User login
Stopping TNF inhibitors before 20 weeks’ gestation not linked to worsening RA, JIA
In pregnant women with arthritis, discontinuing tumor necrosis factor inhibitors prior to gestational week 20 seems feasible without an increased risk of disease worsening, particularly in those with well-controlled disease, according to authors of a recent analysis of a prospective cohort study.
Stopping tumor necrosis factor inhibitor (TNFi) treatment at that point in the second trimester was not linked to any clinically important worsening of patient-reported outcomes later in pregnancy for women with rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA), the researchers said.
However, continuing a TNFi past gestational week 20 may also be warranted for some patients, according to the researchers, led by Frauke Förger, MD, of the University of Bern (Switzerland).
“In case of active disease, the continuation of TNF inhibitors beyond gestational week 20 seems reasonable from the standpoint of improved disease activity in the third trimester, which may in turn lead to improved pregnancy outcomes,” Dr. Förger and her coinvestigators wrote in Arthritis & Rheumatology.
These findings stand in contrast to those of another recent study, in which stopping a TNF inhibitor after a positive pregnancy test was linked to disease flares in women with RA, according to the authors.
“The timing of drug discontinuation during pregnancy may be of importance,” they said in their report.
Beyond these studies, there are very limited data on the effects of discontinuing TNF inhibitors in pregnant women with rheumatoid arthritis, and “a lack of any data” in pregnant women with JIA, they said.
The current investigation by Dr. Förger and her colleagues included 490 pregnant women in the United States or Canada who were enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study. Of those women, 397 had RA and 93 had JIA.
About one-quarter of the women (122, or 24.9%) discontinued TNF inhibitor therapy prior to gestational week 20, while 41% continued on TNF inhibitors beyond that point, and 34.1% did not use a TNF inhibitor in pregnancy.
For those women who discontinued TNF inhibitors before gestational week 20, scores on the Patient Activity Scale (PAS) were stable over time, Dr. Förger and her colleagues reported.
Women who continued TNF inhibitor treatment past gestational week 20 had improved PAS scores in the third trimester, according to results of a univariate analysis (P = .02). However, the improvement appeared to be attenuated after adjustment for factors including race, smoking, use of prednisone or disease-modifying antirheumatic drugs, and gestational age, the investigators said.
They were unable to analyze the effects of ongoing TNFi treatment or discontinuation on patients with JIA separately because of the limited number of such patients in each group.
Another limitation of the study is that a high proportion of women – nearly three-quarters – had low disease activity at the start of pregnancy, according to the investigators, who said that group of women might expect some degree of improvement in the third trimester with or without TNF inhibitor discontinuation.
“In this context, the ameliorating effect of pregnancy on RA and JIA, which is most pronounced in the third trimester, may play a role,” they explained.
A certain proportion of women choose to discontinue certain arthritis treatments during pregnancy because of concerns that the medication may lead to fetal harm, but that may be changing, the investigators noted in their report.
“In recent years, more patients requiring treatment have been continuing on effective TNF inhibitors beyond conception as the available data on the safety of TNF inhibitors during pregnancy has increased,” they wrote.
Dr. Förger and her coauthors reported no financial disclosures or conflicts of interest. Financial support for the OTIS Collaborative Research Group comes from industry sources including AbbVie, Bristol-Myers Squibb, Celgene, Hoffman La Roche-Genentech, Janssen, Pfizer, Regeneron, Sandoz, and UCB, among others.
SOURCE: Förger F et al. Arthritis Rheumatol. 2019 Jan 21. doi: 10.1002/art.40821
In pregnant women with arthritis, discontinuing tumor necrosis factor inhibitors prior to gestational week 20 seems feasible without an increased risk of disease worsening, particularly in those with well-controlled disease, according to authors of a recent analysis of a prospective cohort study.
Stopping tumor necrosis factor inhibitor (TNFi) treatment at that point in the second trimester was not linked to any clinically important worsening of patient-reported outcomes later in pregnancy for women with rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA), the researchers said.
However, continuing a TNFi past gestational week 20 may also be warranted for some patients, according to the researchers, led by Frauke Förger, MD, of the University of Bern (Switzerland).
“In case of active disease, the continuation of TNF inhibitors beyond gestational week 20 seems reasonable from the standpoint of improved disease activity in the third trimester, which may in turn lead to improved pregnancy outcomes,” Dr. Förger and her coinvestigators wrote in Arthritis & Rheumatology.
These findings stand in contrast to those of another recent study, in which stopping a TNF inhibitor after a positive pregnancy test was linked to disease flares in women with RA, according to the authors.
“The timing of drug discontinuation during pregnancy may be of importance,” they said in their report.
Beyond these studies, there are very limited data on the effects of discontinuing TNF inhibitors in pregnant women with rheumatoid arthritis, and “a lack of any data” in pregnant women with JIA, they said.
The current investigation by Dr. Förger and her colleagues included 490 pregnant women in the United States or Canada who were enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study. Of those women, 397 had RA and 93 had JIA.
About one-quarter of the women (122, or 24.9%) discontinued TNF inhibitor therapy prior to gestational week 20, while 41% continued on TNF inhibitors beyond that point, and 34.1% did not use a TNF inhibitor in pregnancy.
For those women who discontinued TNF inhibitors before gestational week 20, scores on the Patient Activity Scale (PAS) were stable over time, Dr. Förger and her colleagues reported.
Women who continued TNF inhibitor treatment past gestational week 20 had improved PAS scores in the third trimester, according to results of a univariate analysis (P = .02). However, the improvement appeared to be attenuated after adjustment for factors including race, smoking, use of prednisone or disease-modifying antirheumatic drugs, and gestational age, the investigators said.
They were unable to analyze the effects of ongoing TNFi treatment or discontinuation on patients with JIA separately because of the limited number of such patients in each group.
Another limitation of the study is that a high proportion of women – nearly three-quarters – had low disease activity at the start of pregnancy, according to the investigators, who said that group of women might expect some degree of improvement in the third trimester with or without TNF inhibitor discontinuation.
“In this context, the ameliorating effect of pregnancy on RA and JIA, which is most pronounced in the third trimester, may play a role,” they explained.
A certain proportion of women choose to discontinue certain arthritis treatments during pregnancy because of concerns that the medication may lead to fetal harm, but that may be changing, the investigators noted in their report.
“In recent years, more patients requiring treatment have been continuing on effective TNF inhibitors beyond conception as the available data on the safety of TNF inhibitors during pregnancy has increased,” they wrote.
Dr. Förger and her coauthors reported no financial disclosures or conflicts of interest. Financial support for the OTIS Collaborative Research Group comes from industry sources including AbbVie, Bristol-Myers Squibb, Celgene, Hoffman La Roche-Genentech, Janssen, Pfizer, Regeneron, Sandoz, and UCB, among others.
SOURCE: Förger F et al. Arthritis Rheumatol. 2019 Jan 21. doi: 10.1002/art.40821
In pregnant women with arthritis, discontinuing tumor necrosis factor inhibitors prior to gestational week 20 seems feasible without an increased risk of disease worsening, particularly in those with well-controlled disease, according to authors of a recent analysis of a prospective cohort study.
Stopping tumor necrosis factor inhibitor (TNFi) treatment at that point in the second trimester was not linked to any clinically important worsening of patient-reported outcomes later in pregnancy for women with rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA), the researchers said.
However, continuing a TNFi past gestational week 20 may also be warranted for some patients, according to the researchers, led by Frauke Förger, MD, of the University of Bern (Switzerland).
“In case of active disease, the continuation of TNF inhibitors beyond gestational week 20 seems reasonable from the standpoint of improved disease activity in the third trimester, which may in turn lead to improved pregnancy outcomes,” Dr. Förger and her coinvestigators wrote in Arthritis & Rheumatology.
These findings stand in contrast to those of another recent study, in which stopping a TNF inhibitor after a positive pregnancy test was linked to disease flares in women with RA, according to the authors.
“The timing of drug discontinuation during pregnancy may be of importance,” they said in their report.
Beyond these studies, there are very limited data on the effects of discontinuing TNF inhibitors in pregnant women with rheumatoid arthritis, and “a lack of any data” in pregnant women with JIA, they said.
The current investigation by Dr. Förger and her colleagues included 490 pregnant women in the United States or Canada who were enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study. Of those women, 397 had RA and 93 had JIA.
About one-quarter of the women (122, or 24.9%) discontinued TNF inhibitor therapy prior to gestational week 20, while 41% continued on TNF inhibitors beyond that point, and 34.1% did not use a TNF inhibitor in pregnancy.
For those women who discontinued TNF inhibitors before gestational week 20, scores on the Patient Activity Scale (PAS) were stable over time, Dr. Förger and her colleagues reported.
Women who continued TNF inhibitor treatment past gestational week 20 had improved PAS scores in the third trimester, according to results of a univariate analysis (P = .02). However, the improvement appeared to be attenuated after adjustment for factors including race, smoking, use of prednisone or disease-modifying antirheumatic drugs, and gestational age, the investigators said.
They were unable to analyze the effects of ongoing TNFi treatment or discontinuation on patients with JIA separately because of the limited number of such patients in each group.
Another limitation of the study is that a high proportion of women – nearly three-quarters – had low disease activity at the start of pregnancy, according to the investigators, who said that group of women might expect some degree of improvement in the third trimester with or without TNF inhibitor discontinuation.
“In this context, the ameliorating effect of pregnancy on RA and JIA, which is most pronounced in the third trimester, may play a role,” they explained.
A certain proportion of women choose to discontinue certain arthritis treatments during pregnancy because of concerns that the medication may lead to fetal harm, but that may be changing, the investigators noted in their report.
“In recent years, more patients requiring treatment have been continuing on effective TNF inhibitors beyond conception as the available data on the safety of TNF inhibitors during pregnancy has increased,” they wrote.
Dr. Förger and her coauthors reported no financial disclosures or conflicts of interest. Financial support for the OTIS Collaborative Research Group comes from industry sources including AbbVie, Bristol-Myers Squibb, Celgene, Hoffman La Roche-Genentech, Janssen, Pfizer, Regeneron, Sandoz, and UCB, among others.
SOURCE: Förger F et al. Arthritis Rheumatol. 2019 Jan 21. doi: 10.1002/art.40821
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: In contrast to a previous report,
Major finding: Patient Activity Scale (PAS) scores were stable over time in women who discontinued TNF inhibitors before gestational week 20. Those who continued past week 20 had improved PAS scores in the third trimester (univariate analysis; P = .02).
Study details: Analysis including 490 pregnant women in the United States or Canada who enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study.
Disclosures: Dr. Förger and her coauthors reported no financial disclosures or conflicts of interest. Financial support for the OTIS Collaborative Research Group comes from industry sources including AbbVie, Bristol-Myers Squibb, Celgene, Hoffman La Roche-Genentech, Janssen, Pfizer, Regeneron, Sandoz, and UCB, among others.
Source: Förger F et al. Arthritis Rheumatol. 2019 Jan 21. doi: 10.1002/art.40821.
Long-term opioid use substantial in elderly adults prior to total joint replacement
In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.
Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.
This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.
Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.
Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.
Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.
Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.
Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.
SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.
Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.
This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.
Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.
Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.
Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.
Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.
Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.
SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.
Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.
This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.
Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.
Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.
Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.
Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.
Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.
SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Long-term opioid use is highly prevalent among older adults with osteoarthritis who underwent total joint replacement.
Major finding: Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama.
Study details: An observational cohort study including 358,121 Medicare enrollees with advanced osteoarthritis.
Disclosures: Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Coauthors provided disclosures related to a number of pharmaceutical companies.
Source: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
Chemo-resistant reserve HSCs maintained in bone marrow
A small subpopulation of quiescent hematopoietic stem cells (HSCs) that restores the HSC pool and supports hematopoietic regeneration after chemotherapy has been identified, researchers reported.
These “reserve” HSCs were resistant to chemotherapy, whereas “primed” HSCs were sensitive to DNA damage from chemotherapy, the researchers said.
Both reserve and active stem cells were maintained in the bone marrow by specific niches, researchers demonstrated in experiments described in detail in Cell Reports.
Of note, primitive reserve HSCs were maintained in a bone marrow region that enriches N-cadherin expressing (N-cad+) bone and marrow stromal progenitor cells. According to investigators, those N-cad+ cells protected primitive reserve HSCs from chemotherapy-related stress, which survived to support hematopoietic regeneration after myeloablation.
These findings advance understanding of HSC biology, and could open new avenues for treating blood diseases and autoimmune disorders.
“In effect, we showed that hematopoietic stem cells have functionally distinct subpopulations: one that acts under normal conditions, and the other that acts under times of stress,” study senior author Linheng Li, PhD, a researcher at Stowers Institute for Medical Research in Kansas City, Mo., said in a statement.
Hematopoietic stem cells are heterogeneous, with some maintained in an active state, and others in a quiescent state that is related to their self-renewal capacity and linked to low metabolic activity, sometimes called HSC dormancy or hibernation, Dr. Li and his coinvestigators explained in their report.
However, despite their quiescence, the majority of those HSCs will not survive chemotherapeutic stress, they added.
A small subpopulation of cells termed reserve HSCs can survive stress related to 5-fluorouracil chemotherapy in mice and following transplantation, Dr. Li and his colleagues demonstrated in experiments described in the paper. By contrast, a much larger population of quiescent cells, primed HSCs, were chemotherapy sensitive.
“Most likely, primed HSCs reflect a transitional state between [reserve HSCs] and proliferating [short-term HSCs],” Dr. Li and his colleagues said in their report.
In one key experiment, Dr. Li and his coinvestigators used a cell surface marker to isolate reserve HSCs and primed HSCs, which were transplanted into mice. Following engraftment, the mice were treated with 5-fluorouracil. They found that reserve HSCs, reflected by their derived blood cells, were unaffected by treatment, whereas derivatives of primed HSCs declined.
In another experiment, the researchers labeled HSCs with fluorescent tags to identify their location in the bone marrow. They found reserve cells concentrated in a specific bone marrow niche adjacent to N-cad+ cells.
The N-cad+ cells were bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes, according to investigators.
Ablating the N-cad+ niche cells impaired reserve HSC maintenance in both homeostasis and regeneration, investigators added.
The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.
SOURCE: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.
A small subpopulation of quiescent hematopoietic stem cells (HSCs) that restores the HSC pool and supports hematopoietic regeneration after chemotherapy has been identified, researchers reported.
These “reserve” HSCs were resistant to chemotherapy, whereas “primed” HSCs were sensitive to DNA damage from chemotherapy, the researchers said.
Both reserve and active stem cells were maintained in the bone marrow by specific niches, researchers demonstrated in experiments described in detail in Cell Reports.
Of note, primitive reserve HSCs were maintained in a bone marrow region that enriches N-cadherin expressing (N-cad+) bone and marrow stromal progenitor cells. According to investigators, those N-cad+ cells protected primitive reserve HSCs from chemotherapy-related stress, which survived to support hematopoietic regeneration after myeloablation.
These findings advance understanding of HSC biology, and could open new avenues for treating blood diseases and autoimmune disorders.
“In effect, we showed that hematopoietic stem cells have functionally distinct subpopulations: one that acts under normal conditions, and the other that acts under times of stress,” study senior author Linheng Li, PhD, a researcher at Stowers Institute for Medical Research in Kansas City, Mo., said in a statement.
Hematopoietic stem cells are heterogeneous, with some maintained in an active state, and others in a quiescent state that is related to their self-renewal capacity and linked to low metabolic activity, sometimes called HSC dormancy or hibernation, Dr. Li and his coinvestigators explained in their report.
However, despite their quiescence, the majority of those HSCs will not survive chemotherapeutic stress, they added.
A small subpopulation of cells termed reserve HSCs can survive stress related to 5-fluorouracil chemotherapy in mice and following transplantation, Dr. Li and his colleagues demonstrated in experiments described in the paper. By contrast, a much larger population of quiescent cells, primed HSCs, were chemotherapy sensitive.
“Most likely, primed HSCs reflect a transitional state between [reserve HSCs] and proliferating [short-term HSCs],” Dr. Li and his colleagues said in their report.
In one key experiment, Dr. Li and his coinvestigators used a cell surface marker to isolate reserve HSCs and primed HSCs, which were transplanted into mice. Following engraftment, the mice were treated with 5-fluorouracil. They found that reserve HSCs, reflected by their derived blood cells, were unaffected by treatment, whereas derivatives of primed HSCs declined.
In another experiment, the researchers labeled HSCs with fluorescent tags to identify their location in the bone marrow. They found reserve cells concentrated in a specific bone marrow niche adjacent to N-cad+ cells.
The N-cad+ cells were bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes, according to investigators.
Ablating the N-cad+ niche cells impaired reserve HSC maintenance in both homeostasis and regeneration, investigators added.
The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.
SOURCE: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.
A small subpopulation of quiescent hematopoietic stem cells (HSCs) that restores the HSC pool and supports hematopoietic regeneration after chemotherapy has been identified, researchers reported.
These “reserve” HSCs were resistant to chemotherapy, whereas “primed” HSCs were sensitive to DNA damage from chemotherapy, the researchers said.
Both reserve and active stem cells were maintained in the bone marrow by specific niches, researchers demonstrated in experiments described in detail in Cell Reports.
Of note, primitive reserve HSCs were maintained in a bone marrow region that enriches N-cadherin expressing (N-cad+) bone and marrow stromal progenitor cells. According to investigators, those N-cad+ cells protected primitive reserve HSCs from chemotherapy-related stress, which survived to support hematopoietic regeneration after myeloablation.
These findings advance understanding of HSC biology, and could open new avenues for treating blood diseases and autoimmune disorders.
“In effect, we showed that hematopoietic stem cells have functionally distinct subpopulations: one that acts under normal conditions, and the other that acts under times of stress,” study senior author Linheng Li, PhD, a researcher at Stowers Institute for Medical Research in Kansas City, Mo., said in a statement.
Hematopoietic stem cells are heterogeneous, with some maintained in an active state, and others in a quiescent state that is related to their self-renewal capacity and linked to low metabolic activity, sometimes called HSC dormancy or hibernation, Dr. Li and his coinvestigators explained in their report.
However, despite their quiescence, the majority of those HSCs will not survive chemotherapeutic stress, they added.
A small subpopulation of cells termed reserve HSCs can survive stress related to 5-fluorouracil chemotherapy in mice and following transplantation, Dr. Li and his colleagues demonstrated in experiments described in the paper. By contrast, a much larger population of quiescent cells, primed HSCs, were chemotherapy sensitive.
“Most likely, primed HSCs reflect a transitional state between [reserve HSCs] and proliferating [short-term HSCs],” Dr. Li and his colleagues said in their report.
In one key experiment, Dr. Li and his coinvestigators used a cell surface marker to isolate reserve HSCs and primed HSCs, which were transplanted into mice. Following engraftment, the mice were treated with 5-fluorouracil. They found that reserve HSCs, reflected by their derived blood cells, were unaffected by treatment, whereas derivatives of primed HSCs declined.
In another experiment, the researchers labeled HSCs with fluorescent tags to identify their location in the bone marrow. They found reserve cells concentrated in a specific bone marrow niche adjacent to N-cad+ cells.
The N-cad+ cells were bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes, according to investigators.
Ablating the N-cad+ niche cells impaired reserve HSC maintenance in both homeostasis and regeneration, investigators added.
The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.
SOURCE: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.
FROM CELL REPORTS
Key clinical point:
Major finding: Reserve HSCs were resistant to chemotherapy, whereas by contrast, primed HSCs were chemosensitive.
Study details: A series of preclinical experiments designed to characterize HSCs and document the effects of chemotherapy-related stress.
Disclosures: The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.
Source: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.
Women with RA have reduced chance of live birth after assisted reproduction treatment
Women with rheumatoid arthritis who undergo assisted reproduction treatment have a decreased likelihood of live births versus women without rheumatoid arthritis, according to authors of a recent Denmark-wide cohort study.
The problem might be caused by an impaired chance of embryo implantation, authors of the study reported in the Annals of the Rheumatic Diseases.
Corticosteroids prescribed before embryo transfer might have improved the likelihood of live birth in these women with rheumatoid arthritis, according to the investigators, led by Professor Bente Mertz Nørgård of the center for clinical epidemiology at the Odense (Denmark) University Hospital.
However, findings with regard to that potential effect of corticosteroids were “not unambiguous,” said Prof. Nørgård and her coauthors said in their report.
The cohort study, based on Danish registry data from 1994-2017, included 1,149 embryo transfers in women and rheumatoid arthritis with 198,941 embryo transfers in women without rheumatoid arthritis.
Live births per embryo transfer were less likely in women with rheumatoid arthritis versus those they were in women with no rheumatoid arthritis, with an adjusted odds ratio of 0.78 (95% confidence interval, 0.65-0.92), according to investigators.
Chances of biochemical and clinical pregnancies were also lower in women with rheumatoid arthritis, with odds ratios of 0.81 (95% CI, 0.68-0.95) and 0.82 (95% CI, 0.59-1.15), respectively, the investigators found in an analysis of secondary outcomes in the study.
Corticosteroids prescribed before embryo transfer increased odds of live birth, with an adjusted odds ratio of 1.32 (95% CI, 0.85-2.05), though the underlying reason why corticosteroids were prescribed could not be established in this data set, investigators cautioned.
“The impact of corticosteroid prior to embryo transfer, found in our study, could be due to a suppression of ‘abnormalities in the immune system’ in women with RA, but we have to underline that this is speculative,” Prof. Nørgård and her colleagues said in a discussion of their results.
Future investigations are needed to clarify the role of corticosteroids in women with rheumatoid arthritis undergoing assisted reproduction treatment, they added.
Support for the study came from the Research Foundation of the Region of Southern Denmark and the Free Research Foundation at Odense University Hospital. Dr. Nørgård and her coauthors said they had no competing interests related to the research.
SOURCE: Nørgård BM et al. Ann Rheum Dis. 2019 Jan 12. doi: 10.1136/annrheumdis-2018-214619.
Women with rheumatoid arthritis who undergo assisted reproduction treatment have a decreased likelihood of live births versus women without rheumatoid arthritis, according to authors of a recent Denmark-wide cohort study.
The problem might be caused by an impaired chance of embryo implantation, authors of the study reported in the Annals of the Rheumatic Diseases.
Corticosteroids prescribed before embryo transfer might have improved the likelihood of live birth in these women with rheumatoid arthritis, according to the investigators, led by Professor Bente Mertz Nørgård of the center for clinical epidemiology at the Odense (Denmark) University Hospital.
However, findings with regard to that potential effect of corticosteroids were “not unambiguous,” said Prof. Nørgård and her coauthors said in their report.
The cohort study, based on Danish registry data from 1994-2017, included 1,149 embryo transfers in women and rheumatoid arthritis with 198,941 embryo transfers in women without rheumatoid arthritis.
Live births per embryo transfer were less likely in women with rheumatoid arthritis versus those they were in women with no rheumatoid arthritis, with an adjusted odds ratio of 0.78 (95% confidence interval, 0.65-0.92), according to investigators.
Chances of biochemical and clinical pregnancies were also lower in women with rheumatoid arthritis, with odds ratios of 0.81 (95% CI, 0.68-0.95) and 0.82 (95% CI, 0.59-1.15), respectively, the investigators found in an analysis of secondary outcomes in the study.
Corticosteroids prescribed before embryo transfer increased odds of live birth, with an adjusted odds ratio of 1.32 (95% CI, 0.85-2.05), though the underlying reason why corticosteroids were prescribed could not be established in this data set, investigators cautioned.
“The impact of corticosteroid prior to embryo transfer, found in our study, could be due to a suppression of ‘abnormalities in the immune system’ in women with RA, but we have to underline that this is speculative,” Prof. Nørgård and her colleagues said in a discussion of their results.
Future investigations are needed to clarify the role of corticosteroids in women with rheumatoid arthritis undergoing assisted reproduction treatment, they added.
Support for the study came from the Research Foundation of the Region of Southern Denmark and the Free Research Foundation at Odense University Hospital. Dr. Nørgård and her coauthors said they had no competing interests related to the research.
SOURCE: Nørgård BM et al. Ann Rheum Dis. 2019 Jan 12. doi: 10.1136/annrheumdis-2018-214619.
Women with rheumatoid arthritis who undergo assisted reproduction treatment have a decreased likelihood of live births versus women without rheumatoid arthritis, according to authors of a recent Denmark-wide cohort study.
The problem might be caused by an impaired chance of embryo implantation, authors of the study reported in the Annals of the Rheumatic Diseases.
Corticosteroids prescribed before embryo transfer might have improved the likelihood of live birth in these women with rheumatoid arthritis, according to the investigators, led by Professor Bente Mertz Nørgård of the center for clinical epidemiology at the Odense (Denmark) University Hospital.
However, findings with regard to that potential effect of corticosteroids were “not unambiguous,” said Prof. Nørgård and her coauthors said in their report.
The cohort study, based on Danish registry data from 1994-2017, included 1,149 embryo transfers in women and rheumatoid arthritis with 198,941 embryo transfers in women without rheumatoid arthritis.
Live births per embryo transfer were less likely in women with rheumatoid arthritis versus those they were in women with no rheumatoid arthritis, with an adjusted odds ratio of 0.78 (95% confidence interval, 0.65-0.92), according to investigators.
Chances of biochemical and clinical pregnancies were also lower in women with rheumatoid arthritis, with odds ratios of 0.81 (95% CI, 0.68-0.95) and 0.82 (95% CI, 0.59-1.15), respectively, the investigators found in an analysis of secondary outcomes in the study.
Corticosteroids prescribed before embryo transfer increased odds of live birth, with an adjusted odds ratio of 1.32 (95% CI, 0.85-2.05), though the underlying reason why corticosteroids were prescribed could not be established in this data set, investigators cautioned.
“The impact of corticosteroid prior to embryo transfer, found in our study, could be due to a suppression of ‘abnormalities in the immune system’ in women with RA, but we have to underline that this is speculative,” Prof. Nørgård and her colleagues said in a discussion of their results.
Future investigations are needed to clarify the role of corticosteroids in women with rheumatoid arthritis undergoing assisted reproduction treatment, they added.
Support for the study came from the Research Foundation of the Region of Southern Denmark and the Free Research Foundation at Odense University Hospital. Dr. Nørgård and her coauthors said they had no competing interests related to the research.
SOURCE: Nørgård BM et al. Ann Rheum Dis. 2019 Jan 12. doi: 10.1136/annrheumdis-2018-214619.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point: Women with rheumatoid arthritis (RA) who undergo assisted reproduction treatment have decreased chances of live births, compared with women without RA.
Major finding: The odds ratio for live births per embryo transfer in women with RA, as compared to women without RA, was 0.78 (95% confidence interval, 0.65-0.92).
Study details: A nationwide cohort study including 1,149 embryo transfers in women with rheumatoid arthritis and 198,941 without rheumatoid arthritis
Disclosures: Study authors had no disclosures. Support for the study came from the Research Foundation of the Region of Southern Denmark and the Free Research Foundation at Odense (Denmark) University Hospital.
Source: Nørgård BM et al. Ann Rheum Dis. 2019 Jan 12. doi: 10.1136/annrheumdis-2018-214619.
No evidence for disease-modifying effect of levodopa in Parkinson’s disease
investigators reported. The disease course was not significantly different for patients who had a full 80 weeks of levodopa/carbodopa therapy, compared with that seen with those who started treatment after a 40-week delay, according to the investigators.
“These findings imply that levodopa had no disease-modifying effect on Parkinson’s disease over the period of the trial,” wrote investigator Rob M. A. de Bie, MD, PhD, professor of movement disorders at the University of Amsterdam, and his colleagues in the New England Journal of Medicine.
By contrast, results of an earlier randomized, placebo-controlled trial suggested that levodopa had disease-modifying effects, though the findings of that study were inconclusive, according to authors of an editorial (see Views on the News).
In the current multicenter trial, known as LEAP (Levodopa in Early Parkinson’s Disease) a total of 445 patients with early Parkinson’s disease were randomized to either 80 weeks of levodopa and carbodopa or to 40 weeks of placebo followed by 40 weeks of levodopa/carbodopa.
Levodopa was dosed at 100 mg three times per day, and carbodopa at 25 mg three times per day, according to the report.
There was no significant difference between the early and delayed treatment groups for primary outcome of the trial, which was change in the Unified Parkinson’s Disease Rating Scale (UPDRS) from baseline to week 80.
The mean change in UPDRS was –1.0 in the group of patients who had the full 80 weeks of levodopa/carbodopa and –2.0 for those who had delayed therapy, for a difference of 1 point (P = .44). Higher scores on the UPDRS signify worse disease.
At week 40, there was a change in UPDRS favoring the early-initiation strategy, which reflected the effects of levodopa on disease symptoms, investigators added.
Nausea was more common in the early-start group during the first 40 weeks of the trial. However, there were no differences between groups in other adverse events of particular interest, including dyskinesias and motor fluctuations related to levodopa, Dr. de Bie and his colleagues reported.
Taken together, these results suggest no beneficial or detrimental disease-modifying effect for an early treatment strategy, although further trials are warranted to evaluate other strategies, such as higher levodopa doses, longer administration, or starting the drug at later stages of disease, they wrote.
Dr. de Bie reported grants from ZonMw, Parkinson Vereniging, and Stichting Parkinsonfonds during the conduct of the study, as well as grants from GE Health and Medtronic outside the submitted work. Study authors provided disclosures related to Netherlands Organization for Scientific Research, Michael J. Fox Foundation, UCB, AbbVie, Boston Scientific, Biogen, Merck, and others.
SOURCE: Verschuur CVM et al. N Engl J Med. 2019;380:315-24.
This trial supports current clinical practice in two ways, according to Susan Bressman, MD, and Rachel Saunders‑Pullman, MD, MPH. On one hand, the study provides no evidence to suggest that levodopa slows Parkinson’s disease progression, Dr. Bressman and Dr. Saunders-Pullman wrote in an editorial accompanying the study. On the other hand, they added, it provides no evidence that clinicians should delay therapy when it is clinically indicated.
The LEAP trial (Levodopa in Early Parkinson’s Disease) was designed to resolve uncertainty over the potential effects of levodopa on disease progression, they noted. This was necessary because of the results of the placebo-controlled ELLDOPA trial, which was published about 14 years ago and suggested that patients randomized to 40 weeks of levodopa did not deteriorate clinically to the degree that was observed in patients randomized to placebo.
The primary end point of that trial was Unified Parkinson’s Disease Rating Scale (UPDRS) scores after a 2-week washout period.
While one interpretation of the UPDRS results from ELLDOPA was that levodopa slowed disease progression, another was that the 2-week washout period was too short, allowing for residual effects of levodopa on symptoms, suggested Dr. Bressman and Dr. Saunders-Pullman.
The randomized LEAP study now shows not only that there were no differences in UPDRS scores when using a delayed start trial design – which implies that there was no disease-modifying effect – but also that starting levodopa early did not have negative effects, the editorial authors wrote.
In particular, the researchers showed no differences in rates of dyskinesia or levodopa-related fluctuations in those started early versus those started later.
“The results of the current trial, taken together with those of other trials, support treatment that is guided by clinical need and that uses the lowest dose that provides a satisfactory clinical effect,” wrote the editorial’s authors.
Dr. Bressman and Dr. Saunders‑Pullman are with the Icahn School of Medicine at Mt. Sinai, New York. Their editorial appears in the New England Journal of Medicine (2019;380:389-90). Dr. Bressman reported disclosures related to Denali Therapeutics, the Michael J. Fox Foundation, and Prevail Therapeutics, while Dr. Saunders-Pullman reported disclosures with Denali Therapeutics, the National Institutes of Health, Genzyme Sanofi, and the Bigglesworth Family Foundation.
This trial supports current clinical practice in two ways, according to Susan Bressman, MD, and Rachel Saunders‑Pullman, MD, MPH. On one hand, the study provides no evidence to suggest that levodopa slows Parkinson’s disease progression, Dr. Bressman and Dr. Saunders-Pullman wrote in an editorial accompanying the study. On the other hand, they added, it provides no evidence that clinicians should delay therapy when it is clinically indicated.
The LEAP trial (Levodopa in Early Parkinson’s Disease) was designed to resolve uncertainty over the potential effects of levodopa on disease progression, they noted. This was necessary because of the results of the placebo-controlled ELLDOPA trial, which was published about 14 years ago and suggested that patients randomized to 40 weeks of levodopa did not deteriorate clinically to the degree that was observed in patients randomized to placebo.
The primary end point of that trial was Unified Parkinson’s Disease Rating Scale (UPDRS) scores after a 2-week washout period.
While one interpretation of the UPDRS results from ELLDOPA was that levodopa slowed disease progression, another was that the 2-week washout period was too short, allowing for residual effects of levodopa on symptoms, suggested Dr. Bressman and Dr. Saunders-Pullman.
The randomized LEAP study now shows not only that there were no differences in UPDRS scores when using a delayed start trial design – which implies that there was no disease-modifying effect – but also that starting levodopa early did not have negative effects, the editorial authors wrote.
In particular, the researchers showed no differences in rates of dyskinesia or levodopa-related fluctuations in those started early versus those started later.
“The results of the current trial, taken together with those of other trials, support treatment that is guided by clinical need and that uses the lowest dose that provides a satisfactory clinical effect,” wrote the editorial’s authors.
Dr. Bressman and Dr. Saunders‑Pullman are with the Icahn School of Medicine at Mt. Sinai, New York. Their editorial appears in the New England Journal of Medicine (2019;380:389-90). Dr. Bressman reported disclosures related to Denali Therapeutics, the Michael J. Fox Foundation, and Prevail Therapeutics, while Dr. Saunders-Pullman reported disclosures with Denali Therapeutics, the National Institutes of Health, Genzyme Sanofi, and the Bigglesworth Family Foundation.
This trial supports current clinical practice in two ways, according to Susan Bressman, MD, and Rachel Saunders‑Pullman, MD, MPH. On one hand, the study provides no evidence to suggest that levodopa slows Parkinson’s disease progression, Dr. Bressman and Dr. Saunders-Pullman wrote in an editorial accompanying the study. On the other hand, they added, it provides no evidence that clinicians should delay therapy when it is clinically indicated.
The LEAP trial (Levodopa in Early Parkinson’s Disease) was designed to resolve uncertainty over the potential effects of levodopa on disease progression, they noted. This was necessary because of the results of the placebo-controlled ELLDOPA trial, which was published about 14 years ago and suggested that patients randomized to 40 weeks of levodopa did not deteriorate clinically to the degree that was observed in patients randomized to placebo.
The primary end point of that trial was Unified Parkinson’s Disease Rating Scale (UPDRS) scores after a 2-week washout period.
While one interpretation of the UPDRS results from ELLDOPA was that levodopa slowed disease progression, another was that the 2-week washout period was too short, allowing for residual effects of levodopa on symptoms, suggested Dr. Bressman and Dr. Saunders-Pullman.
The randomized LEAP study now shows not only that there were no differences in UPDRS scores when using a delayed start trial design – which implies that there was no disease-modifying effect – but also that starting levodopa early did not have negative effects, the editorial authors wrote.
In particular, the researchers showed no differences in rates of dyskinesia or levodopa-related fluctuations in those started early versus those started later.
“The results of the current trial, taken together with those of other trials, support treatment that is guided by clinical need and that uses the lowest dose that provides a satisfactory clinical effect,” wrote the editorial’s authors.
Dr. Bressman and Dr. Saunders‑Pullman are with the Icahn School of Medicine at Mt. Sinai, New York. Their editorial appears in the New England Journal of Medicine (2019;380:389-90). Dr. Bressman reported disclosures related to Denali Therapeutics, the Michael J. Fox Foundation, and Prevail Therapeutics, while Dr. Saunders-Pullman reported disclosures with Denali Therapeutics, the National Institutes of Health, Genzyme Sanofi, and the Bigglesworth Family Foundation.
investigators reported. The disease course was not significantly different for patients who had a full 80 weeks of levodopa/carbodopa therapy, compared with that seen with those who started treatment after a 40-week delay, according to the investigators.
“These findings imply that levodopa had no disease-modifying effect on Parkinson’s disease over the period of the trial,” wrote investigator Rob M. A. de Bie, MD, PhD, professor of movement disorders at the University of Amsterdam, and his colleagues in the New England Journal of Medicine.
By contrast, results of an earlier randomized, placebo-controlled trial suggested that levodopa had disease-modifying effects, though the findings of that study were inconclusive, according to authors of an editorial (see Views on the News).
In the current multicenter trial, known as LEAP (Levodopa in Early Parkinson’s Disease) a total of 445 patients with early Parkinson’s disease were randomized to either 80 weeks of levodopa and carbodopa or to 40 weeks of placebo followed by 40 weeks of levodopa/carbodopa.
Levodopa was dosed at 100 mg three times per day, and carbodopa at 25 mg three times per day, according to the report.
There was no significant difference between the early and delayed treatment groups for primary outcome of the trial, which was change in the Unified Parkinson’s Disease Rating Scale (UPDRS) from baseline to week 80.
The mean change in UPDRS was –1.0 in the group of patients who had the full 80 weeks of levodopa/carbodopa and –2.0 for those who had delayed therapy, for a difference of 1 point (P = .44). Higher scores on the UPDRS signify worse disease.
At week 40, there was a change in UPDRS favoring the early-initiation strategy, which reflected the effects of levodopa on disease symptoms, investigators added.
Nausea was more common in the early-start group during the first 40 weeks of the trial. However, there were no differences between groups in other adverse events of particular interest, including dyskinesias and motor fluctuations related to levodopa, Dr. de Bie and his colleagues reported.
Taken together, these results suggest no beneficial or detrimental disease-modifying effect for an early treatment strategy, although further trials are warranted to evaluate other strategies, such as higher levodopa doses, longer administration, or starting the drug at later stages of disease, they wrote.
Dr. de Bie reported grants from ZonMw, Parkinson Vereniging, and Stichting Parkinsonfonds during the conduct of the study, as well as grants from GE Health and Medtronic outside the submitted work. Study authors provided disclosures related to Netherlands Organization for Scientific Research, Michael J. Fox Foundation, UCB, AbbVie, Boston Scientific, Biogen, Merck, and others.
SOURCE: Verschuur CVM et al. N Engl J Med. 2019;380:315-24.
investigators reported. The disease course was not significantly different for patients who had a full 80 weeks of levodopa/carbodopa therapy, compared with that seen with those who started treatment after a 40-week delay, according to the investigators.
“These findings imply that levodopa had no disease-modifying effect on Parkinson’s disease over the period of the trial,” wrote investigator Rob M. A. de Bie, MD, PhD, professor of movement disorders at the University of Amsterdam, and his colleagues in the New England Journal of Medicine.
By contrast, results of an earlier randomized, placebo-controlled trial suggested that levodopa had disease-modifying effects, though the findings of that study were inconclusive, according to authors of an editorial (see Views on the News).
In the current multicenter trial, known as LEAP (Levodopa in Early Parkinson’s Disease) a total of 445 patients with early Parkinson’s disease were randomized to either 80 weeks of levodopa and carbodopa or to 40 weeks of placebo followed by 40 weeks of levodopa/carbodopa.
Levodopa was dosed at 100 mg three times per day, and carbodopa at 25 mg three times per day, according to the report.
There was no significant difference between the early and delayed treatment groups for primary outcome of the trial, which was change in the Unified Parkinson’s Disease Rating Scale (UPDRS) from baseline to week 80.
The mean change in UPDRS was –1.0 in the group of patients who had the full 80 weeks of levodopa/carbodopa and –2.0 for those who had delayed therapy, for a difference of 1 point (P = .44). Higher scores on the UPDRS signify worse disease.
At week 40, there was a change in UPDRS favoring the early-initiation strategy, which reflected the effects of levodopa on disease symptoms, investigators added.
Nausea was more common in the early-start group during the first 40 weeks of the trial. However, there were no differences between groups in other adverse events of particular interest, including dyskinesias and motor fluctuations related to levodopa, Dr. de Bie and his colleagues reported.
Taken together, these results suggest no beneficial or detrimental disease-modifying effect for an early treatment strategy, although further trials are warranted to evaluate other strategies, such as higher levodopa doses, longer administration, or starting the drug at later stages of disease, they wrote.
Dr. de Bie reported grants from ZonMw, Parkinson Vereniging, and Stichting Parkinsonfonds during the conduct of the study, as well as grants from GE Health and Medtronic outside the submitted work. Study authors provided disclosures related to Netherlands Organization for Scientific Research, Michael J. Fox Foundation, UCB, AbbVie, Boston Scientific, Biogen, Merck, and others.
SOURCE: Verschuur CVM et al. N Engl J Med. 2019;380:315-24.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Levodopa did not have any significant disease-modifying effects in patients with early Parkinson’s disease.
Major finding: Change in the Unified Parkinson’s Disease Rating Scale (UPDRS) was –1.0 after 80 weeks of levodopa/carbodopa versus –2.0 for 40 weeks of placebo followed by 40 weeks of treatment (P = .44).
Study details: A delayed-start trial including 445 patients with early Parkinson’s disease randomized to 80 weeks of treatment or 40 weeks of placebo plus 40 weeks of treatment.
Disclosures: Study authors reported disclosures related to Netherlands Organization for Scientific Research, Michael J. Fox Foundation, UCB, AbbVie, Boston Scientific, Biogen, Merck, and others.
Source: Verschuur CVM et al. N Engl J Med. 2019;380:315-324.
Avelumab active in recurrent or refractory ovarian cancer
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients enrolled in a large phase 1b trial, investigators have reported.
Treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months, according to investigators in the JAVELIN Solid Tumor trial.
There was no association between PD-L1 or BRCA status and response, which is a novel finding, investigators wrote in JAMA Oncology.
“Very few patients had tumors with high-level PD-L1 expression, which is associated with an increased probability of clinical benefit with anti–PD-1 or anti–PD-L1 treatment of non–small cell lung cancer,” said the investigators, led by Mary L. Disis, MD, of the Cancer Vaccine Institute at the University of Washington, Seattle.
The phase 1b, global, open-label study included 125 women with stage III or IV epithelial ovarian, fallopian tube, or peritoneal cancer who had recurrent or refractory disease and had received a median of three previous treatments for locally advanced or metastatic disease.
All patients received avelumab 10 mg/kg in a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined criteria for study withdrawal.
Confirmed objective responses were seen in 12 patients, or 9.6%, including one complete response and 11 partial responses, the investigators reported. Another 53 patients, or 42.4%, had stable disease as their best response, for a combined disease control rate of 52.0%.
Median progression-free survival was 2.6 months, and median overall survival was 11.2 months, with a 12-month overall survival rate of 47.0%, investigators said.
Responses occurred irrespective of PD-L1 expression status, according to investigators, with no discernible trends in response looking at different PD-L1 expression cutoffs for tumor cells.
For example, at a PD-L1 expression cutoff of 5% or more, patients with positive tumors had an overall response rate of 12.5%, median progression-free survival of 2.7 months, and median overall survival of 10.6 months, they reported, while among negative patients, overall response rate was 9.8%, and median progression-free and overall survival were 2.2 and 11.9 months, respectively.
Treatment-related adverse events occurred in 86 patients, or 68.8%, of which infusion-related reactions and related symptoms were the most common, occurring in 25 patients (20%), investigators wrote. Immune-related adverse events were seen in 16.8% of patients, including three patients (2.4%) with grade 3, and zero with grade 4 or 5.
These findings track with results of other checkpoint inhibitor monotherapy trials in advanced, previously treated ovarian cancer, including smaller studies of pembrolizumab and nivolumab with overall response rates of 11.5% and 15.0%, respectively, according to investigators.
“Although response and survival findings with avelumab monotherapy in this study are encouraging, it would be of interest to determine whether efficacy can be increased through combination or sequential regimens involving chemotherapy or PARP [poly ADP-ribose polymerase] inhibitors,” said the investigators.
Combination studies are underway in women with ovarian cancer, including two global phase 3 trials evaluating avelumab plus chemotherapy in the first-line setting and in patients with platinum-resistant or platinum-refractory disease.
“Results from these ongoing studies will help to define an appropriate role for checkpoint inhibitors within the treatment of ovarian cancer,” study authors concluded.
The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Dr. Disis reported disclosures related to Celgene, EMD Serono, Epithany, Janssen, Pfizer, and Seattle Genetics. Coauthors reported disclosures with Merck, Blueprint, Bristol-Myers Squibb, Eisai, Loxo, Novartis, and others.
SOURCE: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
FROM JAMA ONCOLOGY
Key clinical point: Single-agent treatment with the anti–programmed death-ligand 1 (anti–PD-L1) agent avelumab had antitumor activity and acceptable safety in heavily pretreated ovarian cancer patients.
Major finding: Treatment yielded an overall response rate of 9.6%, with a median duration of response exceeding 10 months and median overall survival greater than 11 months.
Study details: Phase 1b results from the JAVELIN solid tumor trial, which included 125 women with recurrent or refractory ovarian cancer.
Disclosures: The JAVELIN trial is sponsored by Merck KGaA as part of an arrangement between the company and Pfizer. Study authors reported disclosures related to Pfizer, Merck, Celgene, EMD Serono, Epithany, Janssen, and Seattle Genetics, among others.
Source: Disis ML et al. JAMA Oncol. 2019 Jan 24. doi: 10.1001/jamaoncol.2018.6258.
Four distinct IgG4-related disease groups described in study
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: The highest IgG4 concentrations (1,170 mg/dL) were seen in a group of patients with Mikulicz syndrome and systemic involvement. Females and Asian patients were overrepresented in a group characterized by head and neck involvement.
Study details: Two cross-sectional studies including a total of 765 cases of IgG4-related disease submitted by 52 investigators in 17 countries.
Disclosures: Authors reported no conflicts of interest.
Source: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603.
Matched transplant improves stroke risk indicator in sickle cell anemia
, suggesting that this intervention may improve outcomes related to cerebral vasculopathy.
Matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) was linked to significantly lower transcranial Doppler (TCD) velocities at one year compared to standard care in the 9-center study, investigators reported in JAMA.
The study enrolled children with sickle cell anemia who required chronic transfusion due to persistently high TCD velocities, which are associated with increased stroke risk, researchers said.
“Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up,” said the researchers, led by Françoise Bernaudin, MD, of Centre Hospitalier Intercommunal de Créteil, Créteil, France
In the non-randomized, prospective DREPAGREFFE study by Dr. Bernaudin and colleagues, 32 children with sickle cell anemia who had a matched sibling donor underwent transplantation, while another 35 children received standard therapy. The primary end point of the study was time-averaged mean of maximum velocities (TAMV) in cerebral arteries at one year.
The highest TAMV at one year was on average 129.6 cm/s in the MSD-HSCT group, versus 170.4 cm/s in the standard care group, for a difference of -40.8 cm/s (P less than .001), Dr. Bernaudin and co-investigators reported.
The improvement persisted at 3 years, with a TAMV of 112.4 cm/s in the transplantation group and 156.7 cm/s in the standard care group (P less than .001), which they also reported as a secondary outcome of the study.
These findings indicate that MSD-HSCT may allow patients with a history of abnormal TCD velocities to stop transfusions and hydroxyurea, Dr. Bernaudin and colleagues said.
The improvement in TCD velocities may be due in part to anemia correction, but also to the “exclusive presence” of normal red blood cells following transplantation, as opposed to simultaneous presence of normal and sickled cells as would be seen after transfusion, they added.
This study wasn’t powered to determine whether a 40 cm/s reduction in TCD velocities would translate into clinical benefits such as reduction in stenosis and silent infarct, or improved cognitive function, they said. Even so, there were no infarcts or stenoses in the MSD-HSCT group, whereas those event occurred in 9% and 6% of patients in the standard care group, respectively, they added.
Dr. Bernaudin reported disclosures related to Addmedica and bluebird bio. Co-authors reported disclosures with Addmedica, Novartis, Alexion, Amgen, Jazz Pharmaceuticals, and others.
SOURCE: Bernaudin F, et al. JAMA. 2019;321(3):266-276.
Results of DREPAGREFFE illustrate the benefits of matched sibling donor hematopoietic stem cell transplantation (HSCT) for a select group of children with sickle cell anemia, according to the author of an editorial on the study.
Matched sibling donor HSCT was well-tolerated in the study and linked to improved control of transcranial Doppler velocities compared to standard care, Janet L. Kwiatkowski, MD, said in the editorial.
“As a curative therapy, it also obviates the need for long-term treatment wrought with adherence challenges with the potential consequence of stroke, and morbidity from iron overload with transfusion therapy,” wrote Dr. Kwiatkowski.
Only a certain proportion of patients have matched sibling donor HSCT as a potential treatment choice, however, she added.
In this particular study, conducted at 9 sites in France, a higher-than-expected 48% of children with sickle cell anemia had a matched sibling donor, whereas in the United States, she said, less than 1 out of 5 such children would be expected to have an HLA-identical sibling donor.
Because many children don’t have an appropriate matched sibling donor, additional studies are needed not only to evaluate the role of HSCT using matched unrelated and haploidentical donors, Dr. Kwiatkowski said, but also to assess how gene therapy interventions impact cerebrovascular outcomes.
These comments are taken from the accompanying editorial in JAMA by Janet L. Kwiatkowski, MD, MSCE, of Children’s Hospital of Philadelphia, and the Department of Pediatrics at Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr. Kwiatowski disclosed relationships with bluebird bio, Apopharma, and Novartis.
Results of DREPAGREFFE illustrate the benefits of matched sibling donor hematopoietic stem cell transplantation (HSCT) for a select group of children with sickle cell anemia, according to the author of an editorial on the study.
Matched sibling donor HSCT was well-tolerated in the study and linked to improved control of transcranial Doppler velocities compared to standard care, Janet L. Kwiatkowski, MD, said in the editorial.
“As a curative therapy, it also obviates the need for long-term treatment wrought with adherence challenges with the potential consequence of stroke, and morbidity from iron overload with transfusion therapy,” wrote Dr. Kwiatkowski.
Only a certain proportion of patients have matched sibling donor HSCT as a potential treatment choice, however, she added.
In this particular study, conducted at 9 sites in France, a higher-than-expected 48% of children with sickle cell anemia had a matched sibling donor, whereas in the United States, she said, less than 1 out of 5 such children would be expected to have an HLA-identical sibling donor.
Because many children don’t have an appropriate matched sibling donor, additional studies are needed not only to evaluate the role of HSCT using matched unrelated and haploidentical donors, Dr. Kwiatkowski said, but also to assess how gene therapy interventions impact cerebrovascular outcomes.
These comments are taken from the accompanying editorial in JAMA by Janet L. Kwiatkowski, MD, MSCE, of Children’s Hospital of Philadelphia, and the Department of Pediatrics at Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr. Kwiatowski disclosed relationships with bluebird bio, Apopharma, and Novartis.
Results of DREPAGREFFE illustrate the benefits of matched sibling donor hematopoietic stem cell transplantation (HSCT) for a select group of children with sickle cell anemia, according to the author of an editorial on the study.
Matched sibling donor HSCT was well-tolerated in the study and linked to improved control of transcranial Doppler velocities compared to standard care, Janet L. Kwiatkowski, MD, said in the editorial.
“As a curative therapy, it also obviates the need for long-term treatment wrought with adherence challenges with the potential consequence of stroke, and morbidity from iron overload with transfusion therapy,” wrote Dr. Kwiatkowski.
Only a certain proportion of patients have matched sibling donor HSCT as a potential treatment choice, however, she added.
In this particular study, conducted at 9 sites in France, a higher-than-expected 48% of children with sickle cell anemia had a matched sibling donor, whereas in the United States, she said, less than 1 out of 5 such children would be expected to have an HLA-identical sibling donor.
Because many children don’t have an appropriate matched sibling donor, additional studies are needed not only to evaluate the role of HSCT using matched unrelated and haploidentical donors, Dr. Kwiatkowski said, but also to assess how gene therapy interventions impact cerebrovascular outcomes.
These comments are taken from the accompanying editorial in JAMA by Janet L. Kwiatkowski, MD, MSCE, of Children’s Hospital of Philadelphia, and the Department of Pediatrics at Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr. Kwiatowski disclosed relationships with bluebird bio, Apopharma, and Novartis.
, suggesting that this intervention may improve outcomes related to cerebral vasculopathy.
Matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) was linked to significantly lower transcranial Doppler (TCD) velocities at one year compared to standard care in the 9-center study, investigators reported in JAMA.
The study enrolled children with sickle cell anemia who required chronic transfusion due to persistently high TCD velocities, which are associated with increased stroke risk, researchers said.
“Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up,” said the researchers, led by Françoise Bernaudin, MD, of Centre Hospitalier Intercommunal de Créteil, Créteil, France
In the non-randomized, prospective DREPAGREFFE study by Dr. Bernaudin and colleagues, 32 children with sickle cell anemia who had a matched sibling donor underwent transplantation, while another 35 children received standard therapy. The primary end point of the study was time-averaged mean of maximum velocities (TAMV) in cerebral arteries at one year.
The highest TAMV at one year was on average 129.6 cm/s in the MSD-HSCT group, versus 170.4 cm/s in the standard care group, for a difference of -40.8 cm/s (P less than .001), Dr. Bernaudin and co-investigators reported.
The improvement persisted at 3 years, with a TAMV of 112.4 cm/s in the transplantation group and 156.7 cm/s in the standard care group (P less than .001), which they also reported as a secondary outcome of the study.
These findings indicate that MSD-HSCT may allow patients with a history of abnormal TCD velocities to stop transfusions and hydroxyurea, Dr. Bernaudin and colleagues said.
The improvement in TCD velocities may be due in part to anemia correction, but also to the “exclusive presence” of normal red blood cells following transplantation, as opposed to simultaneous presence of normal and sickled cells as would be seen after transfusion, they added.
This study wasn’t powered to determine whether a 40 cm/s reduction in TCD velocities would translate into clinical benefits such as reduction in stenosis and silent infarct, or improved cognitive function, they said. Even so, there were no infarcts or stenoses in the MSD-HSCT group, whereas those event occurred in 9% and 6% of patients in the standard care group, respectively, they added.
Dr. Bernaudin reported disclosures related to Addmedica and bluebird bio. Co-authors reported disclosures with Addmedica, Novartis, Alexion, Amgen, Jazz Pharmaceuticals, and others.
SOURCE: Bernaudin F, et al. JAMA. 2019;321(3):266-276.
, suggesting that this intervention may improve outcomes related to cerebral vasculopathy.
Matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) was linked to significantly lower transcranial Doppler (TCD) velocities at one year compared to standard care in the 9-center study, investigators reported in JAMA.
The study enrolled children with sickle cell anemia who required chronic transfusion due to persistently high TCD velocities, which are associated with increased stroke risk, researchers said.
“Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up,” said the researchers, led by Françoise Bernaudin, MD, of Centre Hospitalier Intercommunal de Créteil, Créteil, France
In the non-randomized, prospective DREPAGREFFE study by Dr. Bernaudin and colleagues, 32 children with sickle cell anemia who had a matched sibling donor underwent transplantation, while another 35 children received standard therapy. The primary end point of the study was time-averaged mean of maximum velocities (TAMV) in cerebral arteries at one year.
The highest TAMV at one year was on average 129.6 cm/s in the MSD-HSCT group, versus 170.4 cm/s in the standard care group, for a difference of -40.8 cm/s (P less than .001), Dr. Bernaudin and co-investigators reported.
The improvement persisted at 3 years, with a TAMV of 112.4 cm/s in the transplantation group and 156.7 cm/s in the standard care group (P less than .001), which they also reported as a secondary outcome of the study.
These findings indicate that MSD-HSCT may allow patients with a history of abnormal TCD velocities to stop transfusions and hydroxyurea, Dr. Bernaudin and colleagues said.
The improvement in TCD velocities may be due in part to anemia correction, but also to the “exclusive presence” of normal red blood cells following transplantation, as opposed to simultaneous presence of normal and sickled cells as would be seen after transfusion, they added.
This study wasn’t powered to determine whether a 40 cm/s reduction in TCD velocities would translate into clinical benefits such as reduction in stenosis and silent infarct, or improved cognitive function, they said. Even so, there were no infarcts or stenoses in the MSD-HSCT group, whereas those event occurred in 9% and 6% of patients in the standard care group, respectively, they added.
Dr. Bernaudin reported disclosures related to Addmedica and bluebird bio. Co-authors reported disclosures with Addmedica, Novartis, Alexion, Amgen, Jazz Pharmaceuticals, and others.
SOURCE: Bernaudin F, et al. JAMA. 2019;321(3):266-276.
FROM JAMA
Key clinical point: In children with sickle cell anemia, matched sibling donor hematopoietic stem cell transplants (HSCT) reduced an indicator of stroke risk, suggesting that the intervention may improve cerebrovascular outcomes.
Major finding: The primary end point, time-averaged mean of maximum velocities in cerebral arteries at one year, was on average 129.6 cm/s in the MSD-HSCT group, versus 170.4 cm/s in the standard care group (P less than .001).
Study details: A multicenter, non-randomized, prospective study (DREPAGREFFE) including 32 children with sickle cell anemia who underwent MSD-HSCT and 35 who received standard therapy.
Disclosures: Study authors provided disclosures related to Addmedica, bluebird bio, Novartis, Alexion, Amgen, Jazz Pharmaceuticals, and others.
Source: Bernaudin F, et al. JAMA. 2019;321(3):266-276.
Renal transplant improves survival in lupus nephritis patients
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: Renal transplant is associated with a substantial survival benefit in patients with end-stage renal disease (ESRD) due to lupus nephritis,
Major finding: Transplant conferred a 70% reduction in overall death risk in these lupus nephritis ESRD patients, largely due to reduced deaths caused by infection and cardiovascular disease,
Study details: Analysis of 9,659 patients with lupus nephritis ESRD in the United States Renal Data System.
Disclosures: Support for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One co-author provided disclosures related to Teva Pharmaceuticals and Gilead Sciences.
Source: Jorge A, et al. Ann Intern Med. 2019 Jan 21. doi: 10.7326/M18-1570.
Autologous transplant linked to PFS benefit in MCL
Autologous hematopoietic cell transplantation (AHCT) was linked to improved progression-free survival, but not improved overall survival, in a retrospective cohort study including more than 1,000 mantle cell lymphoma (MCL) patients.
Use of consolidative AHCT was associated with improved progression-free survival even after the researchers controlled for disease severity in this cohort of younger, transplantation-eligible patients treated in the rituximab era, according to Stefan K. Barta, MD, of the University of Pennsylvania, Philadelphia, and his coinvestigators.
There was no such link between AHCT and improved overall survival in a propensity score–weighted analysis, though certain subgroups did seem to have an overall survival benefit, such as patients with high-risk features, Dr. Barta and his colleagues reported in the Journal of Clinical Oncology.
By contrast, other recent studies have found an association between consolidative AHCT and improved overall survival in MCL, including another recently reported retrospective analysis of 10,000 patients in the National Cancer Database.
The lack of overall survival improvement seen in the present study may be due to effective salvage therapy with novel agents or additional transplantation, abrogating any improvement that otherwise might be attributable to AHCT, Dr. Barta and his coauthors said in a discussion of their results.
The present analysis included 1,029 transplantation-eligible adults aged 65 years or younger with a new diagnosis of MCL, who were treated between 2000 and 2015 at one of 25 medical centers. About two-thirds of the patients underwent consolidative AHCT.
With a median follow-up of 76 months, median progression-free survival was 62 months, and median overall survival was 138 months, the investigators reported.
While AHCT was linked to improved progression-free survival and overall survival in an unadjusted analysis, subsequent analyses showed only a trend toward improvement or no improvement in overall survival.
Specifically, AHCT was associated with improved progression-free survival in multivariable regression analysis, with a hazard ratio (HR) of 0.53 (95% confidence interval, 0.43-0.66; P less than .01) and in propensity score–weighted analysis (HR, 0.70; 95% CI, 0.59-0.84; P less than .05).
By contrast, AHCT was associated with a trend toward improved overall survival in the multivariable analysis (HR, 0.77; 95% CI, 0.98 to 1.01; P = .06) and no improvement in overall survival in the propensity score–weighted analysis (HR, 0.87; 95% CI, 0.69 to 1.10; P = .24).
A subgroup analysis conducted after the multivariable analysis found that overall survival improvements were seen only in patients who received CHOP-like induction or induction without cytarabine, or those who had blastoid or pleomorphic variant or who scored high on the MCL International Prognostic Index.
Randomized trials are “urgently needed” to determine the true benefit of consolidative AHCT in MCL, Dr. Barta and his coauthors said, since some subgroups likely derive minimal benefit from it, including patients with TP53 mutations or those who are minimal residual disease (MRD) negative following induction.
One such study is EA4151, an ongoing randomized, phase 3 clinical trial, which is evaluating consolidation with AHCT followed by maintenance rituximab versus maintenance rituximab alone for MCL patients in MRD-negative first complete remission.
“With this and other well-designed prospective trials as well as with well-validated predictive biomarkers, clinicians will be better able to provide a more refined, risk-adapted approach to first-line management of MCL,” the investigators said.
Dr. Barta provided no disclosures related to the research. Coauthors had disclosures related to Sanofi, AstraZeneca, Celgene, Adaptive Biotechnologies, Janssen Oncology, Seattle Genetics, Genentech, Pharmacyclics, Merck, Bristol-Myers Squibb, and others.
SOURCE: Gerson JN et al. J Clin Oncol. 2019 Jan 7. doi: 10.1200/JCO.18.00690.
Autologous hematopoietic cell transplantation (AHCT) was linked to improved progression-free survival, but not improved overall survival, in a retrospective cohort study including more than 1,000 mantle cell lymphoma (MCL) patients.
Use of consolidative AHCT was associated with improved progression-free survival even after the researchers controlled for disease severity in this cohort of younger, transplantation-eligible patients treated in the rituximab era, according to Stefan K. Barta, MD, of the University of Pennsylvania, Philadelphia, and his coinvestigators.
There was no such link between AHCT and improved overall survival in a propensity score–weighted analysis, though certain subgroups did seem to have an overall survival benefit, such as patients with high-risk features, Dr. Barta and his colleagues reported in the Journal of Clinical Oncology.
By contrast, other recent studies have found an association between consolidative AHCT and improved overall survival in MCL, including another recently reported retrospective analysis of 10,000 patients in the National Cancer Database.
The lack of overall survival improvement seen in the present study may be due to effective salvage therapy with novel agents or additional transplantation, abrogating any improvement that otherwise might be attributable to AHCT, Dr. Barta and his coauthors said in a discussion of their results.
The present analysis included 1,029 transplantation-eligible adults aged 65 years or younger with a new diagnosis of MCL, who were treated between 2000 and 2015 at one of 25 medical centers. About two-thirds of the patients underwent consolidative AHCT.
With a median follow-up of 76 months, median progression-free survival was 62 months, and median overall survival was 138 months, the investigators reported.
While AHCT was linked to improved progression-free survival and overall survival in an unadjusted analysis, subsequent analyses showed only a trend toward improvement or no improvement in overall survival.
Specifically, AHCT was associated with improved progression-free survival in multivariable regression analysis, with a hazard ratio (HR) of 0.53 (95% confidence interval, 0.43-0.66; P less than .01) and in propensity score–weighted analysis (HR, 0.70; 95% CI, 0.59-0.84; P less than .05).
By contrast, AHCT was associated with a trend toward improved overall survival in the multivariable analysis (HR, 0.77; 95% CI, 0.98 to 1.01; P = .06) and no improvement in overall survival in the propensity score–weighted analysis (HR, 0.87; 95% CI, 0.69 to 1.10; P = .24).
A subgroup analysis conducted after the multivariable analysis found that overall survival improvements were seen only in patients who received CHOP-like induction or induction without cytarabine, or those who had blastoid or pleomorphic variant or who scored high on the MCL International Prognostic Index.
Randomized trials are “urgently needed” to determine the true benefit of consolidative AHCT in MCL, Dr. Barta and his coauthors said, since some subgroups likely derive minimal benefit from it, including patients with TP53 mutations or those who are minimal residual disease (MRD) negative following induction.
One such study is EA4151, an ongoing randomized, phase 3 clinical trial, which is evaluating consolidation with AHCT followed by maintenance rituximab versus maintenance rituximab alone for MCL patients in MRD-negative first complete remission.
“With this and other well-designed prospective trials as well as with well-validated predictive biomarkers, clinicians will be better able to provide a more refined, risk-adapted approach to first-line management of MCL,” the investigators said.
Dr. Barta provided no disclosures related to the research. Coauthors had disclosures related to Sanofi, AstraZeneca, Celgene, Adaptive Biotechnologies, Janssen Oncology, Seattle Genetics, Genentech, Pharmacyclics, Merck, Bristol-Myers Squibb, and others.
SOURCE: Gerson JN et al. J Clin Oncol. 2019 Jan 7. doi: 10.1200/JCO.18.00690.
Autologous hematopoietic cell transplantation (AHCT) was linked to improved progression-free survival, but not improved overall survival, in a retrospective cohort study including more than 1,000 mantle cell lymphoma (MCL) patients.
Use of consolidative AHCT was associated with improved progression-free survival even after the researchers controlled for disease severity in this cohort of younger, transplantation-eligible patients treated in the rituximab era, according to Stefan K. Barta, MD, of the University of Pennsylvania, Philadelphia, and his coinvestigators.
There was no such link between AHCT and improved overall survival in a propensity score–weighted analysis, though certain subgroups did seem to have an overall survival benefit, such as patients with high-risk features, Dr. Barta and his colleagues reported in the Journal of Clinical Oncology.
By contrast, other recent studies have found an association between consolidative AHCT and improved overall survival in MCL, including another recently reported retrospective analysis of 10,000 patients in the National Cancer Database.
The lack of overall survival improvement seen in the present study may be due to effective salvage therapy with novel agents or additional transplantation, abrogating any improvement that otherwise might be attributable to AHCT, Dr. Barta and his coauthors said in a discussion of their results.
The present analysis included 1,029 transplantation-eligible adults aged 65 years or younger with a new diagnosis of MCL, who were treated between 2000 and 2015 at one of 25 medical centers. About two-thirds of the patients underwent consolidative AHCT.
With a median follow-up of 76 months, median progression-free survival was 62 months, and median overall survival was 138 months, the investigators reported.
While AHCT was linked to improved progression-free survival and overall survival in an unadjusted analysis, subsequent analyses showed only a trend toward improvement or no improvement in overall survival.
Specifically, AHCT was associated with improved progression-free survival in multivariable regression analysis, with a hazard ratio (HR) of 0.53 (95% confidence interval, 0.43-0.66; P less than .01) and in propensity score–weighted analysis (HR, 0.70; 95% CI, 0.59-0.84; P less than .05).
By contrast, AHCT was associated with a trend toward improved overall survival in the multivariable analysis (HR, 0.77; 95% CI, 0.98 to 1.01; P = .06) and no improvement in overall survival in the propensity score–weighted analysis (HR, 0.87; 95% CI, 0.69 to 1.10; P = .24).
A subgroup analysis conducted after the multivariable analysis found that overall survival improvements were seen only in patients who received CHOP-like induction or induction without cytarabine, or those who had blastoid or pleomorphic variant or who scored high on the MCL International Prognostic Index.
Randomized trials are “urgently needed” to determine the true benefit of consolidative AHCT in MCL, Dr. Barta and his coauthors said, since some subgroups likely derive minimal benefit from it, including patients with TP53 mutations or those who are minimal residual disease (MRD) negative following induction.
One such study is EA4151, an ongoing randomized, phase 3 clinical trial, which is evaluating consolidation with AHCT followed by maintenance rituximab versus maintenance rituximab alone for MCL patients in MRD-negative first complete remission.
“With this and other well-designed prospective trials as well as with well-validated predictive biomarkers, clinicians will be better able to provide a more refined, risk-adapted approach to first-line management of MCL,” the investigators said.
Dr. Barta provided no disclosures related to the research. Coauthors had disclosures related to Sanofi, AstraZeneca, Celgene, Adaptive Biotechnologies, Janssen Oncology, Seattle Genetics, Genentech, Pharmacyclics, Merck, Bristol-Myers Squibb, and others.
SOURCE: Gerson JN et al. J Clin Oncol. 2019 Jan 7. doi: 10.1200/JCO.18.00690.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: AHCT was associated with improved progression-free survival in a propensity score–weighted analysis (hazard ratio, 0.70; P less than .05).
Study details: A retrospective cohort study including 1,029 transplantation-eligible adults aged 65 years or younger with newly diagnosed MCL.
Disclosures: The authors reported disclosures related to Sanofi, AstraZeneca, Celgene, Adaptive Biotechnologies, Janssen Oncology, Seattle Genetics, Genentech, Pharmacyclics, Merck, Bristol-Myers Squibb, and others.
Source: Gerson JN et al. J Clin Oncol. 2019 Jan 7. doi: 10.1200/JCO.18.00690.