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Physical activity may cut death risk in male cancer survivors
Credit: Jason E. Miller
Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.
In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.
This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.
Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.
The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.
In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.
In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.
Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)
This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.
When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.
The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.
Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.
The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up. 
Credit: Jason E. Miller
Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.
In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.
This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.
Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.
The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.
In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.
In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.
Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)
This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.
When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.
The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.
Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.
The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.
Credit: Jason E. Miller
Physical activity may reduce the risk of mortality in male cancer survivors, according to research published in the Journal of Physical Activity & Health.
In a study of more than 1000 male cancer survivors, participants who were most active—expending more than 12,600 kilojoules per week in physical activity—cut their risk of death roughly in half.
This was in comparison to the least active cancer survivors—those who burned fewer than 2100 kilojoules per week.
Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, and her colleagues conducted this research using data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950.
The researchers looked at 1021 men, with an average age of 71, who had been diagnosed with cancers.
In 1988, the men completed questionnaires reporting their physical activities, including walking, stair-climbing, and participation in sports and recreational activities. Their physical activities were updated in 1993, and researchers followed the men until 2008.
In all, 777 of the men died—337 from cancer, 190 from cardiovascular disease, 228 from other causes, and 22 from unknown causes.
Compared with men who expended fewer than 2100 kilojoules per week in physical activity, men who expended more than 12,600 kilojoules per week were 48% less likely to die of any cause during the follow-up period. (Expending 12,600 kilojoules can be achieved with about 6 to 8 hours of moderate-intensity physical activity.)
This finding was adjusted for age, smoking habits, body mass index, early parental mortality, and dietary variables.
When the researchers tried to adjust for cancer severity and treatment, they were only able to collect data for 70 men. But the results were not very different from the prior analysis. The most active men were 49% less likely to die of any cause than the least active men.
The team also decided to analyze men who were diagnosed with cancer at least 5 years before baseline (n=421). And among these men, the most active were 52% less likely than the least active to die.
Similarly, among men diagnosed at least 10 years before baseline (n=262), the most active cancer survivors were 63% less likely to die of any cause than the least active survivors.
The researchers also obtained similar results when they assessed mortality from cancer and cardiovascular disease. The most physically active cancer survivors were 38% less likely to die of cancer and 49% less likely to die of cardiovascular disease during follow-up.
Ibrutinib trial stopped early
Credit: Steven Harbour
The phase 3 RESONATE study has been stopped early due to positive results in patients receiving ibrutinib.
In this trial, researchers compared the BTK inhibitor ibrutinib to the CD20-directed antibody ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
The study has ended early because 2 key endpoints were met—namely, ibrutinib significantly improved progression-free and overall survival rates.
The RESONATE study enrolled 391 patients with relapsed or refractory CLL or SLL with measurable nodal disease who were not eligible for treatment with purine-analog-based therapy. Patients had received at least 1 prior therapy.
The researchers randomized patients to receive 420 mg of ibrutinib orally once daily or intravenous doses of ofatumumab over the course of 24 weeks until disease progression or unacceptable toxicity.
At the planned interim analysis, ibrutinib had significantly improved progression-free survival (the primary endpoint) and overall survival (a secondary endpoint).
And the safety profile of ibrutinib was acceptable, according to the companies developing the drug (Pharmacyclics, Inc. and Janssen Research and Development, LLC).
Based on these results, an independent data monitoring committee recommended that patients in the ofatumumab arm be given access to ibrutinib.
Pharmacyclics has informed the US Food and Drug Administration of this recommendation, and Janssen has informed the European Medicines Agency. Both companies are in talks with the health authorities to define the next regulatory steps.
Pharmacyclics has said detailed data from the RESONATE study will be presented at an upcoming oncology conference.
Ibrutinib was recently approved by the US Food and Drug Administration to treat mantle cell lymphoma.
Credit: Steven Harbour
The phase 3 RESONATE study has been stopped early due to positive results in patients receiving ibrutinib.
In this trial, researchers compared the BTK inhibitor ibrutinib to the CD20-directed antibody ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
The study has ended early because 2 key endpoints were met—namely, ibrutinib significantly improved progression-free and overall survival rates.
The RESONATE study enrolled 391 patients with relapsed or refractory CLL or SLL with measurable nodal disease who were not eligible for treatment with purine-analog-based therapy. Patients had received at least 1 prior therapy.
The researchers randomized patients to receive 420 mg of ibrutinib orally once daily or intravenous doses of ofatumumab over the course of 24 weeks until disease progression or unacceptable toxicity.
At the planned interim analysis, ibrutinib had significantly improved progression-free survival (the primary endpoint) and overall survival (a secondary endpoint).
And the safety profile of ibrutinib was acceptable, according to the companies developing the drug (Pharmacyclics, Inc. and Janssen Research and Development, LLC).
Based on these results, an independent data monitoring committee recommended that patients in the ofatumumab arm be given access to ibrutinib.
Pharmacyclics has informed the US Food and Drug Administration of this recommendation, and Janssen has informed the European Medicines Agency. Both companies are in talks with the health authorities to define the next regulatory steps.
Pharmacyclics has said detailed data from the RESONATE study will be presented at an upcoming oncology conference.
Ibrutinib was recently approved by the US Food and Drug Administration to treat mantle cell lymphoma.
Credit: Steven Harbour
The phase 3 RESONATE study has been stopped early due to positive results in patients receiving ibrutinib.
In this trial, researchers compared the BTK inhibitor ibrutinib to the CD20-directed antibody ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
The study has ended early because 2 key endpoints were met—namely, ibrutinib significantly improved progression-free and overall survival rates.
The RESONATE study enrolled 391 patients with relapsed or refractory CLL or SLL with measurable nodal disease who were not eligible for treatment with purine-analog-based therapy. Patients had received at least 1 prior therapy.
The researchers randomized patients to receive 420 mg of ibrutinib orally once daily or intravenous doses of ofatumumab over the course of 24 weeks until disease progression or unacceptable toxicity.
At the planned interim analysis, ibrutinib had significantly improved progression-free survival (the primary endpoint) and overall survival (a secondary endpoint).
And the safety profile of ibrutinib was acceptable, according to the companies developing the drug (Pharmacyclics, Inc. and Janssen Research and Development, LLC).
Based on these results, an independent data monitoring committee recommended that patients in the ofatumumab arm be given access to ibrutinib.
Pharmacyclics has informed the US Food and Drug Administration of this recommendation, and Janssen has informed the European Medicines Agency. Both companies are in talks with the health authorities to define the next regulatory steps.
Pharmacyclics has said detailed data from the RESONATE study will be presented at an upcoming oncology conference.
Ibrutinib was recently approved by the US Food and Drug Administration to treat mantle cell lymphoma.
Mutation could be target for MDS/AML treatment
Scientists have found evidence to suggest that a genetic alteration in osteoblasts can induce acute myeloid leukemia (AML).
And this provides a potential therapeutic target for AML and myelodysplastic syndromes (MDS).
Stavroula Kousteni, PhD, of Columbia University Medical Center in New York, and her colleagues described these findings in Nature.
The researchers discovered that an activating mutation of beta-catenin in mouse osteoblasts induces AML.
This mutation leads to cancer in adjacent hematopoietic stem cells (HSCs) through a series of events. First, the mutated beta-catenin protein moves from its normal location on the exterior of the osteoblast to the cell’s nucleus, where it activates production of the protein jagged1.
Jagged1 proteins are then shipped to the osteoblast’s exterior membrane, where they can bind to Notch proteins—which activate signaling pathways—on neighboring HSCs. When this happens, Notch transmits signals inside the HSCs that enable leukemic transformation.
To confirm the role of jagged1 in AML development, the investigators removed 1 allele of jagged1 in osteoblasts. This decreased Notch signaling in Lin-Sca+c-Kit+ cells, rescued anemia and deregulation of HSC lineage differentiation, and prevented AML development.
The researchers then evaluated the effects of blocking Notch signaling using a gamma-secretase inhibitor. The treatment reversed hematopoietic deregulation and myeloid expansion in the blood, marrow, and spleens of the mice and reversed their AML.
“If the [process] works the same way in humans, our study suggests practical ways that we may be able to intervene with a drug or an antibody,” Dr Kousteni said.
With this in mind, she and her colleagues analyzed cells from 107 patients with AML or MDS. About 38% of the patients had changes in beta-catenin, jagged1, and Notch signaling that mirrored the changes in the mice. But none of the 56 healthy control subjects studied had these changes.
The investigators therefore concluded that these findings provide new insight into AML/MDS pathogenesis and may have implications for treatment.
Scientists have found evidence to suggest that a genetic alteration in osteoblasts can induce acute myeloid leukemia (AML).
And this provides a potential therapeutic target for AML and myelodysplastic syndromes (MDS).
Stavroula Kousteni, PhD, of Columbia University Medical Center in New York, and her colleagues described these findings in Nature.
The researchers discovered that an activating mutation of beta-catenin in mouse osteoblasts induces AML.
This mutation leads to cancer in adjacent hematopoietic stem cells (HSCs) through a series of events. First, the mutated beta-catenin protein moves from its normal location on the exterior of the osteoblast to the cell’s nucleus, where it activates production of the protein jagged1.
Jagged1 proteins are then shipped to the osteoblast’s exterior membrane, where they can bind to Notch proteins—which activate signaling pathways—on neighboring HSCs. When this happens, Notch transmits signals inside the HSCs that enable leukemic transformation.
To confirm the role of jagged1 in AML development, the investigators removed 1 allele of jagged1 in osteoblasts. This decreased Notch signaling in Lin-Sca+c-Kit+ cells, rescued anemia and deregulation of HSC lineage differentiation, and prevented AML development.
The researchers then evaluated the effects of blocking Notch signaling using a gamma-secretase inhibitor. The treatment reversed hematopoietic deregulation and myeloid expansion in the blood, marrow, and spleens of the mice and reversed their AML.
“If the [process] works the same way in humans, our study suggests practical ways that we may be able to intervene with a drug or an antibody,” Dr Kousteni said.
With this in mind, she and her colleagues analyzed cells from 107 patients with AML or MDS. About 38% of the patients had changes in beta-catenin, jagged1, and Notch signaling that mirrored the changes in the mice. But none of the 56 healthy control subjects studied had these changes.
The investigators therefore concluded that these findings provide new insight into AML/MDS pathogenesis and may have implications for treatment.
Scientists have found evidence to suggest that a genetic alteration in osteoblasts can induce acute myeloid leukemia (AML).
And this provides a potential therapeutic target for AML and myelodysplastic syndromes (MDS).
Stavroula Kousteni, PhD, of Columbia University Medical Center in New York, and her colleagues described these findings in Nature.
The researchers discovered that an activating mutation of beta-catenin in mouse osteoblasts induces AML.
This mutation leads to cancer in adjacent hematopoietic stem cells (HSCs) through a series of events. First, the mutated beta-catenin protein moves from its normal location on the exterior of the osteoblast to the cell’s nucleus, where it activates production of the protein jagged1.
Jagged1 proteins are then shipped to the osteoblast’s exterior membrane, where they can bind to Notch proteins—which activate signaling pathways—on neighboring HSCs. When this happens, Notch transmits signals inside the HSCs that enable leukemic transformation.
To confirm the role of jagged1 in AML development, the investigators removed 1 allele of jagged1 in osteoblasts. This decreased Notch signaling in Lin-Sca+c-Kit+ cells, rescued anemia and deregulation of HSC lineage differentiation, and prevented AML development.
The researchers then evaluated the effects of blocking Notch signaling using a gamma-secretase inhibitor. The treatment reversed hematopoietic deregulation and myeloid expansion in the blood, marrow, and spleens of the mice and reversed their AML.
“If the [process] works the same way in humans, our study suggests practical ways that we may be able to intervene with a drug or an antibody,” Dr Kousteni said.
With this in mind, she and her colleagues analyzed cells from 107 patients with AML or MDS. About 38% of the patients had changes in beta-catenin, jagged1, and Notch signaling that mirrored the changes in the mice. But none of the 56 healthy control subjects studied had these changes.
The investigators therefore concluded that these findings provide new insight into AML/MDS pathogenesis and may have implications for treatment.
Adding idelalisib improves CLL treatment
The PI3K delta inhibitor idelalisib could turn chronic lymphocytic leukemia (CLL) into a highly treatable disease, according to the lead investigator of a phase 3 trial.
Results of the trial showed that adding idelalisib to treatment with rituximab can improve response and survival rates in patients with relapsed CLL.
In fact, the study was stopped early because idelalisib had a significant impact on progression-free survival.
“This study, and others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL,” said lead investigator Richard R. Furman, MD, of Weill Cornell Medical College in New York.
“Even if this cancer remains incurable, it now can be treated as if it was a chronic disease—with a pill, in the same way that high blood pressure is treated.”
Dr Furman and his colleagues reported the results of this study in The New England Journal of Medicine.
The trial was funded by Gilead, the makers of idelalisib. Dr Furman has served as an advisor for this company.
The study included 220 CLL patients who could not receive chemotherapy. Nearly two-thirds of the patients had advanced-stage disease. The median time from CLL diagnosis was 9 years, and patients had received a median of 3 previous treatments.
Most of the patients were 65 or older (78%). Forty percent had at least moderate renal dysfunction, and 35% had poor bone marrow function.
Half of the patients were randomized to receive idelalisib plus rituximab and the other half to rituximab plus placebo.
“It is remarkable how quickly idelalisib worked in this heavily treated group of patients, many of whom were resistant to chemotherapy,” Dr Furman said. “We saw responses within a week.”
Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.
At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).
And at 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).
The difference in outcomes between the treatment groups prompted an independent data-monitoring committee to halt the study early, in October 2013, so that all participants could receive idelalisib.
Most adverse events (AEs), in either treatment group, were grade 2 or lower. The most common AEs in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common AEs were infusion-related reactions, fatigue, cough, nausea, and dyspnea.
There were more serious AEs in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious AEs were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).
Despite these events, the researchers considered idelalisib to be well-tolerated in this patient population.
“Having a treatment like idelalisib, which is highly effective and well-tolerated, and thus can generate responses in patients that are unable to tolerate treatment and unlikely to respond, indicates the potential for idelalisib in all patients,” Dr Furman said.
The PI3K delta inhibitor idelalisib could turn chronic lymphocytic leukemia (CLL) into a highly treatable disease, according to the lead investigator of a phase 3 trial.
Results of the trial showed that adding idelalisib to treatment with rituximab can improve response and survival rates in patients with relapsed CLL.
In fact, the study was stopped early because idelalisib had a significant impact on progression-free survival.
“This study, and others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL,” said lead investigator Richard R. Furman, MD, of Weill Cornell Medical College in New York.
“Even if this cancer remains incurable, it now can be treated as if it was a chronic disease—with a pill, in the same way that high blood pressure is treated.”
Dr Furman and his colleagues reported the results of this study in The New England Journal of Medicine.
The trial was funded by Gilead, the makers of idelalisib. Dr Furman has served as an advisor for this company.
The study included 220 CLL patients who could not receive chemotherapy. Nearly two-thirds of the patients had advanced-stage disease. The median time from CLL diagnosis was 9 years, and patients had received a median of 3 previous treatments.
Most of the patients were 65 or older (78%). Forty percent had at least moderate renal dysfunction, and 35% had poor bone marrow function.
Half of the patients were randomized to receive idelalisib plus rituximab and the other half to rituximab plus placebo.
“It is remarkable how quickly idelalisib worked in this heavily treated group of patients, many of whom were resistant to chemotherapy,” Dr Furman said. “We saw responses within a week.”
Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.
At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).
And at 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).
The difference in outcomes between the treatment groups prompted an independent data-monitoring committee to halt the study early, in October 2013, so that all participants could receive idelalisib.
Most adverse events (AEs), in either treatment group, were grade 2 or lower. The most common AEs in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common AEs were infusion-related reactions, fatigue, cough, nausea, and dyspnea.
There were more serious AEs in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious AEs were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).
Despite these events, the researchers considered idelalisib to be well-tolerated in this patient population.
“Having a treatment like idelalisib, which is highly effective and well-tolerated, and thus can generate responses in patients that are unable to tolerate treatment and unlikely to respond, indicates the potential for idelalisib in all patients,” Dr Furman said.
The PI3K delta inhibitor idelalisib could turn chronic lymphocytic leukemia (CLL) into a highly treatable disease, according to the lead investigator of a phase 3 trial.
Results of the trial showed that adding idelalisib to treatment with rituximab can improve response and survival rates in patients with relapsed CLL.
In fact, the study was stopped early because idelalisib had a significant impact on progression-free survival.
“This study, and others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL,” said lead investigator Richard R. Furman, MD, of Weill Cornell Medical College in New York.
“Even if this cancer remains incurable, it now can be treated as if it was a chronic disease—with a pill, in the same way that high blood pressure is treated.”
Dr Furman and his colleagues reported the results of this study in The New England Journal of Medicine.
The trial was funded by Gilead, the makers of idelalisib. Dr Furman has served as an advisor for this company.
The study included 220 CLL patients who could not receive chemotherapy. Nearly two-thirds of the patients had advanced-stage disease. The median time from CLL diagnosis was 9 years, and patients had received a median of 3 previous treatments.
Most of the patients were 65 or older (78%). Forty percent had at least moderate renal dysfunction, and 35% had poor bone marrow function.
Half of the patients were randomized to receive idelalisib plus rituximab and the other half to rituximab plus placebo.
“It is remarkable how quickly idelalisib worked in this heavily treated group of patients, many of whom were resistant to chemotherapy,” Dr Furman said. “We saw responses within a week.”
Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.
At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).
And at 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).
The difference in outcomes between the treatment groups prompted an independent data-monitoring committee to halt the study early, in October 2013, so that all participants could receive idelalisib.
Most adverse events (AEs), in either treatment group, were grade 2 or lower. The most common AEs in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common AEs were infusion-related reactions, fatigue, cough, nausea, and dyspnea.
There were more serious AEs in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious AEs were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).
Despite these events, the researchers considered idelalisib to be well-tolerated in this patient population.
“Having a treatment like idelalisib, which is highly effective and well-tolerated, and thus can generate responses in patients that are unable to tolerate treatment and unlikely to respond, indicates the potential for idelalisib in all patients,” Dr Furman said.
ACA exchanges limiting for patients with blood cancers, report suggests
Credit: CDC
A new report suggests that many health plans in the insurance exchanges mandated by the Affordable Care Act (ACA) will impose high out-of-pocket costs for patients with hematologic malignancies and provide limited access to specialty treatment centers.
Furthermore, although the plans analyzed appear to provide adequate coverage of hematology/oncology drugs, most require prior authorization.
In other words, the insurer must be notified and may not approve the purchase of a drug based on medical evidence or other criteria.
This report, “2014 Individual Exchange Policies in Four States: An Early Look for Patients with Blood Cancers,” was commissioned by the Leukemia & Lymphoma Society and prepared by Milliman, Inc.
It provides a look at the 2014 individual benefit designs, coverage benefits, and premiums for policies sold on 4 state health insurance exchanges—California, New York, Florida, and Texas—with a focus on items of interest for patients with hematologic malignancies.
“[W]hile many new rules under ACA make obtaining insurance easier for people with blood cancers, such as prohibiting companies from turning away patients with pre-existing conditions and eliminating lifetime coverage limitations, the Milliman report identifies several areas of concern that we want cancer patients to be aware of and policymakers to address,” said Mark Velleca, MD, PhD, chief policy and advocacy officer of the Leukemia & Lymphoma Society.
Premium costs
To compare monthly premium rates, the report’s authors captured rates for a 50-year-old non-smoker with an annual income of $90,000 residing in Houston, Los Angeles, Miami, or New York City.
They found considerable variation according to plan type and location, but overall, plans were cheapest in Houston. Monthly premiums for Houston ranged from $234 to $520. The range was $274 to $566 for Los Angeles, $277 to $635 for Miami, and $307 to $896 for New York.
The ranges reflect the costs according to plan type. Each insurer offers 4 different health plans: Platinum (about 10% cost-sharing), Gold (roughly 20%), Silver (roughly 30%), and Bronze (roughly 40%).
Cost-sharing
The authors noted that the lower-tier Bronze and Silver plans require significant cost-sharing for patients. The report revealed high deductibles in the health plans, sometimes nearly as high as the out-of-pocket ceiling.
Deductibles for the Silver and Bronze plans are often at least $2000 and $4000, respectively, for individuals. The maximum out-of-pocket limits set for 2014 are $6350 for an individual policy and $12,799 for a family policy.
Some insurers offer plans in some states with lower out-of-pocket limits. However, the out-of-pocket limit does not apply to non-covered drugs or treatment centers.
Drug coverage
When analyzing drug coverage, the authors decided to look at 3 drugs used to treat chronic myeloid leukemia—imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel)—and 5 drugs used to treat multiple myeloma—thalidomide (Thalomid), lenalidomide (Revlimid), pomalidomide (Pomalyst), cyclophosphamide (Cytoxan), and melphalan (Alkeran).
Most of the insurers require prior authorization for these drugs, but most of them cover all 3 chronic myeloid leukemia drugs and a majority of the myeloma drugs. Pomalyst and Cytoxan are often not covered, although most insurers do cover generic cyclophosphamide.
Network adequacy
Most of the insurers studied do not cover all NCI-designated cancer and transplant centers, and a few do not cover any of these centers. The authors said this could discourage patient enrollment in these plans or mean that a patient’s recommended treatment is not covered.
And since it is unlikely that any out-of-network expenses will count toward a patient’s out-of-pocket maximum, cancer patients could accumulate thousands of dollars of medical expenses and never reach their out-of-pocket maximum.
The authors did note, however, that satisfactory cancer care can be provided outside of NCI-designated cancer and transplant centers.
For more details, see the full report.
Credit: CDC
A new report suggests that many health plans in the insurance exchanges mandated by the Affordable Care Act (ACA) will impose high out-of-pocket costs for patients with hematologic malignancies and provide limited access to specialty treatment centers.
Furthermore, although the plans analyzed appear to provide adequate coverage of hematology/oncology drugs, most require prior authorization.
In other words, the insurer must be notified and may not approve the purchase of a drug based on medical evidence or other criteria.
This report, “2014 Individual Exchange Policies in Four States: An Early Look for Patients with Blood Cancers,” was commissioned by the Leukemia & Lymphoma Society and prepared by Milliman, Inc.
It provides a look at the 2014 individual benefit designs, coverage benefits, and premiums for policies sold on 4 state health insurance exchanges—California, New York, Florida, and Texas—with a focus on items of interest for patients with hematologic malignancies.
“[W]hile many new rules under ACA make obtaining insurance easier for people with blood cancers, such as prohibiting companies from turning away patients with pre-existing conditions and eliminating lifetime coverage limitations, the Milliman report identifies several areas of concern that we want cancer patients to be aware of and policymakers to address,” said Mark Velleca, MD, PhD, chief policy and advocacy officer of the Leukemia & Lymphoma Society.
Premium costs
To compare monthly premium rates, the report’s authors captured rates for a 50-year-old non-smoker with an annual income of $90,000 residing in Houston, Los Angeles, Miami, or New York City.
They found considerable variation according to plan type and location, but overall, plans were cheapest in Houston. Monthly premiums for Houston ranged from $234 to $520. The range was $274 to $566 for Los Angeles, $277 to $635 for Miami, and $307 to $896 for New York.
The ranges reflect the costs according to plan type. Each insurer offers 4 different health plans: Platinum (about 10% cost-sharing), Gold (roughly 20%), Silver (roughly 30%), and Bronze (roughly 40%).
Cost-sharing
The authors noted that the lower-tier Bronze and Silver plans require significant cost-sharing for patients. The report revealed high deductibles in the health plans, sometimes nearly as high as the out-of-pocket ceiling.
Deductibles for the Silver and Bronze plans are often at least $2000 and $4000, respectively, for individuals. The maximum out-of-pocket limits set for 2014 are $6350 for an individual policy and $12,799 for a family policy.
Some insurers offer plans in some states with lower out-of-pocket limits. However, the out-of-pocket limit does not apply to non-covered drugs or treatment centers.
Drug coverage
When analyzing drug coverage, the authors decided to look at 3 drugs used to treat chronic myeloid leukemia—imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel)—and 5 drugs used to treat multiple myeloma—thalidomide (Thalomid), lenalidomide (Revlimid), pomalidomide (Pomalyst), cyclophosphamide (Cytoxan), and melphalan (Alkeran).
Most of the insurers require prior authorization for these drugs, but most of them cover all 3 chronic myeloid leukemia drugs and a majority of the myeloma drugs. Pomalyst and Cytoxan are often not covered, although most insurers do cover generic cyclophosphamide.
Network adequacy
Most of the insurers studied do not cover all NCI-designated cancer and transplant centers, and a few do not cover any of these centers. The authors said this could discourage patient enrollment in these plans or mean that a patient’s recommended treatment is not covered.
And since it is unlikely that any out-of-network expenses will count toward a patient’s out-of-pocket maximum, cancer patients could accumulate thousands of dollars of medical expenses and never reach their out-of-pocket maximum.
The authors did note, however, that satisfactory cancer care can be provided outside of NCI-designated cancer and transplant centers.
For more details, see the full report.
Credit: CDC
A new report suggests that many health plans in the insurance exchanges mandated by the Affordable Care Act (ACA) will impose high out-of-pocket costs for patients with hematologic malignancies and provide limited access to specialty treatment centers.
Furthermore, although the plans analyzed appear to provide adequate coverage of hematology/oncology drugs, most require prior authorization.
In other words, the insurer must be notified and may not approve the purchase of a drug based on medical evidence or other criteria.
This report, “2014 Individual Exchange Policies in Four States: An Early Look for Patients with Blood Cancers,” was commissioned by the Leukemia & Lymphoma Society and prepared by Milliman, Inc.
It provides a look at the 2014 individual benefit designs, coverage benefits, and premiums for policies sold on 4 state health insurance exchanges—California, New York, Florida, and Texas—with a focus on items of interest for patients with hematologic malignancies.
“[W]hile many new rules under ACA make obtaining insurance easier for people with blood cancers, such as prohibiting companies from turning away patients with pre-existing conditions and eliminating lifetime coverage limitations, the Milliman report identifies several areas of concern that we want cancer patients to be aware of and policymakers to address,” said Mark Velleca, MD, PhD, chief policy and advocacy officer of the Leukemia & Lymphoma Society.
Premium costs
To compare monthly premium rates, the report’s authors captured rates for a 50-year-old non-smoker with an annual income of $90,000 residing in Houston, Los Angeles, Miami, or New York City.
They found considerable variation according to plan type and location, but overall, plans were cheapest in Houston. Monthly premiums for Houston ranged from $234 to $520. The range was $274 to $566 for Los Angeles, $277 to $635 for Miami, and $307 to $896 for New York.
The ranges reflect the costs according to plan type. Each insurer offers 4 different health plans: Platinum (about 10% cost-sharing), Gold (roughly 20%), Silver (roughly 30%), and Bronze (roughly 40%).
Cost-sharing
The authors noted that the lower-tier Bronze and Silver plans require significant cost-sharing for patients. The report revealed high deductibles in the health plans, sometimes nearly as high as the out-of-pocket ceiling.
Deductibles for the Silver and Bronze plans are often at least $2000 and $4000, respectively, for individuals. The maximum out-of-pocket limits set for 2014 are $6350 for an individual policy and $12,799 for a family policy.
Some insurers offer plans in some states with lower out-of-pocket limits. However, the out-of-pocket limit does not apply to non-covered drugs or treatment centers.
Drug coverage
When analyzing drug coverage, the authors decided to look at 3 drugs used to treat chronic myeloid leukemia—imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel)—and 5 drugs used to treat multiple myeloma—thalidomide (Thalomid), lenalidomide (Revlimid), pomalidomide (Pomalyst), cyclophosphamide (Cytoxan), and melphalan (Alkeran).
Most of the insurers require prior authorization for these drugs, but most of them cover all 3 chronic myeloid leukemia drugs and a majority of the myeloma drugs. Pomalyst and Cytoxan are often not covered, although most insurers do cover generic cyclophosphamide.
Network adequacy
Most of the insurers studied do not cover all NCI-designated cancer and transplant centers, and a few do not cover any of these centers. The authors said this could discourage patient enrollment in these plans or mean that a patient’s recommended treatment is not covered.
And since it is unlikely that any out-of-network expenses will count toward a patient’s out-of-pocket maximum, cancer patients could accumulate thousands of dollars of medical expenses and never reach their out-of-pocket maximum.
The authors did note, however, that satisfactory cancer care can be provided outside of NCI-designated cancer and transplant centers.
For more details, see the full report.
Ponatinib back on the market
Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.
Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.
The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).
Safety concerns prompt action
Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.
Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.
The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.
Now, ponatinib is indicated for the treatment of:
- Adults with T315I-positive CML (chronic, accelerated, or blast phase)
- Adults with T315I-positive Ph+ ALL
- Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
- Adults with Ph+ ALL who cannot receive another TKI.
The starting dose of ponatinib remains 45 mg daily.
IND program
On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.
The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.
Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.
Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.
Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.
Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.
The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).
Safety concerns prompt action
Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.
Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.
The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.
Now, ponatinib is indicated for the treatment of:
- Adults with T315I-positive CML (chronic, accelerated, or blast phase)
- Adults with T315I-positive Ph+ ALL
- Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
- Adults with Ph+ ALL who cannot receive another TKI.
The starting dose of ponatinib remains 45 mg daily.
IND program
On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.
The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.
Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.
Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.
Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.
Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.
The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).
Safety concerns prompt action
Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.
Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.
The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.
Now, ponatinib is indicated for the treatment of:
- Adults with T315I-positive CML (chronic, accelerated, or blast phase)
- Adults with T315I-positive Ph+ ALL
- Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
- Adults with Ph+ ALL who cannot receive another TKI.
The starting dose of ponatinib remains 45 mg daily.
IND program
On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.
The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.
Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.
Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.
Histone discovery may have implications for blood cancers
Credit: Eric Smith
Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.
And this finding could have implications for the treatment of leukemias and lymphomas.
Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.
Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.
Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.
Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.
But how the methylase’s activity was directed toward the appropriate targets was unclear.
Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.
The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.
The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.
“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”
Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.
The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.
This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.
But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.
The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.
Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.
In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.
The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.
The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.
The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.
Credit: Eric Smith
Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.
And this finding could have implications for the treatment of leukemias and lymphomas.
Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.
Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.
Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.
Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.
But how the methylase’s activity was directed toward the appropriate targets was unclear.
Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.
The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.
The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.
“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”
Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.
The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.
This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.
But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.
The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.
Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.
In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.
The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.
The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.
The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.
Credit: Eric Smith
Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.
And this finding could have implications for the treatment of leukemias and lymphomas.
Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.
Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.
Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.
Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.
But how the methylase’s activity was directed toward the appropriate targets was unclear.
Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.
The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.
The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.
“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”
Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.
The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.
This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.
But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.
The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.
Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.
In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.
The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.
The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.
The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.
Case raises questions about BRAF inhibitor’s mechanism
Credit: University of Leicester
Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.
The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.
Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).
But new results in a patient with HCL suggest otherwise.
Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.
The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.
They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.
But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.
“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”
The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.
A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.
“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.
Credit: University of Leicester
Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.
The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.
Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).
But new results in a patient with HCL suggest otherwise.
Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.
The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.
They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.
But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.
“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”
The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.
A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.
“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.
Credit: University of Leicester
Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.
The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.
Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).
But new results in a patient with HCL suggest otherwise.
Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.
The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.
They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.
But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.
“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”
The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.
A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.
“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.
Group discovers how drugs fight APL
Credit: The Armed Forces
Institute of Pathology
Results of a new study appear to explain how retinoic acid and arsenic trioxide work against acute promyelocytic leukemia (APL).
Researchers found that retinoic acid, either alone or in combination with arsenic trioxide, causes a cascade of molecular events that lead to cellular senescence.
And this halts APL-initiating activity in patient samples and mouse models of the disease.
The team said this mechanism could be activated to fight malignancies other than APL as well.
Hugues de Thé, MD, PhD, of Université Paris Diderot in France, and his colleagues described this research in Nature Medicine.
The group knew that APL is driven by the promyelocytic leukemia-retinoic acid receptor fusion protein (PML-RARA), which interferes with nuclear receptor signaling and PML nuclear body assembly.
Furthermore, APL can be cured by retinoic acid and arsenic trioxide (alone or in combination), both of which trigger PML-RARA degradation through non-overlapping pathways.
However, exactly how these treatments work in APL has been unclear. Dr de Thé’s research indicates that both drugs incite a cascade of events leading to senescence.
The researchers found evidence suggesting that a functional PML-transformation-related protein 53 (Trp53) axis is required to halt APL-initiating activity.
When retinoic acid induces PML-RARA degradation, normal PML elicits nuclear body reformation and prompts a Trp53 response that exhibits features of senescence. And this halts APL-initiating activity.
In addition, normal PML seems to play a role in the synergy between retinoic acid and arsenic trioxide. The researchers discovered that arsenic increases retinoic acid-induced PML-RARA degradation.
But arsenic also appears to cooperate with retinoic acid to cure APL by binding PML, accelerating nuclear body reformation, and enhancing downstream TP53 signaling.
The researchers said it seems likely that the same PML/p53 pathway can be activated in cancers other than PML as well.
Credit: The Armed Forces
Institute of Pathology
Results of a new study appear to explain how retinoic acid and arsenic trioxide work against acute promyelocytic leukemia (APL).
Researchers found that retinoic acid, either alone or in combination with arsenic trioxide, causes a cascade of molecular events that lead to cellular senescence.
And this halts APL-initiating activity in patient samples and mouse models of the disease.
The team said this mechanism could be activated to fight malignancies other than APL as well.
Hugues de Thé, MD, PhD, of Université Paris Diderot in France, and his colleagues described this research in Nature Medicine.
The group knew that APL is driven by the promyelocytic leukemia-retinoic acid receptor fusion protein (PML-RARA), which interferes with nuclear receptor signaling and PML nuclear body assembly.
Furthermore, APL can be cured by retinoic acid and arsenic trioxide (alone or in combination), both of which trigger PML-RARA degradation through non-overlapping pathways.
However, exactly how these treatments work in APL has been unclear. Dr de Thé’s research indicates that both drugs incite a cascade of events leading to senescence.
The researchers found evidence suggesting that a functional PML-transformation-related protein 53 (Trp53) axis is required to halt APL-initiating activity.
When retinoic acid induces PML-RARA degradation, normal PML elicits nuclear body reformation and prompts a Trp53 response that exhibits features of senescence. And this halts APL-initiating activity.
In addition, normal PML seems to play a role in the synergy between retinoic acid and arsenic trioxide. The researchers discovered that arsenic increases retinoic acid-induced PML-RARA degradation.
But arsenic also appears to cooperate with retinoic acid to cure APL by binding PML, accelerating nuclear body reformation, and enhancing downstream TP53 signaling.
The researchers said it seems likely that the same PML/p53 pathway can be activated in cancers other than PML as well.
Credit: The Armed Forces
Institute of Pathology
Results of a new study appear to explain how retinoic acid and arsenic trioxide work against acute promyelocytic leukemia (APL).
Researchers found that retinoic acid, either alone or in combination with arsenic trioxide, causes a cascade of molecular events that lead to cellular senescence.
And this halts APL-initiating activity in patient samples and mouse models of the disease.
The team said this mechanism could be activated to fight malignancies other than APL as well.
Hugues de Thé, MD, PhD, of Université Paris Diderot in France, and his colleagues described this research in Nature Medicine.
The group knew that APL is driven by the promyelocytic leukemia-retinoic acid receptor fusion protein (PML-RARA), which interferes with nuclear receptor signaling and PML nuclear body assembly.
Furthermore, APL can be cured by retinoic acid and arsenic trioxide (alone or in combination), both of which trigger PML-RARA degradation through non-overlapping pathways.
However, exactly how these treatments work in APL has been unclear. Dr de Thé’s research indicates that both drugs incite a cascade of events leading to senescence.
The researchers found evidence suggesting that a functional PML-transformation-related protein 53 (Trp53) axis is required to halt APL-initiating activity.
When retinoic acid induces PML-RARA degradation, normal PML elicits nuclear body reformation and prompts a Trp53 response that exhibits features of senescence. And this halts APL-initiating activity.
In addition, normal PML seems to play a role in the synergy between retinoic acid and arsenic trioxide. The researchers discovered that arsenic increases retinoic acid-induced PML-RARA degradation.
But arsenic also appears to cooperate with retinoic acid to cure APL by binding PML, accelerating nuclear body reformation, and enhancing downstream TP53 signaling.
The researchers said it seems likely that the same PML/p53 pathway can be activated in cancers other than PML as well.
Compound active against a range of cancers
expressing NFAT3c-GFP
A little-studied chemical compound has “wide and potent” anticancer activity, investigators have reported in Cancer Cell.
The compound, BMH-21, works by inhibiting the RNA polymerase transcription pathway (Pol I), thereby preventing cancer cell communication and replication.
“Without this transcription machinery, cancer cells cannot function,” said study author Marikki Laiho, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.
She and her colleagues homed in on BMH-21 by screening a library of chemical compounds thought to have potential for anticancer activity.
Specifically, the team looked at the compounds’ ability to interfere with transcription in the National Cancer Institute’s collection of 60 human tumor cell lines (known as NCI-60).
BMH-21 demonstrated activity against all 9 cancer types studied—leukemia and melanoma, as well as breast, CNS, colon, lung, ovarian, prostate, and renal cancers.
The drug also repressed tumor growth in mouse models of colon cancer and melanoma.
Additional analyses showed that BMH-21 inhibited Pol I transcription and caused disintegration of the nucleolus. The drug activated loss of the Pol I catalytic subunit RPA194, which led to disassembly of the Pol I holocomplex from the ribosomal DNA.
And the loss of RPA194, which was a result of increased proteasome-mediated turnover, was associated with decreased cancer cell viability.
Dr Laiho and her colleagues are continuing studies of BMH-21 in animal models to confirm the drug’s anticancer activity, identify any toxicities associated with the compound, and determine the optimal dose.
And because Pol I activity is frequently deregulated in cancers, the investigators believe BMH-21 could have therapeutic potential for many malignancies.
Dr Laiho is currently collaborating with experts in multiple myeloma, medullary thyroid cancer, and prostate cancer to explore the drug’s activity in these malignancies.
expressing NFAT3c-GFP
A little-studied chemical compound has “wide and potent” anticancer activity, investigators have reported in Cancer Cell.
The compound, BMH-21, works by inhibiting the RNA polymerase transcription pathway (Pol I), thereby preventing cancer cell communication and replication.
“Without this transcription machinery, cancer cells cannot function,” said study author Marikki Laiho, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.
She and her colleagues homed in on BMH-21 by screening a library of chemical compounds thought to have potential for anticancer activity.
Specifically, the team looked at the compounds’ ability to interfere with transcription in the National Cancer Institute’s collection of 60 human tumor cell lines (known as NCI-60).
BMH-21 demonstrated activity against all 9 cancer types studied—leukemia and melanoma, as well as breast, CNS, colon, lung, ovarian, prostate, and renal cancers.
The drug also repressed tumor growth in mouse models of colon cancer and melanoma.
Additional analyses showed that BMH-21 inhibited Pol I transcription and caused disintegration of the nucleolus. The drug activated loss of the Pol I catalytic subunit RPA194, which led to disassembly of the Pol I holocomplex from the ribosomal DNA.
And the loss of RPA194, which was a result of increased proteasome-mediated turnover, was associated with decreased cancer cell viability.
Dr Laiho and her colleagues are continuing studies of BMH-21 in animal models to confirm the drug’s anticancer activity, identify any toxicities associated with the compound, and determine the optimal dose.
And because Pol I activity is frequently deregulated in cancers, the investigators believe BMH-21 could have therapeutic potential for many malignancies.
Dr Laiho is currently collaborating with experts in multiple myeloma, medullary thyroid cancer, and prostate cancer to explore the drug’s activity in these malignancies.
expressing NFAT3c-GFP
A little-studied chemical compound has “wide and potent” anticancer activity, investigators have reported in Cancer Cell.
The compound, BMH-21, works by inhibiting the RNA polymerase transcription pathway (Pol I), thereby preventing cancer cell communication and replication.
“Without this transcription machinery, cancer cells cannot function,” said study author Marikki Laiho, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.
She and her colleagues homed in on BMH-21 by screening a library of chemical compounds thought to have potential for anticancer activity.
Specifically, the team looked at the compounds’ ability to interfere with transcription in the National Cancer Institute’s collection of 60 human tumor cell lines (known as NCI-60).
BMH-21 demonstrated activity against all 9 cancer types studied—leukemia and melanoma, as well as breast, CNS, colon, lung, ovarian, prostate, and renal cancers.
The drug also repressed tumor growth in mouse models of colon cancer and melanoma.
Additional analyses showed that BMH-21 inhibited Pol I transcription and caused disintegration of the nucleolus. The drug activated loss of the Pol I catalytic subunit RPA194, which led to disassembly of the Pol I holocomplex from the ribosomal DNA.
And the loss of RPA194, which was a result of increased proteasome-mediated turnover, was associated with decreased cancer cell viability.
Dr Laiho and her colleagues are continuing studies of BMH-21 in animal models to confirm the drug’s anticancer activity, identify any toxicities associated with the compound, and determine the optimal dose.
And because Pol I activity is frequently deregulated in cancers, the investigators believe BMH-21 could have therapeutic potential for many malignancies.
Dr Laiho is currently collaborating with experts in multiple myeloma, medullary thyroid cancer, and prostate cancer to explore the drug’s activity in these malignancies.