation was 32 (range, 6-59). The median time from diagnosis was 25 years (range, 5-39).
Compared with controls, cancer survivors were more likely to be male, black, and Hispanic. Cancer survivors were slightly younger and more likely to report a history of congestive heart failure, but they were less likely to be overweight/obese or have ever smoked at the time of the baseline survey.
Results
By age 45, the cumulative incidence of any pulmonary condition was 29.6% among cancer survivors and 26.5% among controls (P=0.001).
The cancer survivors were more likely than controls to report chronic cough (rate ratio [RR]=1.6), the need for extra oxygen (RR=1.8), lung fibrosis (RR=3.5), and recurrent pneumonia (RR=2.0).
Among cancer survivors, the risk of asthma was significantly associated with exposure to asparaginase. Chronic cough was significantly associated with chest wall or lung surgery, anthracyclines, hydroxyurea, and lung radiation doses ≥15 Gy.
Emphysema was significantly associated with lomustine. The need for extra oxygen was significantly associated with hematopoietic stem cell transplant, chest wall or lung surgery, and lung radiation doses ≥10 Gy.
Lung fibrosis was significantly associated with chest wall or lung surgery, asparaginase, platinum-based chemotherapy, and lung radiation doses ≥10 Gy. Recurrent pneumonia was significantly associated with lung radiation doses ≥15 Gy.
The standardized mortality ratio for death from pulmonary causes among all eligible cancer survivors (n=20,690) was 5.9. Pulmonary death was significantly associated with exposure to platinum-based agents and lung radiation doses ≥10 Gy.
“This study adds to our understanding of specific, long-term risks to pulmonary health for survivors of childhood cancer and will help refine guidelines for appropriate screening, health surveillance, and counseling,” said study author Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
He added that this knowledge could potentially contribute to the design and testing of better, targeted interventions to decrease adverse pulmonary events in this population.
Photo by Bill Branson
A new study suggests that survivors of childhood cancer may be plagued by pulmonary complications related to treatment well into their adult lives.
The research indicated that the cumulative incidence of pulmonary complications continues to increase up to 25 years from a patient’s initial cancer diagnosis.
In addition, platinum-based chemotherapy and higher doses of radiation were linked to an increased risk of death from pulmonary causes.
Andrew C. Dietz, MD, of Children’s Hospital Los Angeles in California, and his colleagues reported these findings in Cancer.
The researchers analyzed data from 20,690 five-year cancer survivors who participated in the Childhood Cancer Survivor Study to determine the incidence of death from pulmonary causes.
The team also assessed the incidence of various pulmonary complications in 14,316 of those cancer survivors (who completed a baseline survey and/or 1 of 2 follow-up surveys years later), comparing the results to those seen in a control group of 4027 cancer survivor siblings.
About 34% of the 14,316 cancer survivors had been diagnosed with acute leukemia, and about 21% were diagnosed with Hodgkin or non-Hodgkin lymphoma.
The cancer survivors’ median age at diagnosis was 7 (range, 0-21), and their median age at evaluation was 32 (range, 6-59). The median time from diagnosis was 25 years (range, 5-39).
Compared with controls, cancer survivors were more likely to be male, black, and Hispanic. Cancer survivors were slightly younger and more likely to report a history of congestive heart failure, but they were less likely to be overweight/obese or have ever smoked at the time of the baseline survey.
Results
By age 45, the cumulative incidence of any pulmonary condition was 29.6% among cancer survivors and 26.5% among controls (P=0.001).
The cancer survivors were more likely than controls to report chronic cough (rate ratio [RR]=1.6), the need for extra oxygen (RR=1.8), lung fibrosis (RR=3.5), and recurrent pneumonia (RR=2.0).
Among cancer survivors, the risk of asthma was significantly associated with exposure to asparaginase. Chronic cough was significantly associated with chest wall or lung surgery, anthracyclines, hydroxyurea, and lung radiation doses ≥15 Gy.
Emphysema was significantly associated with lomustine. The need for extra oxygen was significantly associated with hematopoietic stem cell transplant, chest wall or lung surgery, and lung radiation doses ≥10 Gy.
Lung fibrosis was significantly associated with chest wall or lung surgery, asparaginase, platinum-based chemotherapy, and lung radiation doses ≥10 Gy. Recurrent pneumonia was significantly associated with lung radiation doses ≥15 Gy.
The standardized mortality ratio for death from pulmonary causes among all eligible cancer survivors (n=20,690) was 5.9. Pulmonary death was significantly associated with exposure to platinum-based agents and lung radiation doses ≥10 Gy.
“This study adds to our understanding of specific, long-term risks to pulmonary health for survivors of childhood cancer and will help refine guidelines for appropriate screening, health surveillance, and counseling,” said study author Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
He added that this knowledge could potentially contribute to the design and testing of better, targeted interventions to decrease adverse pulmonary events in this population.
Photo by Bill Branson
A new study suggests that survivors of childhood cancer may be plagued by pulmonary complications related to treatment well into their adult lives.
The research indicated that the cumulative incidence of pulmonary complications continues to increase up to 25 years from a patient’s initial cancer diagnosis.
In addition, platinum-based chemotherapy and higher doses of radiation were linked to an increased risk of death from pulmonary causes.
Andrew C. Dietz, MD, of Children’s Hospital Los Angeles in California, and his colleagues reported these findings in Cancer.
The researchers analyzed data from 20,690 five-year cancer survivors who participated in the Childhood Cancer Survivor Study to determine the incidence of death from pulmonary causes.
The team also assessed the incidence of various pulmonary complications in 14,316 of those cancer survivors (who completed a baseline survey and/or 1 of 2 follow-up surveys years later), comparing the results to those seen in a control group of 4027 cancer survivor siblings.
About 34% of the 14,316 cancer survivors had been diagnosed with acute leukemia, and about 21% were diagnosed with Hodgkin or non-Hodgkin lymphoma.
The cancer survivors’ median age at diagnosis was 7 (range, 0-21), and their median age at evaluation was 32 (range, 6-59). The median time from diagnosis was 25 years (range, 5-39).
Compared with controls, cancer survivors were more likely to be male, black, and Hispanic. Cancer survivors were slightly younger and more likely to report a history of congestive heart failure, but they were less likely to be overweight/obese or have ever smoked at the time of the baseline survey.
Results
By age 45, the cumulative incidence of any pulmonary condition was 29.6% among cancer survivors and 26.5% among controls (P=0.001).
The cancer survivors were more likely than controls to report chronic cough (rate ratio [RR]=1.6), the need for extra oxygen (RR=1.8), lung fibrosis (RR=3.5), and recurrent pneumonia (RR=2.0).
Among cancer survivors, the risk of asthma was significantly associated with exposure to asparaginase. Chronic cough was significantly associated with chest wall or lung surgery, anthracyclines, hydroxyurea, and lung radiation doses ≥15 Gy.
Emphysema was significantly associated with lomustine. The need for extra oxygen was significantly associated with hematopoietic stem cell transplant, chest wall or lung surgery, and lung radiation doses ≥10 Gy.
Lung fibrosis was significantly associated with chest wall or lung surgery, asparaginase, platinum-based chemotherapy, and lung radiation doses ≥10 Gy. Recurrent pneumonia was significantly associated with lung radiation doses ≥15 Gy.
The standardized mortality ratio for death from pulmonary causes among all eligible cancer survivors (n=20,690) was 5.9. Pulmonary death was significantly associated with exposure to platinum-based agents and lung radiation doses ≥10 Gy.
“This study adds to our understanding of specific, long-term risks to pulmonary health for survivors of childhood cancer and will help refine guidelines for appropriate screening, health surveillance, and counseling,” said study author Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
He added that this knowledge could potentially contribute to the design and testing of better, targeted interventions to decrease adverse pulmonary events in this population.
Zika prompts HHS to declare public health emergency for Puerto Rico
The United States Department of Health and Human Services (HHS) has declared a public health emergency for Puerto Rico due to the Zika virus outbreak.
The declaration allows the federal government to provide support to the government of Puerto Rico to address the outbreak.
“This administration is committed to meeting the Zika outbreak in Puerto Rico with the necessary urgency,” said HHS Secretary Sylvia M. Burwell.
“This emergency declaration allows us to provide additional support to the Puerto Rican government and reminds us of the importance of pregnant women, women of child-bearing age, and their partners taking additional steps to protect themselves and their families from Zika.”
Through the public health emergency declaration, the government of Puerto Rico can:
- Apply for funding to hire and train unemployed workers to assist in vector control and outreach and education efforts through the US Department of Labor’s National Dislocated Worker Grant program
- Request the temporary reassignment of local public health department or agency personnel who are funded through Public Health Service Act programs in Puerto Rico to assist in the Zika response.
“The declaration made by HHS, which grants access to certain funds, is another example of collaboration between the federal government and the government of Puerto Rico,” said Alejandro García Padilla, governor of the Commonwealth of Puerto Rico.
In April, the HHS awarded $5 million to Puerto Rico health centers to fight the spread of the Zika virus. In March, the HHS shipped blood products to the island in response to the Zika outbreak.
Earlier this month, the US Centers for Disease Control and Prevention (CDC) awarded $16 million to US states and territories, including Puerto Rico, to fight the Zika virus. In July, the CDC awarded $25 million to US states, cities, and territories for the same purpose.
According to the Puerto Rico Department of Health, as of August 12, there have been 10,690 laboratory-confirmed cases of Zika in Puerto Rico, which includes 1035 pregnant women.
The actual number of people infected with Zika may be higher because most people with Zika infections have no symptoms and might not seek testing.
The United States Department of Health and Human Services (HHS) has declared a public health emergency for Puerto Rico due to the Zika virus outbreak.
The declaration allows the federal government to provide support to the government of Puerto Rico to address the outbreak.
“This administration is committed to meeting the Zika outbreak in Puerto Rico with the necessary urgency,” said HHS Secretary Sylvia M. Burwell.
“This emergency declaration allows us to provide additional support to the Puerto Rican government and reminds us of the importance of pregnant women, women of child-bearing age, and their partners taking additional steps to protect themselves and their families from Zika.”
Through the public health emergency declaration, the government of Puerto Rico can:
- Apply for funding to hire and train unemployed workers to assist in vector control and outreach and education efforts through the US Department of Labor’s National Dislocated Worker Grant program
- Request the temporary reassignment of local public health department or agency personnel who are funded through Public Health Service Act programs in Puerto Rico to assist in the Zika response.
“The declaration made by HHS, which grants access to certain funds, is another example of collaboration between the federal government and the government of Puerto Rico,” said Alejandro García Padilla, governor of the Commonwealth of Puerto Rico.
In April, the HHS awarded $5 million to Puerto Rico health centers to fight the spread of the Zika virus. In March, the HHS shipped blood products to the island in response to the Zika outbreak.
Earlier this month, the US Centers for Disease Control and Prevention (CDC) awarded $16 million to US states and territories, including Puerto Rico, to fight the Zika virus. In July, the CDC awarded $25 million to US states, cities, and territories for the same purpose.
According to the Puerto Rico Department of Health, as of August 12, there have been 10,690 laboratory-confirmed cases of Zika in Puerto Rico, which includes 1035 pregnant women.
The actual number of people infected with Zika may be higher because most people with Zika infections have no symptoms and might not seek testing.
The United States Department of Health and Human Services (HHS) has declared a public health emergency for Puerto Rico due to the Zika virus outbreak.
The declaration allows the federal government to provide support to the government of Puerto Rico to address the outbreak.
“This administration is committed to meeting the Zika outbreak in Puerto Rico with the necessary urgency,” said HHS Secretary Sylvia M. Burwell.
“This emergency declaration allows us to provide additional support to the Puerto Rican government and reminds us of the importance of pregnant women, women of child-bearing age, and their partners taking additional steps to protect themselves and their families from Zika.”
Through the public health emergency declaration, the government of Puerto Rico can:
- Apply for funding to hire and train unemployed workers to assist in vector control and outreach and education efforts through the US Department of Labor’s National Dislocated Worker Grant program
- Request the temporary reassignment of local public health department or agency personnel who are funded through Public Health Service Act programs in Puerto Rico to assist in the Zika response.
“The declaration made by HHS, which grants access to certain funds, is another example of collaboration between the federal government and the government of Puerto Rico,” said Alejandro García Padilla, governor of the Commonwealth of Puerto Rico.
In April, the HHS awarded $5 million to Puerto Rico health centers to fight the spread of the Zika virus. In March, the HHS shipped blood products to the island in response to the Zika outbreak.
Earlier this month, the US Centers for Disease Control and Prevention (CDC) awarded $16 million to US states and territories, including Puerto Rico, to fight the Zika virus. In July, the CDC awarded $25 million to US states, cities, and territories for the same purpose.
According to the Puerto Rico Department of Health, as of August 12, there have been 10,690 laboratory-confirmed cases of Zika in Puerto Rico, which includes 1035 pregnant women.
The actual number of people infected with Zika may be higher because most people with Zika infections have no symptoms and might not seek testing.
Research provides new insight into CLL
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
New research explains how an inherited genetic variant associated with an increased risk of chronic lymphocytic leukemia (CLL) helps cancer cells survive.
Previous research showed that DNA variations at 15q15.1 are linked with an increased risk of CLL.
With the current study, researchers believe they have identified the causal variant at 15q15.1 and determined the mechanism by which it influences tumorigenesis.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues conducted this research and detailed the results in Cell Reports.
The researchers said the single nucleotide polymorphism rs539846 underlies the 15q15.1 CLL risk locus.
And the rs539846-A risk allele interferes with BCL-2 modifying factor (BMF), which normally works to produce pro-apoptotic signals.
This interference makes it harder for the protein RELA to “flip on” the activity of BMF and reduces levels of the pro-apoptotic signals, allowing CLL cells to sidestep self-destruction.
“Although many significant risk variants for this type of leukemia have been identified, the biological mechanisms through which these variants affect leukemia development have been less well studied,” Dr Houlston said.
“This study highlights the importance of cell-death-inducing proteins such as BMF in controlling CLL development and could help in the design of new drugs to treat this disease.”
In addition, Dr Houlston and his colleagues said their findings complement work from phase 1 and phase 2 trials of venetoclax (formerly ABT-199) in CLL.
The trials suggested that venetoclax mimics pro-apoptotic proteins by targeting the pro-survival BCL-2 pathway. In this way, the drug can produce anticancer effects in CLL patients.
Dr Houlston and his colleagues believe their discovery could provide important insight into how venetoclax and similar drugs work, which could optimize the drugs’ use.
NICE recommending long-term ticagrelor
Photo from AstraZeneca
The National Institute for Health and Care Excellence (NICE) has published a draft guidance recommending the antiplatelet agent ticagrelor (Brilique, AstraZeneca) be made available on the National Health Service (NHS) at a lower dose that can be used for a longer duration.
NICE previously decided ticagrelor should be available on the NHS as a treatment option for certain patients with acute coronary syndromes.
For these patients, the drug could be given at a dose of 90 mg, in combination with low-dose aspirin, for up to a year to prevent atherothrombotic events.
Now, NICE is recommending an additional option.
The agency’s new draft guidance recommends ticagrelor at 60 mg, to be given twice a day in combination with aspirin at 75 mg to 150 mg daily, as a continuation therapy for the prevention of atherothrombotic events in certain patients with a history of myocardial infarction and a high risk of developing atherothrombotic events.
Patients must have had a myocardial infarction at least a year ago and have already taken ticagrelor at 90 mg (or another adenosine diphosphate receptor inhibitor therapy), in combination with aspirin, for 1 year.
Ticagrelor at 60 mg, plus aspirin, must be continued without interruption. And the treatment must be stopped when clinically indicated or after a maximum of 3 years.
“The evidence shows that ticagrelor, in combination with aspirin, is effective at reducing the risk of further heart attacks and strokes in people who have already had a heart attack,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.
“In provisionally recommending ticagrelor, we are pleased to be able to increase the treatment options available to the many thousands of people who stand to benefit from it.”
NICE’s new draft guidance is not intended to affect the position of patients whose treatment with ticagrelor at 60 mg, in combination with aspirin, as a continuation therapy was started within the NHS before this guidance was published.
Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.
NICE’s draft guidance is open for comments until 5 pm (GMT) on September 5, 2016.
Photo from AstraZeneca
The National Institute for Health and Care Excellence (NICE) has published a draft guidance recommending the antiplatelet agent ticagrelor (Brilique, AstraZeneca) be made available on the National Health Service (NHS) at a lower dose that can be used for a longer duration.
NICE previously decided ticagrelor should be available on the NHS as a treatment option for certain patients with acute coronary syndromes.
For these patients, the drug could be given at a dose of 90 mg, in combination with low-dose aspirin, for up to a year to prevent atherothrombotic events.
Now, NICE is recommending an additional option.
The agency’s new draft guidance recommends ticagrelor at 60 mg, to be given twice a day in combination with aspirin at 75 mg to 150 mg daily, as a continuation therapy for the prevention of atherothrombotic events in certain patients with a history of myocardial infarction and a high risk of developing atherothrombotic events.
Patients must have had a myocardial infarction at least a year ago and have already taken ticagrelor at 90 mg (or another adenosine diphosphate receptor inhibitor therapy), in combination with aspirin, for 1 year.
Ticagrelor at 60 mg, plus aspirin, must be continued without interruption. And the treatment must be stopped when clinically indicated or after a maximum of 3 years.
“The evidence shows that ticagrelor, in combination with aspirin, is effective at reducing the risk of further heart attacks and strokes in people who have already had a heart attack,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.
“In provisionally recommending ticagrelor, we are pleased to be able to increase the treatment options available to the many thousands of people who stand to benefit from it.”
NICE’s new draft guidance is not intended to affect the position of patients whose treatment with ticagrelor at 60 mg, in combination with aspirin, as a continuation therapy was started within the NHS before this guidance was published.
Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.
NICE’s draft guidance is open for comments until 5 pm (GMT) on September 5, 2016.
Photo from AstraZeneca
The National Institute for Health and Care Excellence (NICE) has published a draft guidance recommending the antiplatelet agent ticagrelor (Brilique, AstraZeneca) be made available on the National Health Service (NHS) at a lower dose that can be used for a longer duration.
NICE previously decided ticagrelor should be available on the NHS as a treatment option for certain patients with acute coronary syndromes.
For these patients, the drug could be given at a dose of 90 mg, in combination with low-dose aspirin, for up to a year to prevent atherothrombotic events.
Now, NICE is recommending an additional option.
The agency’s new draft guidance recommends ticagrelor at 60 mg, to be given twice a day in combination with aspirin at 75 mg to 150 mg daily, as a continuation therapy for the prevention of atherothrombotic events in certain patients with a history of myocardial infarction and a high risk of developing atherothrombotic events.
Patients must have had a myocardial infarction at least a year ago and have already taken ticagrelor at 90 mg (or another adenosine diphosphate receptor inhibitor therapy), in combination with aspirin, for 1 year.
Ticagrelor at 60 mg, plus aspirin, must be continued without interruption. And the treatment must be stopped when clinically indicated or after a maximum of 3 years.
“The evidence shows that ticagrelor, in combination with aspirin, is effective at reducing the risk of further heart attacks and strokes in people who have already had a heart attack,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.
“In provisionally recommending ticagrelor, we are pleased to be able to increase the treatment options available to the many thousands of people who stand to benefit from it.”
NICE’s new draft guidance is not intended to affect the position of patients whose treatment with ticagrelor at 60 mg, in combination with aspirin, as a continuation therapy was started within the NHS before this guidance was published.
Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.
NICE’s draft guidance is open for comments until 5 pm (GMT) on September 5, 2016.
Healthcare spending doesn’t impact cancer outcomes
receiving treatment
Photo by Rhoda Baer
A new study suggests that higher healthcare spending is not associated with better cancer outcomes in the US, but state-level wealth is.
Researchers found that higher gross domestic product (GDP) per capita was associated with lower mortality for all cancers, colorectal cancer, and breast cancer.
However, higher healthcare spending was only associated with lower mortality for breast cancer—not colorectal cancer or all cancers combined.
Jad Chahoud, MD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these findings in JNCCN.
To investigate the implications of socioeconomic status and health expenditures on cancer outcomes, the researchers conducted an ecological study at the state level for 3 distinct patient populations: breast cancer, colorectal cancer, and all-cancer patients.
The team extracted data on GDP and healthcare spending per capita from the 2009 Bureau of Economic Analysis and the Centers for Medicare & Medicaid Services, respectively.
Using data from the National Cancer Institute, the researchers retrieved breast, colorectal, and all-cancer age-adjusted rates and computed mortality/incidence (M/I) ratios for each population.
The team found that higher GDP per capita was significantly associated with lower M/I ratios for all cancers (rho=–0.4406; P=0.0017), breast cancer (rho=–0.3605; P=0.0118), and colorectal cancer (rho=–0.3612; P=0.0117).
But higher healthcare spending was only associated with a lower M/I ratio for breast cancer (rho=–0.4237; P=0.0027).
In a related editorial, Melissa A. Simon, MD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois, and her colleagues pointed out that the data in this study predate the Affordable Care Act. So the results may not reflect the current state of affairs in the US.
The authors also said these data should not be used to guide—or misguide—policy makers to cap or decrease spending for certain health issues.
“Increased spending does not necessarily improve quality of care, but capping or cutting spending on healthcare does not necessarily solve problems either,” the authors wrote.
In a counterpoint editorial, Dr Chahoud and his colleagues said the goal of their study was not to misguide policy makers.
The team doesn’t recommend capping healthcare spending. Rather, they want to see “smart” spending that will have an impact on patient outcomes.
receiving treatment
Photo by Rhoda Baer
A new study suggests that higher healthcare spending is not associated with better cancer outcomes in the US, but state-level wealth is.
Researchers found that higher gross domestic product (GDP) per capita was associated with lower mortality for all cancers, colorectal cancer, and breast cancer.
However, higher healthcare spending was only associated with lower mortality for breast cancer—not colorectal cancer or all cancers combined.
Jad Chahoud, MD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these findings in JNCCN.
To investigate the implications of socioeconomic status and health expenditures on cancer outcomes, the researchers conducted an ecological study at the state level for 3 distinct patient populations: breast cancer, colorectal cancer, and all-cancer patients.
The team extracted data on GDP and healthcare spending per capita from the 2009 Bureau of Economic Analysis and the Centers for Medicare & Medicaid Services, respectively.
Using data from the National Cancer Institute, the researchers retrieved breast, colorectal, and all-cancer age-adjusted rates and computed mortality/incidence (M/I) ratios for each population.
The team found that higher GDP per capita was significantly associated with lower M/I ratios for all cancers (rho=–0.4406; P=0.0017), breast cancer (rho=–0.3605; P=0.0118), and colorectal cancer (rho=–0.3612; P=0.0117).
But higher healthcare spending was only associated with a lower M/I ratio for breast cancer (rho=–0.4237; P=0.0027).
In a related editorial, Melissa A. Simon, MD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois, and her colleagues pointed out that the data in this study predate the Affordable Care Act. So the results may not reflect the current state of affairs in the US.
The authors also said these data should not be used to guide—or misguide—policy makers to cap or decrease spending for certain health issues.
“Increased spending does not necessarily improve quality of care, but capping or cutting spending on healthcare does not necessarily solve problems either,” the authors wrote.
In a counterpoint editorial, Dr Chahoud and his colleagues said the goal of their study was not to misguide policy makers.
The team doesn’t recommend capping healthcare spending. Rather, they want to see “smart” spending that will have an impact on patient outcomes.
receiving treatment
Photo by Rhoda Baer
A new study suggests that higher healthcare spending is not associated with better cancer outcomes in the US, but state-level wealth is.
Researchers found that higher gross domestic product (GDP) per capita was associated with lower mortality for all cancers, colorectal cancer, and breast cancer.
However, higher healthcare spending was only associated with lower mortality for breast cancer—not colorectal cancer or all cancers combined.
Jad Chahoud, MD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these findings in JNCCN.
To investigate the implications of socioeconomic status and health expenditures on cancer outcomes, the researchers conducted an ecological study at the state level for 3 distinct patient populations: breast cancer, colorectal cancer, and all-cancer patients.
The team extracted data on GDP and healthcare spending per capita from the 2009 Bureau of Economic Analysis and the Centers for Medicare & Medicaid Services, respectively.
Using data from the National Cancer Institute, the researchers retrieved breast, colorectal, and all-cancer age-adjusted rates and computed mortality/incidence (M/I) ratios for each population.
The team found that higher GDP per capita was significantly associated with lower M/I ratios for all cancers (rho=–0.4406; P=0.0017), breast cancer (rho=–0.3605; P=0.0118), and colorectal cancer (rho=–0.3612; P=0.0117).
But higher healthcare spending was only associated with a lower M/I ratio for breast cancer (rho=–0.4237; P=0.0027).
In a related editorial, Melissa A. Simon, MD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois, and her colleagues pointed out that the data in this study predate the Affordable Care Act. So the results may not reflect the current state of affairs in the US.
The authors also said these data should not be used to guide—or misguide—policy makers to cap or decrease spending for certain health issues.
“Increased spending does not necessarily improve quality of care, but capping or cutting spending on healthcare does not necessarily solve problems either,” the authors wrote.
In a counterpoint editorial, Dr Chahoud and his colleagues said the goal of their study was not to misguide policy makers.
The team doesn’t recommend capping healthcare spending. Rather, they want to see “smart” spending that will have an impact on patient outcomes.
Venetoclax can produce short-term responses in AML
Results of a phase 2 trial suggest the BCL2 inhibitor venetoclax can produce responses in patients with acute myelogenous leukemia (AML) who do not respond to or cannot tolerate chemotherapy.
However, the overall response rate in this trial was low, and responses were not durable.
All of the patients studied discontinued venetoclax, most due to disease progression.
The study was published in Cancer Discovery. It was funded by AbbVie in collaboration with Genentech/Roche.
The trial included 32 patients with AML and a median age of 71 (range, 19–84). Thirteen patients had an antecedent hematologic disorder or myeloproliferative neoplasm, and 4 had therapy-related AML with complex cytogenetics.
Twelve patients had mutations in IDH genes, and 6 had a high BCL2-sensitive protein index.
Thirty patients had received at least 1 prior therapy, and 13 had received at least 3 prior treatment regimens. Two patients were considered unfit for intensive chemotherapy and were treatment-naive at study entry.
The patients received venetoclax at 800 mg daily. All 32 patients received at least 1 dose, and 26 patients received at least 4 weeks of therapy.
Efficacy
The overall response rate was 19%. Two patients had a complete response (CR), and 4 had a CR with incomplete blood count recovery. Three of the 6 responders had an antecedent hematologic disorder.
“[E]ven among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL2 inhibition, even to the point of complete remissions,” said study author Anthony Letai, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days.
The 4 patients who had CRs with incomplete count recovery had IDH mutations. Response to the drug correlated with biomarker results, including indices of BCL2 protein expression and BH3 profiling.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL2,” Dr Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
Safety and discontinuation
All of the patients discontinued therapy—29 due to progressive disease and 1 due to an adverse event (terminal ileitis). One patient withdrew consent, and 1 proceeded to allogeneic transplant after achieving stable disease.
All of the patients experienced treatment-emergent adverse events. The most common were nausea (59%), diarrhea (56%), hypokalemia (41%), vomiting (41%), fatigue (34%), headache (34%), hypomagnesemia (34%), febrile neutropenia (31%), and hypophosphatemia (31%).
Serious adverse events occurred in 84% of patients. These included febrile neutropenia (28%), pneumonia (16%), abdominal pain (6%), acute renal failure (6%), failure to thrive (6%), hypotension (6%), sepsis (6%), and urinary tract infection (6%).
Based on the results of this trial, the researchers concluded that venetoclax may be a viable treatment option for AML patients when used in combination with other therapies.
“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combinations with hypomethylating agents and other approaches,” said study author Marina Konopleva, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”
Results of a phase 2 trial suggest the BCL2 inhibitor venetoclax can produce responses in patients with acute myelogenous leukemia (AML) who do not respond to or cannot tolerate chemotherapy.
However, the overall response rate in this trial was low, and responses were not durable.
All of the patients studied discontinued venetoclax, most due to disease progression.
The study was published in Cancer Discovery. It was funded by AbbVie in collaboration with Genentech/Roche.
The trial included 32 patients with AML and a median age of 71 (range, 19–84). Thirteen patients had an antecedent hematologic disorder or myeloproliferative neoplasm, and 4 had therapy-related AML with complex cytogenetics.
Twelve patients had mutations in IDH genes, and 6 had a high BCL2-sensitive protein index.
Thirty patients had received at least 1 prior therapy, and 13 had received at least 3 prior treatment regimens. Two patients were considered unfit for intensive chemotherapy and were treatment-naive at study entry.
The patients received venetoclax at 800 mg daily. All 32 patients received at least 1 dose, and 26 patients received at least 4 weeks of therapy.
Efficacy
The overall response rate was 19%. Two patients had a complete response (CR), and 4 had a CR with incomplete blood count recovery. Three of the 6 responders had an antecedent hematologic disorder.
“[E]ven among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL2 inhibition, even to the point of complete remissions,” said study author Anthony Letai, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days.
The 4 patients who had CRs with incomplete count recovery had IDH mutations. Response to the drug correlated with biomarker results, including indices of BCL2 protein expression and BH3 profiling.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL2,” Dr Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
Safety and discontinuation
All of the patients discontinued therapy—29 due to progressive disease and 1 due to an adverse event (terminal ileitis). One patient withdrew consent, and 1 proceeded to allogeneic transplant after achieving stable disease.
All of the patients experienced treatment-emergent adverse events. The most common were nausea (59%), diarrhea (56%), hypokalemia (41%), vomiting (41%), fatigue (34%), headache (34%), hypomagnesemia (34%), febrile neutropenia (31%), and hypophosphatemia (31%).
Serious adverse events occurred in 84% of patients. These included febrile neutropenia (28%), pneumonia (16%), abdominal pain (6%), acute renal failure (6%), failure to thrive (6%), hypotension (6%), sepsis (6%), and urinary tract infection (6%).
Based on the results of this trial, the researchers concluded that venetoclax may be a viable treatment option for AML patients when used in combination with other therapies.
“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combinations with hypomethylating agents and other approaches,” said study author Marina Konopleva, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”
Results of a phase 2 trial suggest the BCL2 inhibitor venetoclax can produce responses in patients with acute myelogenous leukemia (AML) who do not respond to or cannot tolerate chemotherapy.
However, the overall response rate in this trial was low, and responses were not durable.
All of the patients studied discontinued venetoclax, most due to disease progression.
The study was published in Cancer Discovery. It was funded by AbbVie in collaboration with Genentech/Roche.
The trial included 32 patients with AML and a median age of 71 (range, 19–84). Thirteen patients had an antecedent hematologic disorder or myeloproliferative neoplasm, and 4 had therapy-related AML with complex cytogenetics.
Twelve patients had mutations in IDH genes, and 6 had a high BCL2-sensitive protein index.
Thirty patients had received at least 1 prior therapy, and 13 had received at least 3 prior treatment regimens. Two patients were considered unfit for intensive chemotherapy and were treatment-naive at study entry.
The patients received venetoclax at 800 mg daily. All 32 patients received at least 1 dose, and 26 patients received at least 4 weeks of therapy.
Efficacy
The overall response rate was 19%. Two patients had a complete response (CR), and 4 had a CR with incomplete blood count recovery. Three of the 6 responders had an antecedent hematologic disorder.
“[E]ven among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL2 inhibition, even to the point of complete remissions,” said study author Anthony Letai, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days.
The 4 patients who had CRs with incomplete count recovery had IDH mutations. Response to the drug correlated with biomarker results, including indices of BCL2 protein expression and BH3 profiling.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL2,” Dr Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
Safety and discontinuation
All of the patients discontinued therapy—29 due to progressive disease and 1 due to an adverse event (terminal ileitis). One patient withdrew consent, and 1 proceeded to allogeneic transplant after achieving stable disease.
All of the patients experienced treatment-emergent adverse events. The most common were nausea (59%), diarrhea (56%), hypokalemia (41%), vomiting (41%), fatigue (34%), headache (34%), hypomagnesemia (34%), febrile neutropenia (31%), and hypophosphatemia (31%).
Serious adverse events occurred in 84% of patients. These included febrile neutropenia (28%), pneumonia (16%), abdominal pain (6%), acute renal failure (6%), failure to thrive (6%), hypotension (6%), sepsis (6%), and urinary tract infection (6%).
Based on the results of this trial, the researchers concluded that venetoclax may be a viable treatment option for AML patients when used in combination with other therapies.
“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combinations with hypomethylating agents and other approaches,” said study author Marina Konopleva, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”
Protein promotes hematopoietic regeneration
Photo by Chad McNeeley
The protein angiogenin (ANG) plays a significant role in the regulation of hematopoiesis, according to a group of researchers.
The team discovered that ANG suppresses the proliferation of hematopoietic stem and progenitor cells (HSPCs) while promoting the proliferation of myeloid progenitor cells.
They also showed that treatment with recombinant ANG protein improved survival in irradiated mice and enhanced the regenerative capabilities of HSPCs.
The researchers believe these findings have significant implications for hematopoietic stem cell transplant (HSCT) and bone marrow injury.
The team reported the findings in Cell.
“We knew that ANG was involved in promoting cell growth, so it was not unexpected to find that ANG stimulates proliferation of myeloid progenitor cells,” said study author Guo-fu Hu, PhD, of Tufts Medical Center in Boston, Massachusetts.
“But it was surprising to find that ANG also suppresses growth of stem cells and that it accomplishes these divergent promotion or suppression functions through RNA processing events specific to individual cell types.”
The researchers discovered that, in HSPCs, ANG induces processing of tiRNA, which suppresses global protein synthesis. And in myeloid progenitor cells, ANG induces processing of rRNA, which enhances protein synthesis.
The team also tested ANG’s ability to prevent and mitigate radiation-induced bone marrow failure. They found that treating mice with recombinant ANG protein, either before or after lethal irradiation, increased survival, improved bone marrow cellularity, and enhanced peripheral blood content.
Finally, the researchers assessed the effects of ANG in the context of HSCT in mice. They found that treating mouse long-term HSCs with ANG ex vivo resulted in a “dramatic” increase in multi-lineage reconstitution over 24 weeks after HSCT.
Upon secondary transplant, enhanced regeneration occurred over 16 weeks, and mice had elevated peripheral blood counts at 1 year post-HSCT, without any signs of leukemia.
The researchers observed similar results in experiments with human cells. They transplanted CD34+ cord blood cells—cultured in the presence or absence of ANG—into mice. Treatment with ANG resulted in enhanced multi-lineage regeneration and enhanced reconstitution upon secondary transplant.
“Proper blood cell production is dependent on functioning hematopoietic stem and progenitor cells that are destroyed during conditioning procedures for transplantation or following bone marrow injury,” said study author Kevin A. Goncalves, of Tufts Medical Center.
“Our study demonstrates that ANG regulates critical functions of both clinically relevant cell types.”
Photo by Chad McNeeley
The protein angiogenin (ANG) plays a significant role in the regulation of hematopoiesis, according to a group of researchers.
The team discovered that ANG suppresses the proliferation of hematopoietic stem and progenitor cells (HSPCs) while promoting the proliferation of myeloid progenitor cells.
They also showed that treatment with recombinant ANG protein improved survival in irradiated mice and enhanced the regenerative capabilities of HSPCs.
The researchers believe these findings have significant implications for hematopoietic stem cell transplant (HSCT) and bone marrow injury.
The team reported the findings in Cell.
“We knew that ANG was involved in promoting cell growth, so it was not unexpected to find that ANG stimulates proliferation of myeloid progenitor cells,” said study author Guo-fu Hu, PhD, of Tufts Medical Center in Boston, Massachusetts.
“But it was surprising to find that ANG also suppresses growth of stem cells and that it accomplishes these divergent promotion or suppression functions through RNA processing events specific to individual cell types.”
The researchers discovered that, in HSPCs, ANG induces processing of tiRNA, which suppresses global protein synthesis. And in myeloid progenitor cells, ANG induces processing of rRNA, which enhances protein synthesis.
The team also tested ANG’s ability to prevent and mitigate radiation-induced bone marrow failure. They found that treating mice with recombinant ANG protein, either before or after lethal irradiation, increased survival, improved bone marrow cellularity, and enhanced peripheral blood content.
Finally, the researchers assessed the effects of ANG in the context of HSCT in mice. They found that treating mouse long-term HSCs with ANG ex vivo resulted in a “dramatic” increase in multi-lineage reconstitution over 24 weeks after HSCT.
Upon secondary transplant, enhanced regeneration occurred over 16 weeks, and mice had elevated peripheral blood counts at 1 year post-HSCT, without any signs of leukemia.
The researchers observed similar results in experiments with human cells. They transplanted CD34+ cord blood cells—cultured in the presence or absence of ANG—into mice. Treatment with ANG resulted in enhanced multi-lineage regeneration and enhanced reconstitution upon secondary transplant.
“Proper blood cell production is dependent on functioning hematopoietic stem and progenitor cells that are destroyed during conditioning procedures for transplantation or following bone marrow injury,” said study author Kevin A. Goncalves, of Tufts Medical Center.
“Our study demonstrates that ANG regulates critical functions of both clinically relevant cell types.”
Photo by Chad McNeeley
The protein angiogenin (ANG) plays a significant role in the regulation of hematopoiesis, according to a group of researchers.
The team discovered that ANG suppresses the proliferation of hematopoietic stem and progenitor cells (HSPCs) while promoting the proliferation of myeloid progenitor cells.
They also showed that treatment with recombinant ANG protein improved survival in irradiated mice and enhanced the regenerative capabilities of HSPCs.
The researchers believe these findings have significant implications for hematopoietic stem cell transplant (HSCT) and bone marrow injury.
The team reported the findings in Cell.
“We knew that ANG was involved in promoting cell growth, so it was not unexpected to find that ANG stimulates proliferation of myeloid progenitor cells,” said study author Guo-fu Hu, PhD, of Tufts Medical Center in Boston, Massachusetts.
“But it was surprising to find that ANG also suppresses growth of stem cells and that it accomplishes these divergent promotion or suppression functions through RNA processing events specific to individual cell types.”
The researchers discovered that, in HSPCs, ANG induces processing of tiRNA, which suppresses global protein synthesis. And in myeloid progenitor cells, ANG induces processing of rRNA, which enhances protein synthesis.
The team also tested ANG’s ability to prevent and mitigate radiation-induced bone marrow failure. They found that treating mice with recombinant ANG protein, either before or after lethal irradiation, increased survival, improved bone marrow cellularity, and enhanced peripheral blood content.
Finally, the researchers assessed the effects of ANG in the context of HSCT in mice. They found that treating mouse long-term HSCs with ANG ex vivo resulted in a “dramatic” increase in multi-lineage reconstitution over 24 weeks after HSCT.
Upon secondary transplant, enhanced regeneration occurred over 16 weeks, and mice had elevated peripheral blood counts at 1 year post-HSCT, without any signs of leukemia.
The researchers observed similar results in experiments with human cells. They transplanted CD34+ cord blood cells—cultured in the presence or absence of ANG—into mice. Treatment with ANG resulted in enhanced multi-lineage regeneration and enhanced reconstitution upon secondary transplant.
“Proper blood cell production is dependent on functioning hematopoietic stem and progenitor cells that are destroyed during conditioning procedures for transplantation or following bone marrow injury,” said study author Kevin A. Goncalves, of Tufts Medical Center.
“Our study demonstrates that ANG regulates critical functions of both clinically relevant cell types.”
Chemo during pregnancy may impact baby’s fertility
Photo by Nina Matthews
Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.
Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.
However, if the drug is given after ovarian follicles have developed, the damage is not significant.
The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.
“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.
“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”
Dr Spears and her colleagues reported these findings in BMC Cancer.
The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.
A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.
Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.
The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.
When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.
In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.
“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.
She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.
Photo by Nina Matthews
Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.
Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.
However, if the drug is given after ovarian follicles have developed, the damage is not significant.
The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.
“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.
“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”
Dr Spears and her colleagues reported these findings in BMC Cancer.
The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.
A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.
Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.
The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.
When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.
In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.
“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.
She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.
Photo by Nina Matthews
Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.
Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.
However, if the drug is given after ovarian follicles have developed, the damage is not significant.
The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.
“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.
“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”
Dr Spears and her colleagues reported these findings in BMC Cancer.
The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.
A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.
Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.
Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.
The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.
When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.
In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.
“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.
She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.