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Longer course of idarubicin consolidation increases leukemia-free survival
In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.
The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.
The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.
More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).
Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.
There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.
In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.
The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.
In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.
The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.
The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.
More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).
Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.
There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.
In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.
The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.
In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.
The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.
The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.
More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).
Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.
There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.
In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.
The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.
Key clinical point:
Major finding: The median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin.
Data source: A multicenter randomized phase III trial involving 293 patients.
Disclosures: The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australis. His associates reported ties to numerous industry sources.
Maintenance lenalidomide prolongs progression-free survival in DLBCL
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Key clinical point:
Major finding: Median progression-free survival was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide.
Data source: A 5-year international, randomized double-blind placebo-controlled phase III trial involving 650 patients aged 60-80 years.
Disclosures: The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
FDA boxed warning leads to drop off in use of ESAs
The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.
Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.
The investigators analyzed data in the SEER cancer registry for the period immediately before and immediately after the 2007 boxed warning was issued. Their sample comprised 45,319 patients aged 66 years and older who were treated either in the “pre” warning period (January 2004-September 2006) or the “post” period (April 2007-September 2009). This included a control group of 3,375 patients with myelodysplastic syndromes. Use of ESAs in these patients was off-label and was not targeted by the boxed warning (J Clin Oncol. 2017 Apr 25. doi: 10.1200/JCO.2017.72.6273).The use of ESAs declined sharply after the boxed warning was issued, except in the control group. The proportion of breast cancer patients receiving ESAs dropped from 49%-55% before 2007 to 30% in 2007, 16% in 2008, and 9% in 2009.
Similarly, the proportion of colorectal cancer patients receiving ESAs declined from about 35%-40% before 2007 to 18% in 2007, 11% in 2008, and 9% in 2009. The proportion of lung cancer patients receiving ESAs decreased from 56%-58% before 2007 to 40% in 2007, 29% in 2008, and 24% in 2009. In contrast, the proportion of patients with myelodysplastic syndromes receiving ESAs – the control group – remained relatively stable at 39%-42% before 2007, 35% in 2007, and 32% in 2008 and 2009.
This represents a reduction of approximately 40% overall in the use of ESAs among targeted patients after the warning was issued. However, this decrease appeared to have little effect on the incidence of hospitalization for venous thromboembolism in this patient population, Dr. Bian and his associates noted.
The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.
The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.
Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.
The investigators analyzed data in the SEER cancer registry for the period immediately before and immediately after the 2007 boxed warning was issued. Their sample comprised 45,319 patients aged 66 years and older who were treated either in the “pre” warning period (January 2004-September 2006) or the “post” period (April 2007-September 2009). This included a control group of 3,375 patients with myelodysplastic syndromes. Use of ESAs in these patients was off-label and was not targeted by the boxed warning (J Clin Oncol. 2017 Apr 25. doi: 10.1200/JCO.2017.72.6273).The use of ESAs declined sharply after the boxed warning was issued, except in the control group. The proportion of breast cancer patients receiving ESAs dropped from 49%-55% before 2007 to 30% in 2007, 16% in 2008, and 9% in 2009.
Similarly, the proportion of colorectal cancer patients receiving ESAs declined from about 35%-40% before 2007 to 18% in 2007, 11% in 2008, and 9% in 2009. The proportion of lung cancer patients receiving ESAs decreased from 56%-58% before 2007 to 40% in 2007, 29% in 2008, and 24% in 2009. In contrast, the proportion of patients with myelodysplastic syndromes receiving ESAs – the control group – remained relatively stable at 39%-42% before 2007, 35% in 2007, and 32% in 2008 and 2009.
This represents a reduction of approximately 40% overall in the use of ESAs among targeted patients after the warning was issued. However, this decrease appeared to have little effect on the incidence of hospitalization for venous thromboembolism in this patient population, Dr. Bian and his associates noted.
The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.
The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.
Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.
The investigators analyzed data in the SEER cancer registry for the period immediately before and immediately after the 2007 boxed warning was issued. Their sample comprised 45,319 patients aged 66 years and older who were treated either in the “pre” warning period (January 2004-September 2006) or the “post” period (April 2007-September 2009). This included a control group of 3,375 patients with myelodysplastic syndromes. Use of ESAs in these patients was off-label and was not targeted by the boxed warning (J Clin Oncol. 2017 Apr 25. doi: 10.1200/JCO.2017.72.6273).The use of ESAs declined sharply after the boxed warning was issued, except in the control group. The proportion of breast cancer patients receiving ESAs dropped from 49%-55% before 2007 to 30% in 2007, 16% in 2008, and 9% in 2009.
Similarly, the proportion of colorectal cancer patients receiving ESAs declined from about 35%-40% before 2007 to 18% in 2007, 11% in 2008, and 9% in 2009. The proportion of lung cancer patients receiving ESAs decreased from 56%-58% before 2007 to 40% in 2007, 29% in 2008, and 24% in 2009. In contrast, the proportion of patients with myelodysplastic syndromes receiving ESAs – the control group – remained relatively stable at 39%-42% before 2007, 35% in 2007, and 32% in 2008 and 2009.
This represents a reduction of approximately 40% overall in the use of ESAs among targeted patients after the warning was issued. However, this decrease appeared to have little effect on the incidence of hospitalization for venous thromboembolism in this patient population, Dr. Bian and his associates noted.
The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.
Key clinical point:
Major finding: The use of ESAs among cancer patients that were targeted by the boxed warning dropped by about 40% after the warning was issued.
Data source: A retrospective cohort study involving 45,319 cancer patients enrolled in the SEER data registry during 2004-2009.
Disclosures: The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.
TNFSF13B variant linked to MS and SLE
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world. 
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
Key clinical point: A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus.
Major finding: BAFF-var was the TNFSF13B variant most strongly associated with MS in Sardinia (OR, 1.27), and was also associated with SLE in Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55).
Data source: A series of genome-wide association studies and other genetic studies involving thousands of patients with MS or SLE in Sardinia and confirmed in thousands of patients across Italy, Spain, Sweden, and the United Kingdom.
Disclosures: The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
USPSTF says check BP at each visit to screen for preeclampsia
Blood pressure should be checked at every prenatal visit to screen for preeclampsia, according to a new recommendation from the U.S. Preventive Services Task Force.
The USPSTF commissioned a review of the current literature to update its initial recommendation regarding preeclampsia screening, which was issued in 1996. The update was considered important “given changes to screening, diagnosis, and management practices, as well as population health, over the past two decades.”
However, the evidence regarding different screening approaches is still quite limited, and the USPSTF did not change its recommendation except to indicate blood pressure checks at every visit rather than “periodically.” The current advice is a “B” recommendation, meaning that the USPSTF recommends the service.
Blood pressure assessment remains the most reliable, least harmful strategy for identifying preeclampsia as early as possible, said Kirsten Bobbins-Domingo, MD, PhD, chair of the USPSTF and lead author of the recommendation statement, and her associates.
“The USPSTF concludes with moderate certainty that screening for preeclampsia in pregnant women with blood pressure measurements has a substantial net benefit,” the researchers wrote (JAMA. 2017;317[16]:1661-7).
The evidence report supporting this recommendation included 21 studies involving 13,982 pregnant women. But no studies directly compared the effectiveness of blood pressure screening between screened and unscreened populations, Jillian T. Henderson, PhD, of Kaiser Permanente Center for Health Research, Portland, Ore., and her associates said in the report.
Fourteen studies assessed tests for protein in the urine to identify preeclampsia, but the accuracy of such tests was highly variable. Sensitivity ranged from 22% to 100% and specificity ranged from 36% to 100%, so the USPSTF did not recommend urine testing for proteinuria as a screen for preeclampsia.
In addition, Dr. Henderson and her associates reviewed four studies (involving 7,123 women) assessing 16 different risk-prediction models. Again, the findings did not support the routine use of such tools in clinical practice: their positive predictive value was just 4% in the largest validation cohort, the investigators reported (JAMA. 2017;317[16]:1668-83).
The American College of Obstetricians and Gynecologists recommends monitoring blood pressure at every prenatal visit to screen for preeclampsia, as well as obtaining a detailed medical history to assess risk factors for the disorder. In contrast, the Society of Obstetricians and Gynaecologists of Canada and the National Institute for Health and Care Excellence in the United Kingdom recommend urinalysis for proteinuria in addition to blood pressure screening.
The full recommendation statement and evidence report are available at www.uspreventiveservicestaskforce.org.
The use of blood pressure measurement at every prenatal visit is a simple and effective way to identify and treat at-risk women without adding any substantial risks. In contrast, the risks related to preeclampsia are very high. Although risk assessment tools for preeclampsia are available, their low positive predictive value currently limits their usefulness for screening. Given the incidence of preeclampsia and the lack of predictability, it is important that all pregnant women have routine blood pressure assessments at every visit during the prenatal period.
The emerging data relating preeclampsia to the risk of future cardiovascular disease make this pregnancy-related issue important not just for obstetricians for the acute risks but also for internists and cardiologists for the long-term risks.
Martha Gulati, MD, is in the division of cardiology at the University of Arizona, Phoenix. She reported having no relevant financial disclosures. These remarks are excerpted from an editorial (JAMA Cardiol. 2017 Apr 25. doi: 10.1001/jamacardio.2017.1276).
The use of blood pressure measurement at every prenatal visit is a simple and effective way to identify and treat at-risk women without adding any substantial risks. In contrast, the risks related to preeclampsia are very high. Although risk assessment tools for preeclampsia are available, their low positive predictive value currently limits their usefulness for screening. Given the incidence of preeclampsia and the lack of predictability, it is important that all pregnant women have routine blood pressure assessments at every visit during the prenatal period.
The emerging data relating preeclampsia to the risk of future cardiovascular disease make this pregnancy-related issue important not just for obstetricians for the acute risks but also for internists and cardiologists for the long-term risks.
Martha Gulati, MD, is in the division of cardiology at the University of Arizona, Phoenix. She reported having no relevant financial disclosures. These remarks are excerpted from an editorial (JAMA Cardiol. 2017 Apr 25. doi: 10.1001/jamacardio.2017.1276).
The use of blood pressure measurement at every prenatal visit is a simple and effective way to identify and treat at-risk women without adding any substantial risks. In contrast, the risks related to preeclampsia are very high. Although risk assessment tools for preeclampsia are available, their low positive predictive value currently limits their usefulness for screening. Given the incidence of preeclampsia and the lack of predictability, it is important that all pregnant women have routine blood pressure assessments at every visit during the prenatal period.
The emerging data relating preeclampsia to the risk of future cardiovascular disease make this pregnancy-related issue important not just for obstetricians for the acute risks but also for internists and cardiologists for the long-term risks.
Martha Gulati, MD, is in the division of cardiology at the University of Arizona, Phoenix. She reported having no relevant financial disclosures. These remarks are excerpted from an editorial (JAMA Cardiol. 2017 Apr 25. doi: 10.1001/jamacardio.2017.1276).
Blood pressure should be checked at every prenatal visit to screen for preeclampsia, according to a new recommendation from the U.S. Preventive Services Task Force.
The USPSTF commissioned a review of the current literature to update its initial recommendation regarding preeclampsia screening, which was issued in 1996. The update was considered important “given changes to screening, diagnosis, and management practices, as well as population health, over the past two decades.”
However, the evidence regarding different screening approaches is still quite limited, and the USPSTF did not change its recommendation except to indicate blood pressure checks at every visit rather than “periodically.” The current advice is a “B” recommendation, meaning that the USPSTF recommends the service.
Blood pressure assessment remains the most reliable, least harmful strategy for identifying preeclampsia as early as possible, said Kirsten Bobbins-Domingo, MD, PhD, chair of the USPSTF and lead author of the recommendation statement, and her associates.
“The USPSTF concludes with moderate certainty that screening for preeclampsia in pregnant women with blood pressure measurements has a substantial net benefit,” the researchers wrote (JAMA. 2017;317[16]:1661-7).
The evidence report supporting this recommendation included 21 studies involving 13,982 pregnant women. But no studies directly compared the effectiveness of blood pressure screening between screened and unscreened populations, Jillian T. Henderson, PhD, of Kaiser Permanente Center for Health Research, Portland, Ore., and her associates said in the report.
Fourteen studies assessed tests for protein in the urine to identify preeclampsia, but the accuracy of such tests was highly variable. Sensitivity ranged from 22% to 100% and specificity ranged from 36% to 100%, so the USPSTF did not recommend urine testing for proteinuria as a screen for preeclampsia.
In addition, Dr. Henderson and her associates reviewed four studies (involving 7,123 women) assessing 16 different risk-prediction models. Again, the findings did not support the routine use of such tools in clinical practice: their positive predictive value was just 4% in the largest validation cohort, the investigators reported (JAMA. 2017;317[16]:1668-83).
The American College of Obstetricians and Gynecologists recommends monitoring blood pressure at every prenatal visit to screen for preeclampsia, as well as obtaining a detailed medical history to assess risk factors for the disorder. In contrast, the Society of Obstetricians and Gynaecologists of Canada and the National Institute for Health and Care Excellence in the United Kingdom recommend urinalysis for proteinuria in addition to blood pressure screening.
The full recommendation statement and evidence report are available at www.uspreventiveservicestaskforce.org.
Blood pressure should be checked at every prenatal visit to screen for preeclampsia, according to a new recommendation from the U.S. Preventive Services Task Force.
The USPSTF commissioned a review of the current literature to update its initial recommendation regarding preeclampsia screening, which was issued in 1996. The update was considered important “given changes to screening, diagnosis, and management practices, as well as population health, over the past two decades.”
However, the evidence regarding different screening approaches is still quite limited, and the USPSTF did not change its recommendation except to indicate blood pressure checks at every visit rather than “periodically.” The current advice is a “B” recommendation, meaning that the USPSTF recommends the service.
Blood pressure assessment remains the most reliable, least harmful strategy for identifying preeclampsia as early as possible, said Kirsten Bobbins-Domingo, MD, PhD, chair of the USPSTF and lead author of the recommendation statement, and her associates.
“The USPSTF concludes with moderate certainty that screening for preeclampsia in pregnant women with blood pressure measurements has a substantial net benefit,” the researchers wrote (JAMA. 2017;317[16]:1661-7).
The evidence report supporting this recommendation included 21 studies involving 13,982 pregnant women. But no studies directly compared the effectiveness of blood pressure screening between screened and unscreened populations, Jillian T. Henderson, PhD, of Kaiser Permanente Center for Health Research, Portland, Ore., and her associates said in the report.
Fourteen studies assessed tests for protein in the urine to identify preeclampsia, but the accuracy of such tests was highly variable. Sensitivity ranged from 22% to 100% and specificity ranged from 36% to 100%, so the USPSTF did not recommend urine testing for proteinuria as a screen for preeclampsia.
In addition, Dr. Henderson and her associates reviewed four studies (involving 7,123 women) assessing 16 different risk-prediction models. Again, the findings did not support the routine use of such tools in clinical practice: their positive predictive value was just 4% in the largest validation cohort, the investigators reported (JAMA. 2017;317[16]:1668-83).
The American College of Obstetricians and Gynecologists recommends monitoring blood pressure at every prenatal visit to screen for preeclampsia, as well as obtaining a detailed medical history to assess risk factors for the disorder. In contrast, the Society of Obstetricians and Gynaecologists of Canada and the National Institute for Health and Care Excellence in the United Kingdom recommend urinalysis for proteinuria in addition to blood pressure screening.
The full recommendation statement and evidence report are available at www.uspreventiveservicestaskforce.org.
Key clinical point:
Major finding: The 14 studies about testing for proteinuria and the 4 studies about 16 different risk prediction tools did not yield evidence to support either approach as a screen for preeclampsia.
Data source: A review of 21 studies involving 13,982 pregnant women, performed since the initial USPSTF recommendation was issued in 1996.
Disclosures: The USPSTF is an independent voluntary group supported by the Agency for Healthcare Research and Quality.
Later follow-up colonoscopy equals higher colorectal cancer risk
Patients who undergo follow-up colonoscopy 10 months or more after a positive fecal immunochemical test are at higher risk for colorectal cancer, and for having more advanced disease at diagnosis, than are those who undergo immediate (within 30 days) follow-up colonoscopy, according to a new report.
Clinical practice guidelines recommend follow-up colonoscopy after a positive fecal immunochemical test (FIT) result but differ about how quickly the procedure should be done, chiefly because there is little evidence on which to base any recommendation regarding timing, reported Douglas A. Corley, MD, PhD, of Kaiser Permanente Northern California, Oakland, and his associates. The study results were published in JAMA.
To examine whether the length of the interval between FIT testing and colonoscopy affected diagnosis, they analyzed clinical data for 70,124 adults aged 50-75 years who were members of two large health organizations and who completed FIT testing during a 3-year period. The investigators compared outcomes among the 27,176 patients who had follow-up colonoscopy within 30 days (the reference group) against those of patients who had follow-up colonoscopy after 2 months (24,644 patients), 3 months (8,666 patients), 4-6 months (5,251 patients), 7-9 months (1,335 patients), 10-12 months (748 patients), or more than 12 months (2,304 patients).
A total of 2,191 colorectal cancers were diagnosed at follow-up colonoscopy, including 601 cases of advanced disease, the investigators reported (JAMA. 2017;317[16]:1631-41).
There was no significant increase in risk for any colorectal cancer or for advanced colorectal cancer among patients who had follow-up colonoscopy within 9 months, compared with the reference group. However, the risks of any colorectal cancer and of advanced colorectal cancer increased significantly at 10 months, with odds ratios of 1.48 and 1.97, respectively.
These risks continued to rise as the interval between testing and colonoscopy lengthened, so that after 1 year, the odds ratios were 2.25 for any colorectal cancer and 3.22 for advanced-stage disease. After 1 year, the odds ratios were 1.32 for advanced adenomas, 2.94 for stage II, 3.07 for stage III, and 3.86 for stage IV colorectal cancer.
The National Cancer Institute supported the study. Dr. Corley reported receiving grant support from Wyeth/Pfizer.
The study by Corley et al. provides important reassurance for patients and physicians. The findings indicate that there is no immediate need to rush to have a colonoscopy after a positive FIT result, reflecting the clinical understanding that colorectal cancer is a disease that generally develops slowly. Longer time to follow-up will reduce the benefit of FIT, with detection of more cancers and more late-stage disease.
The study had one important limitation: The authors were unable to adjust for an important confounder – the indication for colonoscopy. The problem with not being able to account for indication is that patients who wish to avoid colonoscopy may delay the procedure until the onset of symptoms. Patients who return later could disproportionately represent symptomatic patients if colonoscopy-avoidant patients without symptoms are less likely to return for follow-up colonoscopy as they get further from the time of their positive FIT result.
Carolyn M. Rutter, PhD, is at the RAND Corporation, Santa Monica, Calif. John M. Inadomi, MD, is at the University of Washington, Seattle. Dr. Inadomi reported receiving grants from NinePoint Medical. Dr. Rutter reported having no disclosures. These comments are adapted from an accompanying editorial (JAMA 2107;317[16]:1627-8).
The study by Corley et al. provides important reassurance for patients and physicians. The findings indicate that there is no immediate need to rush to have a colonoscopy after a positive FIT result, reflecting the clinical understanding that colorectal cancer is a disease that generally develops slowly. Longer time to follow-up will reduce the benefit of FIT, with detection of more cancers and more late-stage disease.
The study had one important limitation: The authors were unable to adjust for an important confounder – the indication for colonoscopy. The problem with not being able to account for indication is that patients who wish to avoid colonoscopy may delay the procedure until the onset of symptoms. Patients who return later could disproportionately represent symptomatic patients if colonoscopy-avoidant patients without symptoms are less likely to return for follow-up colonoscopy as they get further from the time of their positive FIT result.
Carolyn M. Rutter, PhD, is at the RAND Corporation, Santa Monica, Calif. John M. Inadomi, MD, is at the University of Washington, Seattle. Dr. Inadomi reported receiving grants from NinePoint Medical. Dr. Rutter reported having no disclosures. These comments are adapted from an accompanying editorial (JAMA 2107;317[16]:1627-8).
The study by Corley et al. provides important reassurance for patients and physicians. The findings indicate that there is no immediate need to rush to have a colonoscopy after a positive FIT result, reflecting the clinical understanding that colorectal cancer is a disease that generally develops slowly. Longer time to follow-up will reduce the benefit of FIT, with detection of more cancers and more late-stage disease.
The study had one important limitation: The authors were unable to adjust for an important confounder – the indication for colonoscopy. The problem with not being able to account for indication is that patients who wish to avoid colonoscopy may delay the procedure until the onset of symptoms. Patients who return later could disproportionately represent symptomatic patients if colonoscopy-avoidant patients without symptoms are less likely to return for follow-up colonoscopy as they get further from the time of their positive FIT result.
Carolyn M. Rutter, PhD, is at the RAND Corporation, Santa Monica, Calif. John M. Inadomi, MD, is at the University of Washington, Seattle. Dr. Inadomi reported receiving grants from NinePoint Medical. Dr. Rutter reported having no disclosures. These comments are adapted from an accompanying editorial (JAMA 2107;317[16]:1627-8).
Patients who undergo follow-up colonoscopy 10 months or more after a positive fecal immunochemical test are at higher risk for colorectal cancer, and for having more advanced disease at diagnosis, than are those who undergo immediate (within 30 days) follow-up colonoscopy, according to a new report.
Clinical practice guidelines recommend follow-up colonoscopy after a positive fecal immunochemical test (FIT) result but differ about how quickly the procedure should be done, chiefly because there is little evidence on which to base any recommendation regarding timing, reported Douglas A. Corley, MD, PhD, of Kaiser Permanente Northern California, Oakland, and his associates. The study results were published in JAMA.
To examine whether the length of the interval between FIT testing and colonoscopy affected diagnosis, they analyzed clinical data for 70,124 adults aged 50-75 years who were members of two large health organizations and who completed FIT testing during a 3-year period. The investigators compared outcomes among the 27,176 patients who had follow-up colonoscopy within 30 days (the reference group) against those of patients who had follow-up colonoscopy after 2 months (24,644 patients), 3 months (8,666 patients), 4-6 months (5,251 patients), 7-9 months (1,335 patients), 10-12 months (748 patients), or more than 12 months (2,304 patients).
A total of 2,191 colorectal cancers were diagnosed at follow-up colonoscopy, including 601 cases of advanced disease, the investigators reported (JAMA. 2017;317[16]:1631-41).
There was no significant increase in risk for any colorectal cancer or for advanced colorectal cancer among patients who had follow-up colonoscopy within 9 months, compared with the reference group. However, the risks of any colorectal cancer and of advanced colorectal cancer increased significantly at 10 months, with odds ratios of 1.48 and 1.97, respectively.
These risks continued to rise as the interval between testing and colonoscopy lengthened, so that after 1 year, the odds ratios were 2.25 for any colorectal cancer and 3.22 for advanced-stage disease. After 1 year, the odds ratios were 1.32 for advanced adenomas, 2.94 for stage II, 3.07 for stage III, and 3.86 for stage IV colorectal cancer.
The National Cancer Institute supported the study. Dr. Corley reported receiving grant support from Wyeth/Pfizer.
Patients who undergo follow-up colonoscopy 10 months or more after a positive fecal immunochemical test are at higher risk for colorectal cancer, and for having more advanced disease at diagnosis, than are those who undergo immediate (within 30 days) follow-up colonoscopy, according to a new report.
Clinical practice guidelines recommend follow-up colonoscopy after a positive fecal immunochemical test (FIT) result but differ about how quickly the procedure should be done, chiefly because there is little evidence on which to base any recommendation regarding timing, reported Douglas A. Corley, MD, PhD, of Kaiser Permanente Northern California, Oakland, and his associates. The study results were published in JAMA.
To examine whether the length of the interval between FIT testing and colonoscopy affected diagnosis, they analyzed clinical data for 70,124 adults aged 50-75 years who were members of two large health organizations and who completed FIT testing during a 3-year period. The investigators compared outcomes among the 27,176 patients who had follow-up colonoscopy within 30 days (the reference group) against those of patients who had follow-up colonoscopy after 2 months (24,644 patients), 3 months (8,666 patients), 4-6 months (5,251 patients), 7-9 months (1,335 patients), 10-12 months (748 patients), or more than 12 months (2,304 patients).
A total of 2,191 colorectal cancers were diagnosed at follow-up colonoscopy, including 601 cases of advanced disease, the investigators reported (JAMA. 2017;317[16]:1631-41).
There was no significant increase in risk for any colorectal cancer or for advanced colorectal cancer among patients who had follow-up colonoscopy within 9 months, compared with the reference group. However, the risks of any colorectal cancer and of advanced colorectal cancer increased significantly at 10 months, with odds ratios of 1.48 and 1.97, respectively.
These risks continued to rise as the interval between testing and colonoscopy lengthened, so that after 1 year, the odds ratios were 2.25 for any colorectal cancer and 3.22 for advanced-stage disease. After 1 year, the odds ratios were 1.32 for advanced adenomas, 2.94 for stage II, 3.07 for stage III, and 3.86 for stage IV colorectal cancer.
The National Cancer Institute supported the study. Dr. Corley reported receiving grant support from Wyeth/Pfizer.
Key clinical point:
Major finding: For patients who delayed follow-up colonoscopy for 10 months, the risks of any colorectal cancer (OR, 1.48) and of advanced colorectal cancer (OR, 1.97) increased significantly.
Data source: A retrospective cohort study involving 70,124 patients who had a positive FIT result and a follow-up colonoscopy during a 3-year period.
Disclosures: The National Cancer Institute supported the study. Dr. Corley reported receiving grant support from Wyeth/Pfizer.
Reflectance confocal microscopy offers one-stop solution for BCC
For selected patients with basal cell carcinoma, one-stop shopping – diagnosing, subtyping, and excising the lesion all in one visit – using reflectance confocal microscopy was found noninferior to the standard approach of obtaining a punch biopsy to diagnose and subtype the lesion in one visit and performing surgical excision in a separate visit.
Those were the findings of an open-label, randomized, noninferiority trial in the Netherlands comparing the two approaches in 95 adults with suspected basal cell carcinoma (BCC), investigators reported.
In addition to reducing the number of visits and the total time required for treatment, this new approach uses noninvasive reflectance confocal microscopy in the place of punch biopsy, which patients will likely prefer, said Daniel J. Kadouch, MD, of the department of dermatology, Academic Medical Center, Amsterdam, and his associates (British J Derm. 2017 Apr 9. doi: 10.1111/bjd.15559).
The study excluded patients who had lesions in a high-risk location of the face, lesions larger than 20 mm, recurrent lesions, and macroscopic ulcerating lesions, as well as patients who had basal cell nevus syndrome. Another 22 patients who were found to have non-BCC lesions (1 melanoma, 2 squamous cell carcinomas, 5 cases of Bowen’s disease, and 11 nonmalignant lesions) also were excluded, leaving 40 patients with BCC in the one-stop shopping group and 33 in the standard of care (control) group.
The primary outcome – the proportion of patients with tumor-free margins on the final pathology report after surgical excision – was 100% (40 of 40) in the one-stop shopping group and 94% (31 of 33) in the control group, which demonstrates the noninferiority of the new, less invasive approach, Dr. Kadouch and his associates said.
The mean total treatment time was 2 hours and 23 minutes for the one-stop shopping group. The total treatment time could not be determined for the control group because their surgical times weren’t recorded.
Adverse events included four postoperative wound infections in the one-stop shopping group, all of which were successfully treated with oral antibiotics, and one case of excessive postoperative bleeding in the control group, which required 3 days of hospitalization.
This study was limited in that it excluded patients with large lesions and those with BCC on high-risk areas of the face, which reduces the generalizability of the findings. In addition, a follow-up time of at least 1 year would be needed to detect signs of BCC recurrence in the study participants, the investigators said.
For selected patients with basal cell carcinoma, one-stop shopping – diagnosing, subtyping, and excising the lesion all in one visit – using reflectance confocal microscopy was found noninferior to the standard approach of obtaining a punch biopsy to diagnose and subtype the lesion in one visit and performing surgical excision in a separate visit.
Those were the findings of an open-label, randomized, noninferiority trial in the Netherlands comparing the two approaches in 95 adults with suspected basal cell carcinoma (BCC), investigators reported.
In addition to reducing the number of visits and the total time required for treatment, this new approach uses noninvasive reflectance confocal microscopy in the place of punch biopsy, which patients will likely prefer, said Daniel J. Kadouch, MD, of the department of dermatology, Academic Medical Center, Amsterdam, and his associates (British J Derm. 2017 Apr 9. doi: 10.1111/bjd.15559).
The study excluded patients who had lesions in a high-risk location of the face, lesions larger than 20 mm, recurrent lesions, and macroscopic ulcerating lesions, as well as patients who had basal cell nevus syndrome. Another 22 patients who were found to have non-BCC lesions (1 melanoma, 2 squamous cell carcinomas, 5 cases of Bowen’s disease, and 11 nonmalignant lesions) also were excluded, leaving 40 patients with BCC in the one-stop shopping group and 33 in the standard of care (control) group.
The primary outcome – the proportion of patients with tumor-free margins on the final pathology report after surgical excision – was 100% (40 of 40) in the one-stop shopping group and 94% (31 of 33) in the control group, which demonstrates the noninferiority of the new, less invasive approach, Dr. Kadouch and his associates said.
The mean total treatment time was 2 hours and 23 minutes for the one-stop shopping group. The total treatment time could not be determined for the control group because their surgical times weren’t recorded.
Adverse events included four postoperative wound infections in the one-stop shopping group, all of which were successfully treated with oral antibiotics, and one case of excessive postoperative bleeding in the control group, which required 3 days of hospitalization.
This study was limited in that it excluded patients with large lesions and those with BCC on high-risk areas of the face, which reduces the generalizability of the findings. In addition, a follow-up time of at least 1 year would be needed to detect signs of BCC recurrence in the study participants, the investigators said.
For selected patients with basal cell carcinoma, one-stop shopping – diagnosing, subtyping, and excising the lesion all in one visit – using reflectance confocal microscopy was found noninferior to the standard approach of obtaining a punch biopsy to diagnose and subtype the lesion in one visit and performing surgical excision in a separate visit.
Those were the findings of an open-label, randomized, noninferiority trial in the Netherlands comparing the two approaches in 95 adults with suspected basal cell carcinoma (BCC), investigators reported.
In addition to reducing the number of visits and the total time required for treatment, this new approach uses noninvasive reflectance confocal microscopy in the place of punch biopsy, which patients will likely prefer, said Daniel J. Kadouch, MD, of the department of dermatology, Academic Medical Center, Amsterdam, and his associates (British J Derm. 2017 Apr 9. doi: 10.1111/bjd.15559).
The study excluded patients who had lesions in a high-risk location of the face, lesions larger than 20 mm, recurrent lesions, and macroscopic ulcerating lesions, as well as patients who had basal cell nevus syndrome. Another 22 patients who were found to have non-BCC lesions (1 melanoma, 2 squamous cell carcinomas, 5 cases of Bowen’s disease, and 11 nonmalignant lesions) also were excluded, leaving 40 patients with BCC in the one-stop shopping group and 33 in the standard of care (control) group.
The primary outcome – the proportion of patients with tumor-free margins on the final pathology report after surgical excision – was 100% (40 of 40) in the one-stop shopping group and 94% (31 of 33) in the control group, which demonstrates the noninferiority of the new, less invasive approach, Dr. Kadouch and his associates said.
The mean total treatment time was 2 hours and 23 minutes for the one-stop shopping group. The total treatment time could not be determined for the control group because their surgical times weren’t recorded.
Adverse events included four postoperative wound infections in the one-stop shopping group, all of which were successfully treated with oral antibiotics, and one case of excessive postoperative bleeding in the control group, which required 3 days of hospitalization.
This study was limited in that it excluded patients with large lesions and those with BCC on high-risk areas of the face, which reduces the generalizability of the findings. In addition, a follow-up time of at least 1 year would be needed to detect signs of BCC recurrence in the study participants, the investigators said.
FROM THE BRITISH JOURNAL OF DERMATOLOGY
Key clinical point: For selected patients with BCC, one-stop shopping – diagnosing, subtyping, and excising the lesion all in one visit – using reflectance confocal microscopy was found noninferior to the standard approach using punch biopsy.
Major finding: The percentage of patients with tumor-free margins after surgical excision was 100% (40 of 40) in the one-stop-shopping group and 94% (31 of 33) in the control group.
Data source: An open-label, randomized, controlled, noninferiority trial involving 95 adults.
Disclosures: The study received no outside funding. Dr. Kadouch and his associates reported having no relevant financial disclosures.
Blood donor age, sex do not affect recipient survival
The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.
A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.
A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.
In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).
“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.
“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.
“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.
The findings of Edgren et al. provide reassurance regarding the safety of current transfusion practice.
They present a convincing argument that differences in the statistical approach for controlling confounding likely explained the discrepant results of the Canadian study and their study.
This subtle confounding stems from the fact that increased transfusions expose the recipient to a greater total number of blood products, which in turn is associated with higher comorbidity, greater severity of illness, and higher mortality.
Nareg Roubinian, MD, is at the Blood Systems Research Institute, San Francisco, and in the division of research at Kaiser Permanente Northern California, Oakland. He and his associates reported having no relevant financial disclosures. They made these remarks in an invited commentary accompanying Dr. Edgren’s report (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0914).
The findings of Edgren et al. provide reassurance regarding the safety of current transfusion practice.
They present a convincing argument that differences in the statistical approach for controlling confounding likely explained the discrepant results of the Canadian study and their study.
This subtle confounding stems from the fact that increased transfusions expose the recipient to a greater total number of blood products, which in turn is associated with higher comorbidity, greater severity of illness, and higher mortality.
Nareg Roubinian, MD, is at the Blood Systems Research Institute, San Francisco, and in the division of research at Kaiser Permanente Northern California, Oakland. He and his associates reported having no relevant financial disclosures. They made these remarks in an invited commentary accompanying Dr. Edgren’s report (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0914).
The findings of Edgren et al. provide reassurance regarding the safety of current transfusion practice.
They present a convincing argument that differences in the statistical approach for controlling confounding likely explained the discrepant results of the Canadian study and their study.
This subtle confounding stems from the fact that increased transfusions expose the recipient to a greater total number of blood products, which in turn is associated with higher comorbidity, greater severity of illness, and higher mortality.
Nareg Roubinian, MD, is at the Blood Systems Research Institute, San Francisco, and in the division of research at Kaiser Permanente Northern California, Oakland. He and his associates reported having no relevant financial disclosures. They made these remarks in an invited commentary accompanying Dr. Edgren’s report (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0914).
The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.
A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.
A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.
In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).
“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.
“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.
“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.
The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.
A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.
A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.
In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).
“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.
“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.
“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.
Key clinical point: The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation.
Major finding: The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99.
Data source: A retrospective cohort study involving 968,264 transfusion recipients in Sweden and Denmark during a 10-year period.
Disclosures: The Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Society for Medical Research, Karolinska Institutet’s Strategic Research Program, and the Danish Council for Independent Research supported the study. Dr. Edgren and his associates reported having no relevant financial disclosures.
Prognostic tool may allow tailored therapy for Hodgkin lymphoma
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
Key clinical point: A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score, or CHIPS, may allow more tailored therapy for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Major finding: Patients who had a low CHIPS of 0 or 1 had excellent 4-year event-free survival (93.1% and 88.5%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (77.6% and 69.2%).
Data source: A cohort study to develop (in 562 patients) and validate (in 541 patients) a score for predicting the response to standard treatment in pediatric Hodgkin lymphoma.
Disclosures: This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
Eltrombopag improves frequency, speed, robustness of hematologic recovery
Adding the thrombopoietin-receptor agonist eltrombopag to standard immunosuppressive therapy markedly improved the frequency, speed, and robustness of hematologic recovery in a phase I-II trial of patients with severe aplastic anemia, according to a report published online April 20 in the New England Journal of Medicine.
Previously, researchers found that eltrombopag was effective against aplastic anemia that was refractory to immunosuppression, inducing higher platelet counts, hemoglobin levels, and neutrophil numbers when used as a single agent. They then examined whether adding the drug to immunosuppression in treatment-naive patients would improve the response in this nonrandomized prospective trial, said Danielle M. Townsley, MD, of the hematology branch, National Heart, Lung, and Blood Institute, and her associates.
Ninety-two consecutive patients aged 3-82 years were divided into three cohorts with different timing and duration of treatment. Cohort 1 (30 patients) received eltrombopag from day 14 to 6 months; cohort 2 (31 patients) received it from day 14 to 3 months; and cohort 3 (31 patients) received it from day 1 to 6 months.
The primary efficacy endpoint – the rate of complete hematologic response at 6 months – was highest, at 58%, in cohort 3, which had the earliest initiation and the longest duration of eltrombopag treatment. It was lowest, at 26%, in cohort 2, which had the shortest duration of eltrombopag treatment. The rate of complete hematologic response was intermediate in cohort 1, at 33% (N Engl J Med. 2017 Apr 20. doi:10.1056/NEJMoa1613878).
These complete response rates all exceeded those reported historically, which range from 10% to 20%. Moreover, the rate of partial or complete hematologic response was 87% across all three cohorts, compared with the 66% partial or complete response rate that would be expected with standard immunosuppression alone. Absolute neutrophil counts and platelet counts in all three cohorts also were higher at both 3 and 6 months than were those that have been reported historically.
The average time to independence from transfusions in the entire study population was 1 month, and clinically meaningful improvements in neutrophil levels were seen within a few weeks of initiating eltrombopag.
Two cases of severe cutaneous eruptions led to discontinuation of the study drug. Liver abnormalities were frequent but transient and did not limit the use of eltrombopag.
If these results are validated in future studies, and if no unexpected late complications are identified, adding eltrombopag to standard immunosuppressive therapy “may help patients optimize the timing of allogeneic stem-cell transplantation or avoid it. Of particular interest would be use of eltrombopag in combination with less toxic immunosuppressive regimens that omit antithymocyte globulin, particularly in older patients, in patients with coexisting conditions, and in developing countries where aplastic anemia is prevalent and conventional therapies [are] extremely costly,” Dr. Townsley and her associates noted.
One such confirmatory study, a large randomized placebo-controlled trial (NCT02099747), is now underway in Europe, they wrote.
This trial was supported by the National Heart, Lung, and Blood Institute. Dr. Townsley and her associates reported ties to GlaxoSmithKline and Novartis, makers of eltrombopag.
Adding the thrombopoietin-receptor agonist eltrombopag to standard immunosuppressive therapy markedly improved the frequency, speed, and robustness of hematologic recovery in a phase I-II trial of patients with severe aplastic anemia, according to a report published online April 20 in the New England Journal of Medicine.
Previously, researchers found that eltrombopag was effective against aplastic anemia that was refractory to immunosuppression, inducing higher platelet counts, hemoglobin levels, and neutrophil numbers when used as a single agent. They then examined whether adding the drug to immunosuppression in treatment-naive patients would improve the response in this nonrandomized prospective trial, said Danielle M. Townsley, MD, of the hematology branch, National Heart, Lung, and Blood Institute, and her associates.
Ninety-two consecutive patients aged 3-82 years were divided into three cohorts with different timing and duration of treatment. Cohort 1 (30 patients) received eltrombopag from day 14 to 6 months; cohort 2 (31 patients) received it from day 14 to 3 months; and cohort 3 (31 patients) received it from day 1 to 6 months.
The primary efficacy endpoint – the rate of complete hematologic response at 6 months – was highest, at 58%, in cohort 3, which had the earliest initiation and the longest duration of eltrombopag treatment. It was lowest, at 26%, in cohort 2, which had the shortest duration of eltrombopag treatment. The rate of complete hematologic response was intermediate in cohort 1, at 33% (N Engl J Med. 2017 Apr 20. doi:10.1056/NEJMoa1613878).
These complete response rates all exceeded those reported historically, which range from 10% to 20%. Moreover, the rate of partial or complete hematologic response was 87% across all three cohorts, compared with the 66% partial or complete response rate that would be expected with standard immunosuppression alone. Absolute neutrophil counts and platelet counts in all three cohorts also were higher at both 3 and 6 months than were those that have been reported historically.
The average time to independence from transfusions in the entire study population was 1 month, and clinically meaningful improvements in neutrophil levels were seen within a few weeks of initiating eltrombopag.
Two cases of severe cutaneous eruptions led to discontinuation of the study drug. Liver abnormalities were frequent but transient and did not limit the use of eltrombopag.
If these results are validated in future studies, and if no unexpected late complications are identified, adding eltrombopag to standard immunosuppressive therapy “may help patients optimize the timing of allogeneic stem-cell transplantation or avoid it. Of particular interest would be use of eltrombopag in combination with less toxic immunosuppressive regimens that omit antithymocyte globulin, particularly in older patients, in patients with coexisting conditions, and in developing countries where aplastic anemia is prevalent and conventional therapies [are] extremely costly,” Dr. Townsley and her associates noted.
One such confirmatory study, a large randomized placebo-controlled trial (NCT02099747), is now underway in Europe, they wrote.
This trial was supported by the National Heart, Lung, and Blood Institute. Dr. Townsley and her associates reported ties to GlaxoSmithKline and Novartis, makers of eltrombopag.
Adding the thrombopoietin-receptor agonist eltrombopag to standard immunosuppressive therapy markedly improved the frequency, speed, and robustness of hematologic recovery in a phase I-II trial of patients with severe aplastic anemia, according to a report published online April 20 in the New England Journal of Medicine.
Previously, researchers found that eltrombopag was effective against aplastic anemia that was refractory to immunosuppression, inducing higher platelet counts, hemoglobin levels, and neutrophil numbers when used as a single agent. They then examined whether adding the drug to immunosuppression in treatment-naive patients would improve the response in this nonrandomized prospective trial, said Danielle M. Townsley, MD, of the hematology branch, National Heart, Lung, and Blood Institute, and her associates.
Ninety-two consecutive patients aged 3-82 years were divided into three cohorts with different timing and duration of treatment. Cohort 1 (30 patients) received eltrombopag from day 14 to 6 months; cohort 2 (31 patients) received it from day 14 to 3 months; and cohort 3 (31 patients) received it from day 1 to 6 months.
The primary efficacy endpoint – the rate of complete hematologic response at 6 months – was highest, at 58%, in cohort 3, which had the earliest initiation and the longest duration of eltrombopag treatment. It was lowest, at 26%, in cohort 2, which had the shortest duration of eltrombopag treatment. The rate of complete hematologic response was intermediate in cohort 1, at 33% (N Engl J Med. 2017 Apr 20. doi:10.1056/NEJMoa1613878).
These complete response rates all exceeded those reported historically, which range from 10% to 20%. Moreover, the rate of partial or complete hematologic response was 87% across all three cohorts, compared with the 66% partial or complete response rate that would be expected with standard immunosuppression alone. Absolute neutrophil counts and platelet counts in all three cohorts also were higher at both 3 and 6 months than were those that have been reported historically.
The average time to independence from transfusions in the entire study population was 1 month, and clinically meaningful improvements in neutrophil levels were seen within a few weeks of initiating eltrombopag.
Two cases of severe cutaneous eruptions led to discontinuation of the study drug. Liver abnormalities were frequent but transient and did not limit the use of eltrombopag.
If these results are validated in future studies, and if no unexpected late complications are identified, adding eltrombopag to standard immunosuppressive therapy “may help patients optimize the timing of allogeneic stem-cell transplantation or avoid it. Of particular interest would be use of eltrombopag in combination with less toxic immunosuppressive regimens that omit antithymocyte globulin, particularly in older patients, in patients with coexisting conditions, and in developing countries where aplastic anemia is prevalent and conventional therapies [are] extremely costly,” Dr. Townsley and her associates noted.
One such confirmatory study, a large randomized placebo-controlled trial (NCT02099747), is now underway in Europe, they wrote.
This trial was supported by the National Heart, Lung, and Blood Institute. Dr. Townsley and her associates reported ties to GlaxoSmithKline and Novartis, makers of eltrombopag.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Adding eltrombopag to standard immunosuppression markedly improves the frequency, speed, and robustness of hematologic recovery in patients with severe aplastic anemia.
Major finding: The rate of partial or complete hematologic response was 87% across all 3 cohorts, compared with the 66% partial or complete response rate that would be expected with standard immunosuppression alone.
Data source: A prospective phase I-II study involving 92 patients aged 3-82 years who were followed for a median of 2 years.
Disclosures: This trial was supported by the National Heart, Lung, and Blood Institute. Dr. Townsley and her associates reported ties to GlaxoSmithKline and Novartis, makers of eltrombopag.