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Team identifies mutations that may drive FL
Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.
Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.
The team also identified mutations that seemed to drive FL toward a more aggressive form.
They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.
“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.
“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”
Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.
Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).
Patterns of evolution
The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.
Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.
These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.
Mutation prevalence, timing
The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).
More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).
Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.
The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).
They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).
And 17% of cases had mutations in genes important for B-cell development, including Ebf1.
Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.
On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.
“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.
“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.” 
Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.
Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.
The team also identified mutations that seemed to drive FL toward a more aggressive form.
They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.
“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.
“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”
Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.
Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).
Patterns of evolution
The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.
Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.
These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.
Mutation prevalence, timing
The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).
More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).
Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.
The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).
They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).
And 17% of cases had mutations in genes important for B-cell development, including Ebf1.
Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.
On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.
“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.
“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”
Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.
Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.
The team also identified mutations that seemed to drive FL toward a more aggressive form.
They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.
“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.
“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”
Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.
Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).
Patterns of evolution
The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.
Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.
These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.
Mutation prevalence, timing
The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).
More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).
Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.
The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).
They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).
And 17% of cases had mutations in genes important for B-cell development, including Ebf1.
Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.
On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.
“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.
“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”
MCL-1 proves critical in MYC-driven lymphomas
Walter and Eliza Hall Institute
Results of preclinical research suggest the prosurvival protein MCL-1 is the BCL-2 family member most important for the growth and survival of MYC-driven lymphomas.
Investigators found that MYC-driven lymphoma growth in mice and human cell lines was significantly more dependent upon MCL-1 than BCL-XL.
And mutations in p53 could diminish but not counteract this dependency.
The team described this research is Genes & Development.
The work built on more than 3 decades of research into how MYC drives cancer development, according to study author Gemma Kelly, PhD, of the Walter and Eliza Hall Institute in Victoria, Australia.
“For many years, we have known that proteins from the BCL-2 protein family enhance cell survival and cooperate with MYC to accelerate the development of cancer,” she said. “Until now, it was not known which specific BCL-2 family protein was most important for the survival and growth of MYC-driven cancers.”
To investigate, Dr Kelly and her colleagues first generated mice in which they could delete Mcl-1 or Bcl-x in c-MYC-driven lymphoma cells.
The researchers found that homozygous loss of Bcl-x slightly impaired lymphoma growth. Four percent of Bcl-x-deleted mice had complete lymphoma regression. The rest experienced a modest delay in tumor expansion and slightly prolonged survival compared to controls (P=0.0367).
On the other hand, homozygous Mcl-1 deletion prompted complete lymphoma regression in 30% of mice, and it significantly improved overall survival compared to controls (P<0.0001). Even heterozygous Mcl-1 deletion substantially impaired lymphoma growth.
The investigators also conducted experiments on human Burkitt lymphoma cell lines. And they found evidence suggesting the survival and growth of Burkitt lymphoma cells is largely dependent on MCL-1. In fact, sustained growth and survival may not depend on BCL-XL at all.
Finally, the researchers investigated the role p53 mutations play in MCL-1 dependency. The results showed that mutations in p53 can reduce but not ablate lymphomas’ dependency on MCL-1.
These findings suggest MCL-1 could be an attractive therapeutic target for MYC-driven cancers, the investigators said, particularly because the loss of a single Mcl-1 allele is well-tolerated in healthy tissues.
“Anticancer agents that target the protein BCL-2, which is closely related to MCL-1, are already showing promise in clinical trials . . . ,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute.
“We are hopeful that inhibitors of MCL-1 will soon become available for clinical testing. We will be very interested in determining whether these compounds could be used to treat MYC-driven cancers.”
Walter and Eliza Hall Institute
Results of preclinical research suggest the prosurvival protein MCL-1 is the BCL-2 family member most important for the growth and survival of MYC-driven lymphomas.
Investigators found that MYC-driven lymphoma growth in mice and human cell lines was significantly more dependent upon MCL-1 than BCL-XL.
And mutations in p53 could diminish but not counteract this dependency.
The team described this research is Genes & Development.
The work built on more than 3 decades of research into how MYC drives cancer development, according to study author Gemma Kelly, PhD, of the Walter and Eliza Hall Institute in Victoria, Australia.
“For many years, we have known that proteins from the BCL-2 protein family enhance cell survival and cooperate with MYC to accelerate the development of cancer,” she said. “Until now, it was not known which specific BCL-2 family protein was most important for the survival and growth of MYC-driven cancers.”
To investigate, Dr Kelly and her colleagues first generated mice in which they could delete Mcl-1 or Bcl-x in c-MYC-driven lymphoma cells.
The researchers found that homozygous loss of Bcl-x slightly impaired lymphoma growth. Four percent of Bcl-x-deleted mice had complete lymphoma regression. The rest experienced a modest delay in tumor expansion and slightly prolonged survival compared to controls (P=0.0367).
On the other hand, homozygous Mcl-1 deletion prompted complete lymphoma regression in 30% of mice, and it significantly improved overall survival compared to controls (P<0.0001). Even heterozygous Mcl-1 deletion substantially impaired lymphoma growth.
The investigators also conducted experiments on human Burkitt lymphoma cell lines. And they found evidence suggesting the survival and growth of Burkitt lymphoma cells is largely dependent on MCL-1. In fact, sustained growth and survival may not depend on BCL-XL at all.
Finally, the researchers investigated the role p53 mutations play in MCL-1 dependency. The results showed that mutations in p53 can reduce but not ablate lymphomas’ dependency on MCL-1.
These findings suggest MCL-1 could be an attractive therapeutic target for MYC-driven cancers, the investigators said, particularly because the loss of a single Mcl-1 allele is well-tolerated in healthy tissues.
“Anticancer agents that target the protein BCL-2, which is closely related to MCL-1, are already showing promise in clinical trials . . . ,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute.
“We are hopeful that inhibitors of MCL-1 will soon become available for clinical testing. We will be very interested in determining whether these compounds could be used to treat MYC-driven cancers.”
Walter and Eliza Hall Institute
Results of preclinical research suggest the prosurvival protein MCL-1 is the BCL-2 family member most important for the growth and survival of MYC-driven lymphomas.
Investigators found that MYC-driven lymphoma growth in mice and human cell lines was significantly more dependent upon MCL-1 than BCL-XL.
And mutations in p53 could diminish but not counteract this dependency.
The team described this research is Genes & Development.
The work built on more than 3 decades of research into how MYC drives cancer development, according to study author Gemma Kelly, PhD, of the Walter and Eliza Hall Institute in Victoria, Australia.
“For many years, we have known that proteins from the BCL-2 protein family enhance cell survival and cooperate with MYC to accelerate the development of cancer,” she said. “Until now, it was not known which specific BCL-2 family protein was most important for the survival and growth of MYC-driven cancers.”
To investigate, Dr Kelly and her colleagues first generated mice in which they could delete Mcl-1 or Bcl-x in c-MYC-driven lymphoma cells.
The researchers found that homozygous loss of Bcl-x slightly impaired lymphoma growth. Four percent of Bcl-x-deleted mice had complete lymphoma regression. The rest experienced a modest delay in tumor expansion and slightly prolonged survival compared to controls (P=0.0367).
On the other hand, homozygous Mcl-1 deletion prompted complete lymphoma regression in 30% of mice, and it significantly improved overall survival compared to controls (P<0.0001). Even heterozygous Mcl-1 deletion substantially impaired lymphoma growth.
The investigators also conducted experiments on human Burkitt lymphoma cell lines. And they found evidence suggesting the survival and growth of Burkitt lymphoma cells is largely dependent on MCL-1. In fact, sustained growth and survival may not depend on BCL-XL at all.
Finally, the researchers investigated the role p53 mutations play in MCL-1 dependency. The results showed that mutations in p53 can reduce but not ablate lymphomas’ dependency on MCL-1.
These findings suggest MCL-1 could be an attractive therapeutic target for MYC-driven cancers, the investigators said, particularly because the loss of a single Mcl-1 allele is well-tolerated in healthy tissues.
“Anticancer agents that target the protein BCL-2, which is closely related to MCL-1, are already showing promise in clinical trials . . . ,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute.
“We are hopeful that inhibitors of MCL-1 will soon become available for clinical testing. We will be very interested in determining whether these compounds could be used to treat MYC-driven cancers.”
Leukemia is leading cause of cancer death among young Americans
receiving chemotherapy
Credit: Rhoda Baer
Leukemia is the leading cause of cancer death in the US for men under 40 and women aged 20 and younger, according to a report by the American Cancer Society.
Non-Hodgkin lymphoma (NHL) is also among the 5 leading causes of cancer death for men under 40 and for women age 80 and older.
These data appear in “Cancer Statistics, 2014,” a report published in CA: A Cancer Journal for Clinicians.
The report includes statistics on cancer incidence and death from 1975 to 2010, as well as projections for 2014.
In the latest data (from 2010), NHL was the fifth leading cause of cancer death for men under 20 and for women over 79. It was the fourth leading cause of cancer death for men ages 20 to 39.
And leukemia was the third leading cause of cancer death for women ages 20 to 39, in addition to being the leading cause of cancer death for women under 21 and men under 40.
However, of all cancer types, leukemia and NHL have seen the largest improvements in survival, according to data comparing 5-year survival rates between 1975-1977 and 2003-2009.
Five-year survival rates for leukemia were 34% for 1975-1977 and 59% for 2003-2009 (P<0.05). For NHL, 5-year survival rates were 47% for 1975-1977 and 71% for 2003-2009 (P<0.05).
Projections for 2014
The report authors took past data into account to make estimates on cancer incidence and death for 2014. They projected that 1,665,540 patients will be diagnosed with cancer this year, and 585,720 patients will die of cancer.
Roughly 79,990 patients will be diagnosed with lymphoma—9190 with Hodgkin lymphoma and 70,800 with NHL. Approximately 18,990 patients will die of NHL, and 1180 will die of Hodgkin lymphoma.
There will be 24,050 new cases of myeloma in 2014 and 11,090 myeloma deaths, the authors said.
This year will see 52,380 patients diagnosed with leukemias—6020 with acute lymphocytic leukemia (ALL), 15,720 with chronic lymphocytic leukemia (CLL), 18,860 with acute myeloid leukemia (AML), 5980 with chronic myeloid leukemia (CML), and 5800 with other types of leukemia.
And there will be 24,090 leukemia deaths—1440 from ALL, 4600 from CLL, 10,460 from AML, 810 from CML, and 6780 from other leukemias.
For more information, see the complete report.
receiving chemotherapy
Credit: Rhoda Baer
Leukemia is the leading cause of cancer death in the US for men under 40 and women aged 20 and younger, according to a report by the American Cancer Society.
Non-Hodgkin lymphoma (NHL) is also among the 5 leading causes of cancer death for men under 40 and for women age 80 and older.
These data appear in “Cancer Statistics, 2014,” a report published in CA: A Cancer Journal for Clinicians.
The report includes statistics on cancer incidence and death from 1975 to 2010, as well as projections for 2014.
In the latest data (from 2010), NHL was the fifth leading cause of cancer death for men under 20 and for women over 79. It was the fourth leading cause of cancer death for men ages 20 to 39.
And leukemia was the third leading cause of cancer death for women ages 20 to 39, in addition to being the leading cause of cancer death for women under 21 and men under 40.
However, of all cancer types, leukemia and NHL have seen the largest improvements in survival, according to data comparing 5-year survival rates between 1975-1977 and 2003-2009.
Five-year survival rates for leukemia were 34% for 1975-1977 and 59% for 2003-2009 (P<0.05). For NHL, 5-year survival rates were 47% for 1975-1977 and 71% for 2003-2009 (P<0.05).
Projections for 2014
The report authors took past data into account to make estimates on cancer incidence and death for 2014. They projected that 1,665,540 patients will be diagnosed with cancer this year, and 585,720 patients will die of cancer.
Roughly 79,990 patients will be diagnosed with lymphoma—9190 with Hodgkin lymphoma and 70,800 with NHL. Approximately 18,990 patients will die of NHL, and 1180 will die of Hodgkin lymphoma.
There will be 24,050 new cases of myeloma in 2014 and 11,090 myeloma deaths, the authors said.
This year will see 52,380 patients diagnosed with leukemias—6020 with acute lymphocytic leukemia (ALL), 15,720 with chronic lymphocytic leukemia (CLL), 18,860 with acute myeloid leukemia (AML), 5980 with chronic myeloid leukemia (CML), and 5800 with other types of leukemia.
And there will be 24,090 leukemia deaths—1440 from ALL, 4600 from CLL, 10,460 from AML, 810 from CML, and 6780 from other leukemias.
For more information, see the complete report.
receiving chemotherapy
Credit: Rhoda Baer
Leukemia is the leading cause of cancer death in the US for men under 40 and women aged 20 and younger, according to a report by the American Cancer Society.
Non-Hodgkin lymphoma (NHL) is also among the 5 leading causes of cancer death for men under 40 and for women age 80 and older.
These data appear in “Cancer Statistics, 2014,” a report published in CA: A Cancer Journal for Clinicians.
The report includes statistics on cancer incidence and death from 1975 to 2010, as well as projections for 2014.
In the latest data (from 2010), NHL was the fifth leading cause of cancer death for men under 20 and for women over 79. It was the fourth leading cause of cancer death for men ages 20 to 39.
And leukemia was the third leading cause of cancer death for women ages 20 to 39, in addition to being the leading cause of cancer death for women under 21 and men under 40.
However, of all cancer types, leukemia and NHL have seen the largest improvements in survival, according to data comparing 5-year survival rates between 1975-1977 and 2003-2009.
Five-year survival rates for leukemia were 34% for 1975-1977 and 59% for 2003-2009 (P<0.05). For NHL, 5-year survival rates were 47% for 1975-1977 and 71% for 2003-2009 (P<0.05).
Projections for 2014
The report authors took past data into account to make estimates on cancer incidence and death for 2014. They projected that 1,665,540 patients will be diagnosed with cancer this year, and 585,720 patients will die of cancer.
Roughly 79,990 patients will be diagnosed with lymphoma—9190 with Hodgkin lymphoma and 70,800 with NHL. Approximately 18,990 patients will die of NHL, and 1180 will die of Hodgkin lymphoma.
There will be 24,050 new cases of myeloma in 2014 and 11,090 myeloma deaths, the authors said.
This year will see 52,380 patients diagnosed with leukemias—6020 with acute lymphocytic leukemia (ALL), 15,720 with chronic lymphocytic leukemia (CLL), 18,860 with acute myeloid leukemia (AML), 5980 with chronic myeloid leukemia (CML), and 5800 with other types of leukemia.
And there will be 24,090 leukemia deaths—1440 from ALL, 4600 from CLL, 10,460 from AML, 810 from CML, and 6780 from other leukemias.
For more information, see the complete report.
Internists may be ill-equipped to care for childhood cancer survivors
Credit: CDC
A survey of general internists suggests a few obstacles may prevent these physicians from providing optimal care for childhood cancer survivors.
Most of the internists surveyed were unfamiliar with surveillance guidelines, felt “somewhat uncomfortable” caring for childhood cancer survivors, and would prefer to follow patients in collaboration with a cancer center.
Nevertheless, about half of the survey respondents had recently cared for at least 1 childhood cancer survivor.
And a majority of these physicians said they never received a summary of their patients’ cancer treatment.
Eugene Suh, MD, of Loyola University Medical Center in Maywood, Illinois, and his colleagues reported these findings in Annals of Internal Medicine.
The researchers surveyed 1110 general internists, gauging their care preferences, comfort levels with caring for childhood cancer survivors, and knowledge of surveillance guidelines.
Only 36.9% of respondents said they were “somewhat comfortable” or “comfortable” caring for survivors of Hodgkin lymphoma. Twenty-seven percent felt the same about survivors of acute lymphoblastic leukemia. And 25% felt that way about osteosarcoma survivors.
In all, 51.1% of respondents had cared for at least 1 childhood cancer survivor in the 5 years preceding the survey. But 72% of these physicians had never received treatment summaries for these patients.
Eighty-four percent of respondents said they would prefer to treat childhood cancer survivors in collaboration with a physician based at a cancer center or a long-term follow-up clinic. And 10.5% said they would refer survivors to a cancer center-based physician, long-term follow-up clinic, or another primary care physician.
Only 12% of respondents said they felt at least “somewhat familiar” with surveillance guidelines. And the internists’ responses to a vignette case supported this answer.
The survey included questions about surveillance for a hypothetical 16-year-old Hodgkin lymphoma survivor who had received mantle radiation and anthracycline chemotherapy.
Ninety-one percent of respondents failed to recommend appropriate breast cancer surveillance for this patient, 85% did not recommend appropriate cardiac surveillance, and 24% failed to recommend appropriate thyroid surveillance.
Dr Suh and his colleagues said these results suggest a need for improved education among general internists but also the need for better collaboration between oncologists and primary care physicians.
A related editorial includes suggestions for educational initiatives.
Credit: CDC
A survey of general internists suggests a few obstacles may prevent these physicians from providing optimal care for childhood cancer survivors.
Most of the internists surveyed were unfamiliar with surveillance guidelines, felt “somewhat uncomfortable” caring for childhood cancer survivors, and would prefer to follow patients in collaboration with a cancer center.
Nevertheless, about half of the survey respondents had recently cared for at least 1 childhood cancer survivor.
And a majority of these physicians said they never received a summary of their patients’ cancer treatment.
Eugene Suh, MD, of Loyola University Medical Center in Maywood, Illinois, and his colleagues reported these findings in Annals of Internal Medicine.
The researchers surveyed 1110 general internists, gauging their care preferences, comfort levels with caring for childhood cancer survivors, and knowledge of surveillance guidelines.
Only 36.9% of respondents said they were “somewhat comfortable” or “comfortable” caring for survivors of Hodgkin lymphoma. Twenty-seven percent felt the same about survivors of acute lymphoblastic leukemia. And 25% felt that way about osteosarcoma survivors.
In all, 51.1% of respondents had cared for at least 1 childhood cancer survivor in the 5 years preceding the survey. But 72% of these physicians had never received treatment summaries for these patients.
Eighty-four percent of respondents said they would prefer to treat childhood cancer survivors in collaboration with a physician based at a cancer center or a long-term follow-up clinic. And 10.5% said they would refer survivors to a cancer center-based physician, long-term follow-up clinic, or another primary care physician.
Only 12% of respondents said they felt at least “somewhat familiar” with surveillance guidelines. And the internists’ responses to a vignette case supported this answer.
The survey included questions about surveillance for a hypothetical 16-year-old Hodgkin lymphoma survivor who had received mantle radiation and anthracycline chemotherapy.
Ninety-one percent of respondents failed to recommend appropriate breast cancer surveillance for this patient, 85% did not recommend appropriate cardiac surveillance, and 24% failed to recommend appropriate thyroid surveillance.
Dr Suh and his colleagues said these results suggest a need for improved education among general internists but also the need for better collaboration between oncologists and primary care physicians.
A related editorial includes suggestions for educational initiatives.
Credit: CDC
A survey of general internists suggests a few obstacles may prevent these physicians from providing optimal care for childhood cancer survivors.
Most of the internists surveyed were unfamiliar with surveillance guidelines, felt “somewhat uncomfortable” caring for childhood cancer survivors, and would prefer to follow patients in collaboration with a cancer center.
Nevertheless, about half of the survey respondents had recently cared for at least 1 childhood cancer survivor.
And a majority of these physicians said they never received a summary of their patients’ cancer treatment.
Eugene Suh, MD, of Loyola University Medical Center in Maywood, Illinois, and his colleagues reported these findings in Annals of Internal Medicine.
The researchers surveyed 1110 general internists, gauging their care preferences, comfort levels with caring for childhood cancer survivors, and knowledge of surveillance guidelines.
Only 36.9% of respondents said they were “somewhat comfortable” or “comfortable” caring for survivors of Hodgkin lymphoma. Twenty-seven percent felt the same about survivors of acute lymphoblastic leukemia. And 25% felt that way about osteosarcoma survivors.
In all, 51.1% of respondents had cared for at least 1 childhood cancer survivor in the 5 years preceding the survey. But 72% of these physicians had never received treatment summaries for these patients.
Eighty-four percent of respondents said they would prefer to treat childhood cancer survivors in collaboration with a physician based at a cancer center or a long-term follow-up clinic. And 10.5% said they would refer survivors to a cancer center-based physician, long-term follow-up clinic, or another primary care physician.
Only 12% of respondents said they felt at least “somewhat familiar” with surveillance guidelines. And the internists’ responses to a vignette case supported this answer.
The survey included questions about surveillance for a hypothetical 16-year-old Hodgkin lymphoma survivor who had received mantle radiation and anthracycline chemotherapy.
Ninety-one percent of respondents failed to recommend appropriate breast cancer surveillance for this patient, 85% did not recommend appropriate cardiac surveillance, and 24% failed to recommend appropriate thyroid surveillance.
Dr Suh and his colleagues said these results suggest a need for improved education among general internists but also the need for better collaboration between oncologists and primary care physicians.
A related editorial includes suggestions for educational initiatives.
NICE recommends pixantrone for NHL
Credit: Bill Branson
Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).
In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.
But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.
NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.
The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.
“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”
Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.
Clinical effectiveness
NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.
However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.
The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.
At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).
The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).
Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.
Cost-effectiveness
The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.
The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.
According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.
The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.
Marketing authorization
Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.
The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.
Credit: Bill Branson
Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).
In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.
But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.
NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.
The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.
“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”
Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.
Clinical effectiveness
NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.
However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.
The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.
At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).
The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).
Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.
Cost-effectiveness
The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.
The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.
According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.
The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.
Marketing authorization
Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.
The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.
Credit: Bill Branson
Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).
In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.
But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.
NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.
The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.
“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”
Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.
Clinical effectiveness
NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.
However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.
The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.
At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).
The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).
Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.
Cost-effectiveness
The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.
The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.
According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.
The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.
Marketing authorization
Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.
The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.
Brentuximab vedotin proves active in DLBCL
Credit: Linda Bartlett
NEW ORLEANS—Brentuximab vedotin has demonstrated “compelling” antitumor activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.
The investigators were also surprised
to find that the activity of this anti-CD30 monoclonal antibody
conjugate did not seem to
correlate with a patient’s level of CD30 expression.
In fact, some of
the patients with the weakest CD30 expression had the best responses to
the drug.
Eric Jacobsen, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues presented these results at the 2013 ASH Annual Meeting as abstract 848.
Thus far, the researchers have enrolled 62 patients with B-cell lymphomas, including 44 with DLBCL, on this phase 2 study.
Sixty-five percent of patients had primary refractory disease, 76% were refractory to their most recent prior therapy, and 23% had never responded to any treatment.
However, 40% of the 43 evaluable DLBCL patients had an objective response to brentuximab vedotin. The median response duration was 36 weeks, and some responses lasted more than 8 months.
Seven patients had complete remissions, and 10 had partial remissions. In the other B-cell lymphoma patients, 22 had an objective response.
The researchers called this compelling antitumor activity in a highly refractory population.
“[Brentuximab vedotin] was more active than many expected,” Dr Jacobsen said. “In my opinion, these results are encouraging enough to take the drug forward in diffuse large B-cell lymphoma.”
The researchers said the drug’s safety profile was consistent with previous results. Six patients stopped treatment due to adverse events, including 2 who developed peripheral neuropathy.
Treatment-emergent adverse events included fatigue (40%), nausea (37%), neutropenia (37%), fever (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), anemia (21%), and constipation (21%).
Role of CD30
Brentuximab vedotin is a monoclonal antibody that binds to CD30. This molecule’s expression varies, but researchers have estimated that CD30 is present in a quarter to a third of B-cell non-Hodgkin lymphoma cells.
In this study, some of the patients’ lymphoma cells strongly expressed CD30. But, in other patients, the investigators were unable to detect any CD30 expression at all. And the patients’ level of CD30 expression bore no relationship to how they responded to the drug.
“In fact, although the trend was not statistically significant, there was almost an inverse correlation,” Dr Jacobsen said. “Some patients with the weakest CD30 expression had the most positive responses.”
One possible explanation for this is that the drug bound to another target, but preclinical tests suggested this was not the case. Other possibilities are that brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 in the lab or that different cells have differing abilities to ingest brentuximab once the antibody binds to the cell.
There is no clear answer from the study, Dr Jacobsen said, but lab tests are ongoing. He and his colleagues are beginning to evaluate the drug’s activity in a cohort of patients whose lymphomas have no measurable CD30 expression.
This study was supported by Seattle Genetics.
Credit: Linda Bartlett
NEW ORLEANS—Brentuximab vedotin has demonstrated “compelling” antitumor activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.
The investigators were also surprised
to find that the activity of this anti-CD30 monoclonal antibody
conjugate did not seem to
correlate with a patient’s level of CD30 expression.
In fact, some of
the patients with the weakest CD30 expression had the best responses to
the drug.
Eric Jacobsen, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues presented these results at the 2013 ASH Annual Meeting as abstract 848.
Thus far, the researchers have enrolled 62 patients with B-cell lymphomas, including 44 with DLBCL, on this phase 2 study.
Sixty-five percent of patients had primary refractory disease, 76% were refractory to their most recent prior therapy, and 23% had never responded to any treatment.
However, 40% of the 43 evaluable DLBCL patients had an objective response to brentuximab vedotin. The median response duration was 36 weeks, and some responses lasted more than 8 months.
Seven patients had complete remissions, and 10 had partial remissions. In the other B-cell lymphoma patients, 22 had an objective response.
The researchers called this compelling antitumor activity in a highly refractory population.
“[Brentuximab vedotin] was more active than many expected,” Dr Jacobsen said. “In my opinion, these results are encouraging enough to take the drug forward in diffuse large B-cell lymphoma.”
The researchers said the drug’s safety profile was consistent with previous results. Six patients stopped treatment due to adverse events, including 2 who developed peripheral neuropathy.
Treatment-emergent adverse events included fatigue (40%), nausea (37%), neutropenia (37%), fever (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), anemia (21%), and constipation (21%).
Role of CD30
Brentuximab vedotin is a monoclonal antibody that binds to CD30. This molecule’s expression varies, but researchers have estimated that CD30 is present in a quarter to a third of B-cell non-Hodgkin lymphoma cells.
In this study, some of the patients’ lymphoma cells strongly expressed CD30. But, in other patients, the investigators were unable to detect any CD30 expression at all. And the patients’ level of CD30 expression bore no relationship to how they responded to the drug.
“In fact, although the trend was not statistically significant, there was almost an inverse correlation,” Dr Jacobsen said. “Some patients with the weakest CD30 expression had the most positive responses.”
One possible explanation for this is that the drug bound to another target, but preclinical tests suggested this was not the case. Other possibilities are that brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 in the lab or that different cells have differing abilities to ingest brentuximab once the antibody binds to the cell.
There is no clear answer from the study, Dr Jacobsen said, but lab tests are ongoing. He and his colleagues are beginning to evaluate the drug’s activity in a cohort of patients whose lymphomas have no measurable CD30 expression.
This study was supported by Seattle Genetics.
Credit: Linda Bartlett
NEW ORLEANS—Brentuximab vedotin has demonstrated “compelling” antitumor activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.
The investigators were also surprised
to find that the activity of this anti-CD30 monoclonal antibody
conjugate did not seem to
correlate with a patient’s level of CD30 expression.
In fact, some of
the patients with the weakest CD30 expression had the best responses to
the drug.
Eric Jacobsen, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues presented these results at the 2013 ASH Annual Meeting as abstract 848.
Thus far, the researchers have enrolled 62 patients with B-cell lymphomas, including 44 with DLBCL, on this phase 2 study.
Sixty-five percent of patients had primary refractory disease, 76% were refractory to their most recent prior therapy, and 23% had never responded to any treatment.
However, 40% of the 43 evaluable DLBCL patients had an objective response to brentuximab vedotin. The median response duration was 36 weeks, and some responses lasted more than 8 months.
Seven patients had complete remissions, and 10 had partial remissions. In the other B-cell lymphoma patients, 22 had an objective response.
The researchers called this compelling antitumor activity in a highly refractory population.
“[Brentuximab vedotin] was more active than many expected,” Dr Jacobsen said. “In my opinion, these results are encouraging enough to take the drug forward in diffuse large B-cell lymphoma.”
The researchers said the drug’s safety profile was consistent with previous results. Six patients stopped treatment due to adverse events, including 2 who developed peripheral neuropathy.
Treatment-emergent adverse events included fatigue (40%), nausea (37%), neutropenia (37%), fever (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), anemia (21%), and constipation (21%).
Role of CD30
Brentuximab vedotin is a monoclonal antibody that binds to CD30. This molecule’s expression varies, but researchers have estimated that CD30 is present in a quarter to a third of B-cell non-Hodgkin lymphoma cells.
In this study, some of the patients’ lymphoma cells strongly expressed CD30. But, in other patients, the investigators were unable to detect any CD30 expression at all. And the patients’ level of CD30 expression bore no relationship to how they responded to the drug.
“In fact, although the trend was not statistically significant, there was almost an inverse correlation,” Dr Jacobsen said. “Some patients with the weakest CD30 expression had the most positive responses.”
One possible explanation for this is that the drug bound to another target, but preclinical tests suggested this was not the case. Other possibilities are that brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 in the lab or that different cells have differing abilities to ingest brentuximab once the antibody binds to the cell.
There is no clear answer from the study, Dr Jacobsen said, but lab tests are ongoing. He and his colleagues are beginning to evaluate the drug’s activity in a cohort of patients whose lymphomas have no measurable CD30 expression.
This study was supported by Seattle Genetics.
Lenalidomide therapy renews varicella risk in multiple myeloma
Patients with multiple myeloma who were treated with lenalidomide are susceptible to new-onset or reactivated varicella zoster infection, according to a new report.
Prophylactic acyclovir appears to minimize this risk, said Dr. C. König of the department of hematology and oncology, University of Freiburg (Germany) Medical Center, and associates.
Patients with multiple myeloma are known to be susceptible to infections from the myeloma itself; underlying immunodeficiency; the intensive therapies they receive; age-related conditions such as frailty and immobility; and disease-related conditions such as renal dysfunction, pulmonary impairment, or damage to the alimentary mucosa. In addition, specific antimyeloma agents such as bortezomib are known to raise the risk of varicella zoster virus reactivation or infection.
However, the risk of varicella zoster infection after treatment with lenalidomide is unknown.
Dr. König and colleagues reviewed the medical records of 132 consecutive multiple myeloma patients treated with lenalidomide at their center during a 4-year period and found that 10 (7.6%) had varicella zoster infections. Six patients were infected during treatment with lenalidomide or shortly afterward, and the other four were infected months later.
Of the 10 patients, 7 were men and 3 were women. Their ages ranged from 46 to 81 years
Seven of these cases were typical varicella zoster infections. In addition, one patient had varicella zoster encephalitis, one had disseminated varicella zoster, and one had varicella zoster with conus-cauda syndrome (Ann. Hematol. 2013 [doi:10.1007/s00277-013-1951-6]).
In two patients, the infection was a reactivation of latent varicella zoster.
Given that varicella is a known complication of other antimyeloma agents and acyclovir prophylaxis usually prevents it, Dr. König and associates then introduced routine acyclovir prophylaxis for their multiple myeloma patients slated to receive lenalidomide.
During the next 18 months, they treated 40 more multiple myeloma patients with lenalidomide, but only 37 of these patients adhered to the recommended daily acyclovir prophylaxis. None of those 37 developed varicella zoster infection. However, extensive varicella zoster developed in all three who didn’t take prophylactic acyclovir.
If these findings are confirmed in other, prospective studies, acyclovir prophylaxis may become routine for patients with multiple myeloma who are treated with lenalidomide, the investigators said.
It will be important to monitor renal function in such patients, given that antivirals are known to raise the risk of nephrotoxicity, they noted.
This study was supported by German Cancer Aid (Deutsche Krebshilfe). No financial conflicts of interest were reported.
Patients with multiple myeloma who were treated with lenalidomide are susceptible to new-onset or reactivated varicella zoster infection, according to a new report.
Prophylactic acyclovir appears to minimize this risk, said Dr. C. König of the department of hematology and oncology, University of Freiburg (Germany) Medical Center, and associates.
Patients with multiple myeloma are known to be susceptible to infections from the myeloma itself; underlying immunodeficiency; the intensive therapies they receive; age-related conditions such as frailty and immobility; and disease-related conditions such as renal dysfunction, pulmonary impairment, or damage to the alimentary mucosa. In addition, specific antimyeloma agents such as bortezomib are known to raise the risk of varicella zoster virus reactivation or infection.
However, the risk of varicella zoster infection after treatment with lenalidomide is unknown.
Dr. König and colleagues reviewed the medical records of 132 consecutive multiple myeloma patients treated with lenalidomide at their center during a 4-year period and found that 10 (7.6%) had varicella zoster infections. Six patients were infected during treatment with lenalidomide or shortly afterward, and the other four were infected months later.
Of the 10 patients, 7 were men and 3 were women. Their ages ranged from 46 to 81 years
Seven of these cases were typical varicella zoster infections. In addition, one patient had varicella zoster encephalitis, one had disseminated varicella zoster, and one had varicella zoster with conus-cauda syndrome (Ann. Hematol. 2013 [doi:10.1007/s00277-013-1951-6]).
In two patients, the infection was a reactivation of latent varicella zoster.
Given that varicella is a known complication of other antimyeloma agents and acyclovir prophylaxis usually prevents it, Dr. König and associates then introduced routine acyclovir prophylaxis for their multiple myeloma patients slated to receive lenalidomide.
During the next 18 months, they treated 40 more multiple myeloma patients with lenalidomide, but only 37 of these patients adhered to the recommended daily acyclovir prophylaxis. None of those 37 developed varicella zoster infection. However, extensive varicella zoster developed in all three who didn’t take prophylactic acyclovir.
If these findings are confirmed in other, prospective studies, acyclovir prophylaxis may become routine for patients with multiple myeloma who are treated with lenalidomide, the investigators said.
It will be important to monitor renal function in such patients, given that antivirals are known to raise the risk of nephrotoxicity, they noted.
This study was supported by German Cancer Aid (Deutsche Krebshilfe). No financial conflicts of interest were reported.
Patients with multiple myeloma who were treated with lenalidomide are susceptible to new-onset or reactivated varicella zoster infection, according to a new report.
Prophylactic acyclovir appears to minimize this risk, said Dr. C. König of the department of hematology and oncology, University of Freiburg (Germany) Medical Center, and associates.
Patients with multiple myeloma are known to be susceptible to infections from the myeloma itself; underlying immunodeficiency; the intensive therapies they receive; age-related conditions such as frailty and immobility; and disease-related conditions such as renal dysfunction, pulmonary impairment, or damage to the alimentary mucosa. In addition, specific antimyeloma agents such as bortezomib are known to raise the risk of varicella zoster virus reactivation or infection.
However, the risk of varicella zoster infection after treatment with lenalidomide is unknown.
Dr. König and colleagues reviewed the medical records of 132 consecutive multiple myeloma patients treated with lenalidomide at their center during a 4-year period and found that 10 (7.6%) had varicella zoster infections. Six patients were infected during treatment with lenalidomide or shortly afterward, and the other four were infected months later.
Of the 10 patients, 7 were men and 3 were women. Their ages ranged from 46 to 81 years
Seven of these cases were typical varicella zoster infections. In addition, one patient had varicella zoster encephalitis, one had disseminated varicella zoster, and one had varicella zoster with conus-cauda syndrome (Ann. Hematol. 2013 [doi:10.1007/s00277-013-1951-6]).
In two patients, the infection was a reactivation of latent varicella zoster.
Given that varicella is a known complication of other antimyeloma agents and acyclovir prophylaxis usually prevents it, Dr. König and associates then introduced routine acyclovir prophylaxis for their multiple myeloma patients slated to receive lenalidomide.
During the next 18 months, they treated 40 more multiple myeloma patients with lenalidomide, but only 37 of these patients adhered to the recommended daily acyclovir prophylaxis. None of those 37 developed varicella zoster infection. However, extensive varicella zoster developed in all three who didn’t take prophylactic acyclovir.
If these findings are confirmed in other, prospective studies, acyclovir prophylaxis may become routine for patients with multiple myeloma who are treated with lenalidomide, the investigators said.
It will be important to monitor renal function in such patients, given that antivirals are known to raise the risk of nephrotoxicity, they noted.
This study was supported by German Cancer Aid (Deutsche Krebshilfe). No financial conflicts of interest were reported.
FROM ANNALS OF HEPATOLOGY
Major finding: Ten of 132 patients (7.6%) who received lenalidomide for multiple myeloma developed varicella zoster infection.
Data source: A retrospective study of 132 consecutive patients with multiple myeloma who were treated with lenalidomide during a 4-year period at a single medical center.
Disclosures: This study was supported by German Cancer Aid (Deutsche Krebshilfe). No financial conflicts of interest were reported.
Renal failure in multiple myeloma
This report details the case of a 65-year-old man who was diagnosed with multiple myeloma in 2006 and since 2009, has attempted to control the progression of his disease with the most powerful available treatment regimens, including bortezomib-based regimens, for both induction and consolidation therapy followed by autologous stem-cell transplants. Subsequently, because the patient was deemed treatment refractory, treatment with the newly approved carfilzomib was initiated. Coincidentally, the patient developed acute kidney injury, evidenced by tenfold rise in his creatinine levels, 2 weeks after the initiation of carfilzomib.
Click on the PDF icon at the top of this introduction to read the full article.
This report details the case of a 65-year-old man who was diagnosed with multiple myeloma in 2006 and since 2009, has attempted to control the progression of his disease with the most powerful available treatment regimens, including bortezomib-based regimens, for both induction and consolidation therapy followed by autologous stem-cell transplants. Subsequently, because the patient was deemed treatment refractory, treatment with the newly approved carfilzomib was initiated. Coincidentally, the patient developed acute kidney injury, evidenced by tenfold rise in his creatinine levels, 2 weeks after the initiation of carfilzomib.
Click on the PDF icon at the top of this introduction to read the full article.
This report details the case of a 65-year-old man who was diagnosed with multiple myeloma in 2006 and since 2009, has attempted to control the progression of his disease with the most powerful available treatment regimens, including bortezomib-based regimens, for both induction and consolidation therapy followed by autologous stem-cell transplants. Subsequently, because the patient was deemed treatment refractory, treatment with the newly approved carfilzomib was initiated. Coincidentally, the patient developed acute kidney injury, evidenced by tenfold rise in his creatinine levels, 2 weeks after the initiation of carfilzomib.
Click on the PDF icon at the top of this introduction to read the full article.
Enzastaurin no better than placebo in DLBCL
Convention Center, site of the
2013 ASH Annual Meeting
NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.
All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.
The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.
Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.
Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.
“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.
“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.”
With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.
Patient population
The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.
The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.
The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively).
Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).
Survival outcomes
The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).
The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).
The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).
The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.
Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).
“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”
“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.”
Adverse events
Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.
Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).
Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.
Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.
Convention Center, site of the
2013 ASH Annual Meeting
NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.
All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.
The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.
Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.
Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.
“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.
“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.”
With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.
Patient population
The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.
The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.
The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively).
Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).
Survival outcomes
The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).
The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).
The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).
The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.
Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).
“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”
“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.”
Adverse events
Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.
Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).
Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.
Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.
Convention Center, site of the
2013 ASH Annual Meeting
NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.
All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.
The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.
Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.
Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.
“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.
“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.”
With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.
Patient population
The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.
The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.
The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively).
Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).
Survival outcomes
The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).
The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).
The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).
The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.
Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).
“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”
“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.”
Adverse events
Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.
Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).
Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.
Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.
Diffuse large B-cell lymphoma of the lung in a 63-year-old man with left flank pain
Diffuse large B-cell lymphoma of the lung is a rare entity, and although the prognosis is favorable, its biological features, clinical presentation, prognostic markers, and treatment have not been well defined.1,2 It is the second most common primary pulmonary lymphoma after mucosa-associated lymphoid tissue. PPL itself is very rare; it represents 3%-4% of extranodal non-Hodgkin lymphoma, less than 1% of NHL, and 0.5%-1.0% of primary pulmonary malignancies.2,3 A review of the literature indicates a lack of data on pulmonary DLBCL. The objective of this case report is to highlight areas in which further research may be pursued to better understand this disease.
Click on the PDF icon at the top of this introduction to read the full article.
Diffuse large B-cell lymphoma of the lung is a rare entity, and although the prognosis is favorable, its biological features, clinical presentation, prognostic markers, and treatment have not been well defined.1,2 It is the second most common primary pulmonary lymphoma after mucosa-associated lymphoid tissue. PPL itself is very rare; it represents 3%-4% of extranodal non-Hodgkin lymphoma, less than 1% of NHL, and 0.5%-1.0% of primary pulmonary malignancies.2,3 A review of the literature indicates a lack of data on pulmonary DLBCL. The objective of this case report is to highlight areas in which further research may be pursued to better understand this disease.
Click on the PDF icon at the top of this introduction to read the full article.
Diffuse large B-cell lymphoma of the lung is a rare entity, and although the prognosis is favorable, its biological features, clinical presentation, prognostic markers, and treatment have not been well defined.1,2 It is the second most common primary pulmonary lymphoma after mucosa-associated lymphoid tissue. PPL itself is very rare; it represents 3%-4% of extranodal non-Hodgkin lymphoma, less than 1% of NHL, and 0.5%-1.0% of primary pulmonary malignancies.2,3 A review of the literature indicates a lack of data on pulmonary DLBCL. The objective of this case report is to highlight areas in which further research may be pursued to better understand this disease.
Click on the PDF icon at the top of this introduction to read the full article.