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Encapsulating doxorubicin can reduce heart damage
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Disordered methylation compromises CLL treatment
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
CLL drug can fight AML too, study suggests
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
PFS improvement will translate to OS, speaker says
SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.
The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.
The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.
Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.
Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.
Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.
“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”
Efficacy/survival results
About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).
Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).
The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.
The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.
The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.
Patients who experienced disease progression received a variety of subsequent therapies.
In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.
Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.
He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).
“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”
Dr Moskowitz said another analysis of OS is planned in 2016.
Safety data
The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).
The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).
Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.
Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.
Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.
One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.
Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.
Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.
He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”
SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.
The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.
The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.
Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.
Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.
Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.
“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”
Efficacy/survival results
About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).
Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).
The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.
The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.
The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.
Patients who experienced disease progression received a variety of subsequent therapies.
In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.
Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.
He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).
“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”
Dr Moskowitz said another analysis of OS is planned in 2016.
Safety data
The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).
The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).
Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.
Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.
Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.
One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.
Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.
Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.
He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”
SAN FRANCISCO—Administering brentuximab vedotin immediately after autologous stem cell transplant can improve progression-free survival (PFS) in patients with Hodgkin lymphoma (HL), results of the phase 3 AETHERA trial suggest.
The overall survival (OS) data for this study are not yet mature, but the significant improvement in PFS will likely translate to improved OS in a few years’ time, according to Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr Moskowitz presented results from the AETHERA trial at the 2014 ASH Annual Meeting as abstract 673. The trial was funded by Seattle Genetics, Inc., and Takeda Pharmaceutical Company Limited, the companies developing brentuximab.
The trial included HL patients with at least one risk factor for progression. Eligible patients must have had a history of refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-transplant relapse.
Researchers enrolled 329 patients, and they were randomized to receive brentuximab or placebo every 3 weeks for up to about a year. Baseline characteristics were similar between the 2 arms.
Dr Moskowitz pointed out that 43% of patients in the brentuximab arm and 48% in the placebo arm had required 2 or more prior salvage therapies, and 60% and 59%, respectively, had primary refractory HL.
Patients in both arms received a median of 15 treatment cycles, with an average of 12 cycles on the brentuximab arm and 11 cycles on the placebo arm.
“Patients who progressed in the placebo arm could be unblinded and subsequently receive brentuximab on a companion study,” Dr Moskowitz noted. “So technically, this was a cross-over design, making overall survival at 24 months quite unlikely.”
Efficacy/survival results
About half of patients in each arm completed treatment—47% in the brentuximab arm and 49% in the placebo arm. The reasons for discontinuation included disease progression (15% and 42%, respectively), adverse events (33% and 6%, respectively), and patient decision (5% and 2%, respectively).
Still, the trial achieved its primary endpoint, demonstrating a significant increase in PFS, according to an independent review facility (IRF).
The median PFS per the IRF was 43 months for patients in the brentuximab arm and 24 months in the placebo arm (hazard ratio=0.57, P=0.001). The 2-year PFS rates per the IRF were 63% and 51%, respectively.
The 2-year PFS rate according to investigators was 65% in the brentuximab arm and 45% in the placebo arm. The median PFS per investigators has not yet been reached for brentuximab but was 16 months for placebo.
The PFS benefit was consistent across all pre-specified subgroups, Dr Moskowitz noted, including primary refractory patients, patients who relapsed within 12 months of frontline therapy, and patients who relapsed after 12 months with extranodal disease.
Patients who experienced disease progression received a variety of subsequent therapies.
In the brentuximab arm, 16% of patients receiving subsequent therapy were treated with brentuximab after relapse. In the placebo arm, 85% of patients receiving subsequent therapy were treated with single-agent brentuximab.
Twenty-eight percent of patients in the placebo arm and 25% in the brentuximab arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants. Dr Moskowitz said a second transplant could have improved survival in these patients, but whether it actually did is unclear.
He noted that the OS data are immature, but there is currently no significant difference in OS between the treatment arms (hazard ratio=1.15; P=0.62).
“The median follow-up right now is 24 months,” he said. “So one will have to wait for a survival advantage or disadvantage, but from my point of view, a PFS of 65% at 2 years will translate to an overall survival difference. We’re just going to have to wait a few more years.”
Dr Moskowitz said another analysis of OS is planned in 2016.
Safety data
The most common adverse events in the brentuximab arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).
The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%), and neutropenia (12%).
Eighty-five percent of patients with peripheral neuropathy in the brentuximab arm had a resolution or improvement in symptoms, with a median time to improvement of 23.4 weeks.
Grade 3 or higher adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue, and diarrhea.
Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea, and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.
One death occurred within 30 days of brentuximab treatment. The patient died from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis.
Another death occurred on the brentuximab arm at day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.
Nevertheless, Dr Moskowitz characterized brentuximab consolidation as “very well-tolerated” in this patient population.
He concluded, “For patients with a remission duration of less than a year, patients with primary refractory Hodgkin lymphoma, and patients with Hodgkin lymphoma with extranodal involvement, I do believe this will become standard treatment.”
Mouse model reveals insight into CLL relapse
Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.
Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.
The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.
Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.
The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).
The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.
When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.
In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.
The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.
The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.
When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.
The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.
The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.
From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.
This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.
Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.
Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.
The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.
Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.
The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).
The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.
When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.
In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.
The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.
The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.
When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.
The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.
The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.
From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.
This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.
Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.
Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.
The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.
Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.
The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).
The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.
When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.
In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.
The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.
The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.
When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.
The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.
The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.
From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.
This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.
ASPIRE: Carfilzomib-Len-Dex ‘a new standard of care’ for relapsed multiple myeloma
SAN FRANCISCO – New standards of care are hard to come by in the treatment of relapsed/refractory multiple myeloma, but interim results of a phase III trial of the combination of carfilzomib, lenalidomide, and dexamethasone suggest that it might just fit the bill, investigators say.
In a randomized controlled trial comparing the combination, the comination, labeled KRd (the K is for carfilzomib’s tradename, Kyrpolis), was associated with significantly better progression-free survival (PFS) and a trend toward better overall survival than lenalidomide (Revlimid) and dexamethasone combined (RD), reported Dr. A. Keith Stewart, principal investigator and dean for research at the Mayo Clinic in Scottsdale, Arizona, at the annual meeting of the American Society of Hematology.
“Dr. Stewart’s study will, I think, establish a new standard of care in this patient population,” commented Dr. Brad Kahl of the University of Wisconsin School of Medicine and Public Health in Madison, who moderated a briefing where the data were presented. They were published simultaneously online in the New England Journal of Medicine (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411321]).
Among 792 patients with relapsed/refractory multiple myeloma, PFS with patients randomized to receive KRd was 26.3 months, compared with 17.6 months for patients randomized to RD. The hazard ratio for progression or death with KRd was 0.69 (P = .0001, crossing the pre-specified stopping boundary). Median overall survival had not been reached for either group. Kaplan-Meier 24 month overall survival rates were 73.3% and 65.0%, respec-tively, trending in favor of KRd, but with a P value (.04) that did not meet the pre-specified stopping boundary for survival (P = .005).
“In this same population of patients – this is patients who have relapsed one, two or three times – the best result ever reported before with any combina-tion of chemotherapy was about 19 months, with a very similar cocktail of bortezomib, thalidomide and dexamethasone,” Dr. Stewart said at the briefing.
The KRd combination also appeared to be safe.
“Despite the fact that we added a third drug and patients were on treatment significantly longer, there was a fairly well balanced ratio of patients who had to discontinue treatment due to side effects. It’s important to note that cardiac and renal events which have been reported in some studies of heavily pre-treated patients [with carfilzomib] in the past, were marginally higher in the three-drug regimen, but overall were very consistent or even lower than had previously been reported [with single-agent carilzomib],” Dr. Stewart said.
Carfilzomib is an epoxyketone proteasome inhibitor that binds selectively to the constitutive proteasome and immunoproteasome. Unlike the first-in-class proteasome inhibitor, bortezomib (Velcade), carfilzomib irreversibly binds to and disables its targets, Dr. Stewart said in an interview.
In the ASPIRE (Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma) trial, investigators enrolled 792 adults with relapsed multiple myeloma from 20 countries in North America, Europe, and the Middle East. The patients, who had previously received 1-3 prior lines of therapy, were randomly assigned to receive either KRd (carfilzomib 20 mg/m2 on days 1 and 2 of the first 28-day cycle, then 27 mg/m2 for days 8,9,15, and 16, and all days of subsequent cycles), oral lenolidamide 25 mg days 1-21, and oral dexamethasone days 1, 8, 15 and 22 of each cycle; or RD, which consisted of lenalidomide and dexamethasone in the same doses and on the same schedule as in KRd.
At the time of the data cutoff for the interim analysis in June 2014, 118 of 396 patients assigned to KRd were still on treatment, as were 86 of 396 in the RD group.
At the time of the analysis, 431 PFS events had been documented, and the study met its primary endpoint of superior PFS with the addition of carfilzomib.
Common adverse events, including diarrhea, cough, fever and hypertension were reported more frequently in the KRd group.
Remissions were more durable among patients who received carfilzomib, and these patients reported higher quality-of-life scores on the QLQ-C30 Global Health Status and Quality of Life scale, Dr. Stewart noted.
SAN FRANCISCO – New standards of care are hard to come by in the treatment of relapsed/refractory multiple myeloma, but interim results of a phase III trial of the combination of carfilzomib, lenalidomide, and dexamethasone suggest that it might just fit the bill, investigators say.
In a randomized controlled trial comparing the combination, the comination, labeled KRd (the K is for carfilzomib’s tradename, Kyrpolis), was associated with significantly better progression-free survival (PFS) and a trend toward better overall survival than lenalidomide (Revlimid) and dexamethasone combined (RD), reported Dr. A. Keith Stewart, principal investigator and dean for research at the Mayo Clinic in Scottsdale, Arizona, at the annual meeting of the American Society of Hematology.
“Dr. Stewart’s study will, I think, establish a new standard of care in this patient population,” commented Dr. Brad Kahl of the University of Wisconsin School of Medicine and Public Health in Madison, who moderated a briefing where the data were presented. They were published simultaneously online in the New England Journal of Medicine (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411321]).
Among 792 patients with relapsed/refractory multiple myeloma, PFS with patients randomized to receive KRd was 26.3 months, compared with 17.6 months for patients randomized to RD. The hazard ratio for progression or death with KRd was 0.69 (P = .0001, crossing the pre-specified stopping boundary). Median overall survival had not been reached for either group. Kaplan-Meier 24 month overall survival rates were 73.3% and 65.0%, respec-tively, trending in favor of KRd, but with a P value (.04) that did not meet the pre-specified stopping boundary for survival (P = .005).
“In this same population of patients – this is patients who have relapsed one, two or three times – the best result ever reported before with any combina-tion of chemotherapy was about 19 months, with a very similar cocktail of bortezomib, thalidomide and dexamethasone,” Dr. Stewart said at the briefing.
The KRd combination also appeared to be safe.
“Despite the fact that we added a third drug and patients were on treatment significantly longer, there was a fairly well balanced ratio of patients who had to discontinue treatment due to side effects. It’s important to note that cardiac and renal events which have been reported in some studies of heavily pre-treated patients [with carfilzomib] in the past, were marginally higher in the three-drug regimen, but overall were very consistent or even lower than had previously been reported [with single-agent carilzomib],” Dr. Stewart said.
Carfilzomib is an epoxyketone proteasome inhibitor that binds selectively to the constitutive proteasome and immunoproteasome. Unlike the first-in-class proteasome inhibitor, bortezomib (Velcade), carfilzomib irreversibly binds to and disables its targets, Dr. Stewart said in an interview.
In the ASPIRE (Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma) trial, investigators enrolled 792 adults with relapsed multiple myeloma from 20 countries in North America, Europe, and the Middle East. The patients, who had previously received 1-3 prior lines of therapy, were randomly assigned to receive either KRd (carfilzomib 20 mg/m2 on days 1 and 2 of the first 28-day cycle, then 27 mg/m2 for days 8,9,15, and 16, and all days of subsequent cycles), oral lenolidamide 25 mg days 1-21, and oral dexamethasone days 1, 8, 15 and 22 of each cycle; or RD, which consisted of lenalidomide and dexamethasone in the same doses and on the same schedule as in KRd.
At the time of the data cutoff for the interim analysis in June 2014, 118 of 396 patients assigned to KRd were still on treatment, as were 86 of 396 in the RD group.
At the time of the analysis, 431 PFS events had been documented, and the study met its primary endpoint of superior PFS with the addition of carfilzomib.
Common adverse events, including diarrhea, cough, fever and hypertension were reported more frequently in the KRd group.
Remissions were more durable among patients who received carfilzomib, and these patients reported higher quality-of-life scores on the QLQ-C30 Global Health Status and Quality of Life scale, Dr. Stewart noted.
SAN FRANCISCO – New standards of care are hard to come by in the treatment of relapsed/refractory multiple myeloma, but interim results of a phase III trial of the combination of carfilzomib, lenalidomide, and dexamethasone suggest that it might just fit the bill, investigators say.
In a randomized controlled trial comparing the combination, the comination, labeled KRd (the K is for carfilzomib’s tradename, Kyrpolis), was associated with significantly better progression-free survival (PFS) and a trend toward better overall survival than lenalidomide (Revlimid) and dexamethasone combined (RD), reported Dr. A. Keith Stewart, principal investigator and dean for research at the Mayo Clinic in Scottsdale, Arizona, at the annual meeting of the American Society of Hematology.
“Dr. Stewart’s study will, I think, establish a new standard of care in this patient population,” commented Dr. Brad Kahl of the University of Wisconsin School of Medicine and Public Health in Madison, who moderated a briefing where the data were presented. They were published simultaneously online in the New England Journal of Medicine (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411321]).
Among 792 patients with relapsed/refractory multiple myeloma, PFS with patients randomized to receive KRd was 26.3 months, compared with 17.6 months for patients randomized to RD. The hazard ratio for progression or death with KRd was 0.69 (P = .0001, crossing the pre-specified stopping boundary). Median overall survival had not been reached for either group. Kaplan-Meier 24 month overall survival rates were 73.3% and 65.0%, respec-tively, trending in favor of KRd, but with a P value (.04) that did not meet the pre-specified stopping boundary for survival (P = .005).
“In this same population of patients – this is patients who have relapsed one, two or three times – the best result ever reported before with any combina-tion of chemotherapy was about 19 months, with a very similar cocktail of bortezomib, thalidomide and dexamethasone,” Dr. Stewart said at the briefing.
The KRd combination also appeared to be safe.
“Despite the fact that we added a third drug and patients were on treatment significantly longer, there was a fairly well balanced ratio of patients who had to discontinue treatment due to side effects. It’s important to note that cardiac and renal events which have been reported in some studies of heavily pre-treated patients [with carfilzomib] in the past, were marginally higher in the three-drug regimen, but overall were very consistent or even lower than had previously been reported [with single-agent carilzomib],” Dr. Stewart said.
Carfilzomib is an epoxyketone proteasome inhibitor that binds selectively to the constitutive proteasome and immunoproteasome. Unlike the first-in-class proteasome inhibitor, bortezomib (Velcade), carfilzomib irreversibly binds to and disables its targets, Dr. Stewart said in an interview.
In the ASPIRE (Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma) trial, investigators enrolled 792 adults with relapsed multiple myeloma from 20 countries in North America, Europe, and the Middle East. The patients, who had previously received 1-3 prior lines of therapy, were randomly assigned to receive either KRd (carfilzomib 20 mg/m2 on days 1 and 2 of the first 28-day cycle, then 27 mg/m2 for days 8,9,15, and 16, and all days of subsequent cycles), oral lenolidamide 25 mg days 1-21, and oral dexamethasone days 1, 8, 15 and 22 of each cycle; or RD, which consisted of lenalidomide and dexamethasone in the same doses and on the same schedule as in KRd.
At the time of the data cutoff for the interim analysis in June 2014, 118 of 396 patients assigned to KRd were still on treatment, as were 86 of 396 in the RD group.
At the time of the analysis, 431 PFS events had been documented, and the study met its primary endpoint of superior PFS with the addition of carfilzomib.
Common adverse events, including diarrhea, cough, fever and hypertension were reported more frequently in the KRd group.
Remissions were more durable among patients who received carfilzomib, and these patients reported higher quality-of-life scores on the QLQ-C30 Global Health Status and Quality of Life scale, Dr. Stewart noted.
AT ASH 2014
Key clinical point: Adding the proteasome inhibitor carfilzomib to lenalidomide and dexamethasone resulted in a significantly better PFS in patients with relapsed/refractory multiple myeloma.
Major finding: Progresion-free survival was 26.3 months for the 3-drug combo compared with 17.6 months for len-dex alone.
Data source: Phase III open-label randomized controlled trial in 792 patients with relapsed/refractory multiple myeloma.
Disclosures: The study was supported by Onyx Pharmaceuticals. Dr. Stewart reports support from Onyx during the conduct of the study, and grant support from Onyx and personal fees from Celgene outside the study.
Health Canada approves ibrutinib for CLL
Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).
The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.
Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.
The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.
The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.
At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.
Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).
Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.
Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.
Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.
Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.
Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).
The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.
Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.
The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.
The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.
At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.
Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).
Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.
Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.
Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.
Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.
Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).
The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.
Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.
The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.
The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.
At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.
Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).
Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.
Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.
Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.
Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.
People often dismiss cancer symptoms, survey suggests
Credit: NIH
People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.
In a survey of about 1700 people, more than half of respondents said they had experienced at least
one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but
only 2% of them thought cancer was a possible cause.
The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.
Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.
Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.
This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.
Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.
Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.
However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.
“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.
“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”
“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”
Credit: NIH
People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.
In a survey of about 1700 people, more than half of respondents said they had experienced at least
one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but
only 2% of them thought cancer was a possible cause.
The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.
Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.
Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.
This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.
Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.
Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.
However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.
“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.
“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”
“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”
Credit: NIH
People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.
In a survey of about 1700 people, more than half of respondents said they had experienced at least
one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but
only 2% of them thought cancer was a possible cause.
The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.
Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.
Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.
This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.
Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.
Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.
However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.
“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.
“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”
“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”
NICE reconsiders obinutuzumab for CLL
Credit: Linda Bartlett
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance that recommends obinutuzumab, marketed by Roche as Gazyvaro, for certain patients with untreated chronic lymphocytic leukemia (CLL).
In an earlier preliminary guidance, NICE said it could not recommend the drug due to uncertainties in the company’s submission.
In response, Roche submitted revised cost-effectiveness analyses and a patient access scheme.
This prompted NICE to recommend obinutuzumab in combination with chlorambucil as an option for adults with untreated CLL who have comorbidities that make them ineligible for full-dose fludarabine-based therapy.
But NICE is only recommending this as an option if bendamustine-based therapy has been deemed unsuitable and if Roche provides obinutuzumab with the discount agreed in the patient access scheme.
“We are pleased that Roche responded to our consultation and provided further analyses to allow us to propose recommending obinutuzumab as a treatment option for untreated chronic lymphocytic leukemia,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.
“Half of the people who need treatment for their condition are not able to use the standard first-line treatment of fludarabine combination therapy. NICE recommends alternative treatment with bendamustine, but there are some patients for whom this is also unsuitable. Obinutuzumab is a clinically effective treatment which is associated with fewer adverse events and provides another option to help prevent people’s disease from progressing.”
NICE recommends obinutuzumab on the basis that Roche provides the treatment to the National Health Service (NHS) at a reduced price. The company has agreed with the Department of Health that the size of the discount is to be confidential.
The list price of obinutuzumab is £3312 per 1000 mg vial (excluding value-added tax). According to Roche, a course of treatment costs £26,496 (£9936 for cycle 1 and £3312 for cycles 2 to 6, excluding tax).
Consultees, including the company, healthcare professionals, and members of the public, have until Tuesday, January 6, 2015, to comment on the preliminary recommendations via the NICE website.
NICE has not yet issued the final guidance to the NHS. Until then, NHS bodies should make decisions locally on the funding of specific treatments.
Credit: Linda Bartlett
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance that recommends obinutuzumab, marketed by Roche as Gazyvaro, for certain patients with untreated chronic lymphocytic leukemia (CLL).
In an earlier preliminary guidance, NICE said it could not recommend the drug due to uncertainties in the company’s submission.
In response, Roche submitted revised cost-effectiveness analyses and a patient access scheme.
This prompted NICE to recommend obinutuzumab in combination with chlorambucil as an option for adults with untreated CLL who have comorbidities that make them ineligible for full-dose fludarabine-based therapy.
But NICE is only recommending this as an option if bendamustine-based therapy has been deemed unsuitable and if Roche provides obinutuzumab with the discount agreed in the patient access scheme.
“We are pleased that Roche responded to our consultation and provided further analyses to allow us to propose recommending obinutuzumab as a treatment option for untreated chronic lymphocytic leukemia,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.
“Half of the people who need treatment for their condition are not able to use the standard first-line treatment of fludarabine combination therapy. NICE recommends alternative treatment with bendamustine, but there are some patients for whom this is also unsuitable. Obinutuzumab is a clinically effective treatment which is associated with fewer adverse events and provides another option to help prevent people’s disease from progressing.”
NICE recommends obinutuzumab on the basis that Roche provides the treatment to the National Health Service (NHS) at a reduced price. The company has agreed with the Department of Health that the size of the discount is to be confidential.
The list price of obinutuzumab is £3312 per 1000 mg vial (excluding value-added tax). According to Roche, a course of treatment costs £26,496 (£9936 for cycle 1 and £3312 for cycles 2 to 6, excluding tax).
Consultees, including the company, healthcare professionals, and members of the public, have until Tuesday, January 6, 2015, to comment on the preliminary recommendations via the NICE website.
NICE has not yet issued the final guidance to the NHS. Until then, NHS bodies should make decisions locally on the funding of specific treatments.
Credit: Linda Bartlett
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance that recommends obinutuzumab, marketed by Roche as Gazyvaro, for certain patients with untreated chronic lymphocytic leukemia (CLL).
In an earlier preliminary guidance, NICE said it could not recommend the drug due to uncertainties in the company’s submission.
In response, Roche submitted revised cost-effectiveness analyses and a patient access scheme.
This prompted NICE to recommend obinutuzumab in combination with chlorambucil as an option for adults with untreated CLL who have comorbidities that make them ineligible for full-dose fludarabine-based therapy.
But NICE is only recommending this as an option if bendamustine-based therapy has been deemed unsuitable and if Roche provides obinutuzumab with the discount agreed in the patient access scheme.
“We are pleased that Roche responded to our consultation and provided further analyses to allow us to propose recommending obinutuzumab as a treatment option for untreated chronic lymphocytic leukemia,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.
“Half of the people who need treatment for their condition are not able to use the standard first-line treatment of fludarabine combination therapy. NICE recommends alternative treatment with bendamustine, but there are some patients for whom this is also unsuitable. Obinutuzumab is a clinically effective treatment which is associated with fewer adverse events and provides another option to help prevent people’s disease from progressing.”
NICE recommends obinutuzumab on the basis that Roche provides the treatment to the National Health Service (NHS) at a reduced price. The company has agreed with the Department of Health that the size of the discount is to be confidential.
The list price of obinutuzumab is £3312 per 1000 mg vial (excluding value-added tax). According to Roche, a course of treatment costs £26,496 (£9936 for cycle 1 and £3312 for cycles 2 to 6, excluding tax).
Consultees, including the company, healthcare professionals, and members of the public, have until Tuesday, January 6, 2015, to comment on the preliminary recommendations via the NICE website.
NICE has not yet issued the final guidance to the NHS. Until then, NHS bodies should make decisions locally on the funding of specific treatments.
ASH adds practices to Choosing Wisely list
Credit: Rhoda Baer
The American Society of Hematology (ASH) has released a second list of 5 commonly used tests, treatments, and procedures that physicians and patients should question in certain circumstances.
The additional items join an initial list of practices released last year as part of the Choosing Wisely® campaign, an initiative of the ABIM Foundation that aims to prompt conversations between patients and physicians about the necessity and potential harm of certain procedures.
These new “practices to question” are also highlighted in a manuscript published in Blood, which further describes the methods for developing the list and the evidentiary basis of the recommendations.
The new recommendations include:
- Don’t treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor.
- Don’t routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication.
- Don’t perform baseline or routine surveillance CT scans in patients with asymptomatic, early stage chronic lymphocytic leukemia.
- Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability of HIT.
- Don’t treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.
The second Choosing Wisely list was developed using a rigorous evidence-based methodology that incorporated suggestions from ASH members and prioritized avoiding harm to patients above all other considerations.
“Unnecessary treatments or tests not only add waste to the healthcare system, but, in some cases, they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St Michael’s Hospital and the University of Toronto and chair of the ASH Choosing Wisely Task Force.
“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research.”
The dominant guiding principle for ASH’s list is the concept of avoiding harm. The four other established guiding principles of ASH’s involvement in the Choosing Wisely campaign are strength of evidence, aggregate cost, frequency, and making recommendations within the purview of hematology. This year, the task force added a sixth overarching principle of potential impact in the field.
“Choosing Wisely set out to stimulate conversations about waste and overuse in our healthcare system,” said Richard J. Baron, MD, President and CEO of the ABIM Foundation.
“We’ve been fortunate to be joined in this effort by many dedicated partners—including ASH—who have committed to addressing unnecessary care in their specialty. ASH’s second Choosing Wisely list gives clinicians and patients a new and important tool to help inform their conversations about what care is best for the patient.”
Credit: Rhoda Baer
The American Society of Hematology (ASH) has released a second list of 5 commonly used tests, treatments, and procedures that physicians and patients should question in certain circumstances.
The additional items join an initial list of practices released last year as part of the Choosing Wisely® campaign, an initiative of the ABIM Foundation that aims to prompt conversations between patients and physicians about the necessity and potential harm of certain procedures.
These new “practices to question” are also highlighted in a manuscript published in Blood, which further describes the methods for developing the list and the evidentiary basis of the recommendations.
The new recommendations include:
- Don’t treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor.
- Don’t routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication.
- Don’t perform baseline or routine surveillance CT scans in patients with asymptomatic, early stage chronic lymphocytic leukemia.
- Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability of HIT.
- Don’t treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.
The second Choosing Wisely list was developed using a rigorous evidence-based methodology that incorporated suggestions from ASH members and prioritized avoiding harm to patients above all other considerations.
“Unnecessary treatments or tests not only add waste to the healthcare system, but, in some cases, they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St Michael’s Hospital and the University of Toronto and chair of the ASH Choosing Wisely Task Force.
“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research.”
The dominant guiding principle for ASH’s list is the concept of avoiding harm. The four other established guiding principles of ASH’s involvement in the Choosing Wisely campaign are strength of evidence, aggregate cost, frequency, and making recommendations within the purview of hematology. This year, the task force added a sixth overarching principle of potential impact in the field.
“Choosing Wisely set out to stimulate conversations about waste and overuse in our healthcare system,” said Richard J. Baron, MD, President and CEO of the ABIM Foundation.
“We’ve been fortunate to be joined in this effort by many dedicated partners—including ASH—who have committed to addressing unnecessary care in their specialty. ASH’s second Choosing Wisely list gives clinicians and patients a new and important tool to help inform their conversations about what care is best for the patient.”
Credit: Rhoda Baer
The American Society of Hematology (ASH) has released a second list of 5 commonly used tests, treatments, and procedures that physicians and patients should question in certain circumstances.
The additional items join an initial list of practices released last year as part of the Choosing Wisely® campaign, an initiative of the ABIM Foundation that aims to prompt conversations between patients and physicians about the necessity and potential harm of certain procedures.
These new “practices to question” are also highlighted in a manuscript published in Blood, which further describes the methods for developing the list and the evidentiary basis of the recommendations.
The new recommendations include:
- Don’t treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor.
- Don’t routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication.
- Don’t perform baseline or routine surveillance CT scans in patients with asymptomatic, early stage chronic lymphocytic leukemia.
- Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability of HIT.
- Don’t treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count.
The second Choosing Wisely list was developed using a rigorous evidence-based methodology that incorporated suggestions from ASH members and prioritized avoiding harm to patients above all other considerations.
“Unnecessary treatments or tests not only add waste to the healthcare system, but, in some cases, they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St Michael’s Hospital and the University of Toronto and chair of the ASH Choosing Wisely Task Force.
“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research.”
The dominant guiding principle for ASH’s list is the concept of avoiding harm. The four other established guiding principles of ASH’s involvement in the Choosing Wisely campaign are strength of evidence, aggregate cost, frequency, and making recommendations within the purview of hematology. This year, the task force added a sixth overarching principle of potential impact in the field.
“Choosing Wisely set out to stimulate conversations about waste and overuse in our healthcare system,” said Richard J. Baron, MD, President and CEO of the ABIM Foundation.
“We’ve been fortunate to be joined in this effort by many dedicated partners—including ASH—who have committed to addressing unnecessary care in their specialty. ASH’s second Choosing Wisely list gives clinicians and patients a new and important tool to help inform their conversations about what care is best for the patient.”