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CAR T-Cell: Do Benefits Still Outweigh Risks?
Importantly, most specialists agree, so far the risk appears no greater than the known risk of secondary primary malignancies that is well established with other cancer therapies.
“The data that we have so far suggest that the risk of secondary T-cell lymphoma in patients treated with CAR T-cells is similar to [that] of patients treated with other cancer therapies, [including] chemotherapy, radiation, transplantation,” Marco Ruella, MD, said in an interview. He reported on a case of a T-cell lymphoma occurring following CAR-T therapy at the University of Pennsylvania.
While his team is still investigating the development of such malignancies, “the FDA notice does not change our clinical practice and patients should be reassured that the benefit of CAR-T therapy significantly outweighs the potential risk of secondary malignancies including T-cell lymphoma,” said Dr. Ruella, scientific director of the Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, at the University of Pennsylvania, Philadelphia.
FDA: 28 Reports of Malignancies; 3 with Evidence of ‘Likely’ CAR T Involvement
Concerns were raised last November when the FDA announced in a safety communication that it was investigating the “serious risk of T-cell malignancy” following B-cell maturation antigen (BCMA)-directed or CD19-directed CAR T-cell immunotherapies, citing reports from clinical trials and/or postmarketing adverse event data sources. Subsequently, in January, the FDA called for the boxed warning on all approved BCMA- and CD19-targeted genetically modified autologous T-cell immunotherapies, which include: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Carvykti (ciltacabtagene autoleucel); Kymriah (tisagenlecleucel); Tecartus (brexucabtagene autoleucel); and Yescarta (axicabtagene ciloleucel).
“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA continues to investigate the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death,” the FDA reported in discussing the safety warnings.
The cases were detailed in a report from FDA researchers published in the New England Journal of Medicine, noting that as of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers occurring following CAR T-cell treatment, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma.
Report coauthor Peter Marks, MD, PhD, of the FDA’s Center for Biologics Evaluation and Research in Silver Spring, Maryland, said in an interview that since the publication of their report, six new cases have emerged.
“As reported in the NEJM Perspective, there were 22 cases of T-cell malignancy after treatment with CAR T-cell immunotherapies as of December 31, 2023, but we have received additional reports and, as of February 9, 2024, FDA has now received 28 reports,” he said. “Note that as new cases are being reported, there will be updates to the total number of cases under ongoing review by FDA.”
The initial 22 cases all occurred relatively soon after treatment. Of 14 cases with sufficient data, all developed within 2 years of the CAR-T therapy, ranging from 1 to 19 months, with about half occurring in the first year after administration.
The cases involved five of the six FDA-approved CAR-T products, with the numbers too low to suggest an association with any particular product.
In three of the cases, the lymphoma was found in genetic testing to contain the CAR construction, “indicating that the CAR-T product was most likely involved in the development of the T-cell cancer,” according to the FDA researchers.
With inadequate genetic sampling in most of the remaining 19 cases, the association is less clear, however “the timing of several of the cases makes association a possibility,” Dr. Marks said. In their report, Dr. Marks and colleagues added that “determination of whether the T-cell cancer is associated with the CAR construct ... most likely won’t be possible for every case reported to date.”
Even if all the reported cases are assumed to be related to CAR-T treatment, the numbers still represent a very small proportion of the more than 27,000 doses of the six CAR-T therapies approved in the United States, the authors noted, but they cautioned that the numbers could indeed be higher than reported.
“Relying on postmarketing reporting may lead to underestimates of such cases,” they said.
Life-Long Monitoring Recommended
In response to the reports, the FDA is urging that clinicians’ monitoring of patients treated with CAR-T therapy should be lifelong.
“Patients and clinical trial participants receiving treatment with these products should be monitored lifelong for new malignancies,” Dr. Marks said.
“In the event that a new malignancy occurs following treatment with these products, contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing for the presence of the CAR transgene.”
In addition, cases should be reported to the FDA, either by calling or through the FDA’s medical product safety reporting program.
T-Cell Malignancy Case Report
In describing the case at their medical center in the report in Nature Medicine, Dr. Ruella and colleagues said a T-cell lymphoma occurred in a patient with non-Hodgkin B-cell lymphoma 3 months after an anti-CD19 CAR T-cell treatment.
As a result, the team conducted a subsequent analysis of 449 patients treated with CAR-T therapy at the University of Pennsylvania center, and with a median follow-up of 10.3 months, 16 patients (3.6%) had developed a secondary primary malignancy, with a median onset time of 26.4 months for solid and 9.7 months for hematological malignancies.
The patient who had developed a T-cell lymphoma tested negative for CAR integration upon diagnosis, and regarding the other cancers, Dr. Ruella noted that “we have no indication that the secondary malignancies are directly caused by the CAR-T therapy.
“We have many patients with a very long follow-up beyond 5 and even 10 years,” he said. “In these patients, we don’t see an increased risk of T-cell lymphoma.”
‘Cautious Reassurance’ Urged in Discussion with Patients
With alarming headlines on the findings suggesting that CAR-T therapy may cause cancer, Rahul Banerjee, MD, and colleagues at the University of Washington, Seattle, recommend the use of “cautious reassurance” in discussing the issue with patients. In a paper published in January in Blood Advances, they suggest a three-part response: underscoring that the benefits of CAR T “far outweigh” the risks in relapsed/refractory malignancies, that the ‘one-and-done’ nature of CAR-T infusions provide meaningful improvements in quality of life, and that the active cancer at hand is “a much larger threat than a hypothetical cancer years later.”
In many cases, patients may only have months to live without CAR-T therapy and will have already had multiple prior lines of therapy, therefore the CAR-T treatment itself may provide time for the secondary primary cancers from any of the treatments to emerge, as experts have noted.
“One has to be alive to be diagnosed with a secondary primary malignancy, and it’s thus very possible that CAR-T may be creating a type of ‘immortal time bias’ wherein patients live long enough to experience the unfortunate sequelae of their previous therapies,” Dr. Banerjee explained in an interview.
Nevertheless, the potential for substantial improvements in quality of life with CAR-T therapy compared with traditional treatments addresses a top priority for patients, he added.
“For most patients with [for instance], myeloma, the ability of CAR-T to put them rapidly into a deep remission without the need for maintenance is an unheard-of potential for them,” Dr. Banerjee said.
“In multiple myeloma, no CAR-T therapy has (yet) demonstrated an overall survival benefit — but I think the substantial quality-of-life benefit stands by itself as a big reason why patients continue to prefer CAR-T.”
Keep Patients In Touch with CAR T Centers
In light of the concerns regarding the secondary malignancies, Dr. Banerjee underscored that CAR-T patients should be kept in close touch with centers that have CAR-T treatment expertise.
With most patients followed primarily at community practices where CAR-T therapy is not administered, “I’d strongly encourage my colleagues in community practices to refer all eligible patients to a CAR-T-capable center for evaluation regardless of what their risk of post-CAR-T secondary primary malignancies may be,” Dr. Banerjee urged.
“Based on the evidence we have currently, which includes the FDA’s updated information, there are many more unknowns about this potential secondary primary malignancy risk than knowns,” he said. “This is of course a much more nuanced issue than any one package insert can convey, and CAR-T experts at treating centers can have these conversations at length with eligible patients who are nervous about these recent updates.”
Dr. Ruella disclosed that he holds patents related to CD19 CAR T cells, as well as relationships with NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scailyte, Bayer, AbClon, Oxford NanoImaging, CURIOX, and Beckman Coulter, and he was the scientific founder of viTToria Biotherapeutics. Dr. Banerjee reported ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
Importantly, most specialists agree, so far the risk appears no greater than the known risk of secondary primary malignancies that is well established with other cancer therapies.
“The data that we have so far suggest that the risk of secondary T-cell lymphoma in patients treated with CAR T-cells is similar to [that] of patients treated with other cancer therapies, [including] chemotherapy, radiation, transplantation,” Marco Ruella, MD, said in an interview. He reported on a case of a T-cell lymphoma occurring following CAR-T therapy at the University of Pennsylvania.
While his team is still investigating the development of such malignancies, “the FDA notice does not change our clinical practice and patients should be reassured that the benefit of CAR-T therapy significantly outweighs the potential risk of secondary malignancies including T-cell lymphoma,” said Dr. Ruella, scientific director of the Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, at the University of Pennsylvania, Philadelphia.
FDA: 28 Reports of Malignancies; 3 with Evidence of ‘Likely’ CAR T Involvement
Concerns were raised last November when the FDA announced in a safety communication that it was investigating the “serious risk of T-cell malignancy” following B-cell maturation antigen (BCMA)-directed or CD19-directed CAR T-cell immunotherapies, citing reports from clinical trials and/or postmarketing adverse event data sources. Subsequently, in January, the FDA called for the boxed warning on all approved BCMA- and CD19-targeted genetically modified autologous T-cell immunotherapies, which include: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Carvykti (ciltacabtagene autoleucel); Kymriah (tisagenlecleucel); Tecartus (brexucabtagene autoleucel); and Yescarta (axicabtagene ciloleucel).
“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA continues to investigate the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death,” the FDA reported in discussing the safety warnings.
The cases were detailed in a report from FDA researchers published in the New England Journal of Medicine, noting that as of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers occurring following CAR T-cell treatment, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma.
Report coauthor Peter Marks, MD, PhD, of the FDA’s Center for Biologics Evaluation and Research in Silver Spring, Maryland, said in an interview that since the publication of their report, six new cases have emerged.
“As reported in the NEJM Perspective, there were 22 cases of T-cell malignancy after treatment with CAR T-cell immunotherapies as of December 31, 2023, but we have received additional reports and, as of February 9, 2024, FDA has now received 28 reports,” he said. “Note that as new cases are being reported, there will be updates to the total number of cases under ongoing review by FDA.”
The initial 22 cases all occurred relatively soon after treatment. Of 14 cases with sufficient data, all developed within 2 years of the CAR-T therapy, ranging from 1 to 19 months, with about half occurring in the first year after administration.
The cases involved five of the six FDA-approved CAR-T products, with the numbers too low to suggest an association with any particular product.
In three of the cases, the lymphoma was found in genetic testing to contain the CAR construction, “indicating that the CAR-T product was most likely involved in the development of the T-cell cancer,” according to the FDA researchers.
With inadequate genetic sampling in most of the remaining 19 cases, the association is less clear, however “the timing of several of the cases makes association a possibility,” Dr. Marks said. In their report, Dr. Marks and colleagues added that “determination of whether the T-cell cancer is associated with the CAR construct ... most likely won’t be possible for every case reported to date.”
Even if all the reported cases are assumed to be related to CAR-T treatment, the numbers still represent a very small proportion of the more than 27,000 doses of the six CAR-T therapies approved in the United States, the authors noted, but they cautioned that the numbers could indeed be higher than reported.
“Relying on postmarketing reporting may lead to underestimates of such cases,” they said.
Life-Long Monitoring Recommended
In response to the reports, the FDA is urging that clinicians’ monitoring of patients treated with CAR-T therapy should be lifelong.
“Patients and clinical trial participants receiving treatment with these products should be monitored lifelong for new malignancies,” Dr. Marks said.
“In the event that a new malignancy occurs following treatment with these products, contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing for the presence of the CAR transgene.”
In addition, cases should be reported to the FDA, either by calling or through the FDA’s medical product safety reporting program.
T-Cell Malignancy Case Report
In describing the case at their medical center in the report in Nature Medicine, Dr. Ruella and colleagues said a T-cell lymphoma occurred in a patient with non-Hodgkin B-cell lymphoma 3 months after an anti-CD19 CAR T-cell treatment.
As a result, the team conducted a subsequent analysis of 449 patients treated with CAR-T therapy at the University of Pennsylvania center, and with a median follow-up of 10.3 months, 16 patients (3.6%) had developed a secondary primary malignancy, with a median onset time of 26.4 months for solid and 9.7 months for hematological malignancies.
The patient who had developed a T-cell lymphoma tested negative for CAR integration upon diagnosis, and regarding the other cancers, Dr. Ruella noted that “we have no indication that the secondary malignancies are directly caused by the CAR-T therapy.
“We have many patients with a very long follow-up beyond 5 and even 10 years,” he said. “In these patients, we don’t see an increased risk of T-cell lymphoma.”
‘Cautious Reassurance’ Urged in Discussion with Patients
With alarming headlines on the findings suggesting that CAR-T therapy may cause cancer, Rahul Banerjee, MD, and colleagues at the University of Washington, Seattle, recommend the use of “cautious reassurance” in discussing the issue with patients. In a paper published in January in Blood Advances, they suggest a three-part response: underscoring that the benefits of CAR T “far outweigh” the risks in relapsed/refractory malignancies, that the ‘one-and-done’ nature of CAR-T infusions provide meaningful improvements in quality of life, and that the active cancer at hand is “a much larger threat than a hypothetical cancer years later.”
In many cases, patients may only have months to live without CAR-T therapy and will have already had multiple prior lines of therapy, therefore the CAR-T treatment itself may provide time for the secondary primary cancers from any of the treatments to emerge, as experts have noted.
“One has to be alive to be diagnosed with a secondary primary malignancy, and it’s thus very possible that CAR-T may be creating a type of ‘immortal time bias’ wherein patients live long enough to experience the unfortunate sequelae of their previous therapies,” Dr. Banerjee explained in an interview.
Nevertheless, the potential for substantial improvements in quality of life with CAR-T therapy compared with traditional treatments addresses a top priority for patients, he added.
“For most patients with [for instance], myeloma, the ability of CAR-T to put them rapidly into a deep remission without the need for maintenance is an unheard-of potential for them,” Dr. Banerjee said.
“In multiple myeloma, no CAR-T therapy has (yet) demonstrated an overall survival benefit — but I think the substantial quality-of-life benefit stands by itself as a big reason why patients continue to prefer CAR-T.”
Keep Patients In Touch with CAR T Centers
In light of the concerns regarding the secondary malignancies, Dr. Banerjee underscored that CAR-T patients should be kept in close touch with centers that have CAR-T treatment expertise.
With most patients followed primarily at community practices where CAR-T therapy is not administered, “I’d strongly encourage my colleagues in community practices to refer all eligible patients to a CAR-T-capable center for evaluation regardless of what their risk of post-CAR-T secondary primary malignancies may be,” Dr. Banerjee urged.
“Based on the evidence we have currently, which includes the FDA’s updated information, there are many more unknowns about this potential secondary primary malignancy risk than knowns,” he said. “This is of course a much more nuanced issue than any one package insert can convey, and CAR-T experts at treating centers can have these conversations at length with eligible patients who are nervous about these recent updates.”
Dr. Ruella disclosed that he holds patents related to CD19 CAR T cells, as well as relationships with NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scailyte, Bayer, AbClon, Oxford NanoImaging, CURIOX, and Beckman Coulter, and he was the scientific founder of viTToria Biotherapeutics. Dr. Banerjee reported ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
Importantly, most specialists agree, so far the risk appears no greater than the known risk of secondary primary malignancies that is well established with other cancer therapies.
“The data that we have so far suggest that the risk of secondary T-cell lymphoma in patients treated with CAR T-cells is similar to [that] of patients treated with other cancer therapies, [including] chemotherapy, radiation, transplantation,” Marco Ruella, MD, said in an interview. He reported on a case of a T-cell lymphoma occurring following CAR-T therapy at the University of Pennsylvania.
While his team is still investigating the development of such malignancies, “the FDA notice does not change our clinical practice and patients should be reassured that the benefit of CAR-T therapy significantly outweighs the potential risk of secondary malignancies including T-cell lymphoma,” said Dr. Ruella, scientific director of the Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, at the University of Pennsylvania, Philadelphia.
FDA: 28 Reports of Malignancies; 3 with Evidence of ‘Likely’ CAR T Involvement
Concerns were raised last November when the FDA announced in a safety communication that it was investigating the “serious risk of T-cell malignancy” following B-cell maturation antigen (BCMA)-directed or CD19-directed CAR T-cell immunotherapies, citing reports from clinical trials and/or postmarketing adverse event data sources. Subsequently, in January, the FDA called for the boxed warning on all approved BCMA- and CD19-targeted genetically modified autologous T-cell immunotherapies, which include: Abecma (idecabtagene vicleucel); Breyanzi (lisocabtagene maraleucel); Carvykti (ciltacabtagene autoleucel); Kymriah (tisagenlecleucel); Tecartus (brexucabtagene autoleucel); and Yescarta (axicabtagene ciloleucel).
“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA continues to investigate the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death,” the FDA reported in discussing the safety warnings.
The cases were detailed in a report from FDA researchers published in the New England Journal of Medicine, noting that as of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers occurring following CAR T-cell treatment, including T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma.
Report coauthor Peter Marks, MD, PhD, of the FDA’s Center for Biologics Evaluation and Research in Silver Spring, Maryland, said in an interview that since the publication of their report, six new cases have emerged.
“As reported in the NEJM Perspective, there were 22 cases of T-cell malignancy after treatment with CAR T-cell immunotherapies as of December 31, 2023, but we have received additional reports and, as of February 9, 2024, FDA has now received 28 reports,” he said. “Note that as new cases are being reported, there will be updates to the total number of cases under ongoing review by FDA.”
The initial 22 cases all occurred relatively soon after treatment. Of 14 cases with sufficient data, all developed within 2 years of the CAR-T therapy, ranging from 1 to 19 months, with about half occurring in the first year after administration.
The cases involved five of the six FDA-approved CAR-T products, with the numbers too low to suggest an association with any particular product.
In three of the cases, the lymphoma was found in genetic testing to contain the CAR construction, “indicating that the CAR-T product was most likely involved in the development of the T-cell cancer,” according to the FDA researchers.
With inadequate genetic sampling in most of the remaining 19 cases, the association is less clear, however “the timing of several of the cases makes association a possibility,” Dr. Marks said. In their report, Dr. Marks and colleagues added that “determination of whether the T-cell cancer is associated with the CAR construct ... most likely won’t be possible for every case reported to date.”
Even if all the reported cases are assumed to be related to CAR-T treatment, the numbers still represent a very small proportion of the more than 27,000 doses of the six CAR-T therapies approved in the United States, the authors noted, but they cautioned that the numbers could indeed be higher than reported.
“Relying on postmarketing reporting may lead to underestimates of such cases,” they said.
Life-Long Monitoring Recommended
In response to the reports, the FDA is urging that clinicians’ monitoring of patients treated with CAR-T therapy should be lifelong.
“Patients and clinical trial participants receiving treatment with these products should be monitored lifelong for new malignancies,” Dr. Marks said.
“In the event that a new malignancy occurs following treatment with these products, contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing for the presence of the CAR transgene.”
In addition, cases should be reported to the FDA, either by calling or through the FDA’s medical product safety reporting program.
T-Cell Malignancy Case Report
In describing the case at their medical center in the report in Nature Medicine, Dr. Ruella and colleagues said a T-cell lymphoma occurred in a patient with non-Hodgkin B-cell lymphoma 3 months after an anti-CD19 CAR T-cell treatment.
As a result, the team conducted a subsequent analysis of 449 patients treated with CAR-T therapy at the University of Pennsylvania center, and with a median follow-up of 10.3 months, 16 patients (3.6%) had developed a secondary primary malignancy, with a median onset time of 26.4 months for solid and 9.7 months for hematological malignancies.
The patient who had developed a T-cell lymphoma tested negative for CAR integration upon diagnosis, and regarding the other cancers, Dr. Ruella noted that “we have no indication that the secondary malignancies are directly caused by the CAR-T therapy.
“We have many patients with a very long follow-up beyond 5 and even 10 years,” he said. “In these patients, we don’t see an increased risk of T-cell lymphoma.”
‘Cautious Reassurance’ Urged in Discussion with Patients
With alarming headlines on the findings suggesting that CAR-T therapy may cause cancer, Rahul Banerjee, MD, and colleagues at the University of Washington, Seattle, recommend the use of “cautious reassurance” in discussing the issue with patients. In a paper published in January in Blood Advances, they suggest a three-part response: underscoring that the benefits of CAR T “far outweigh” the risks in relapsed/refractory malignancies, that the ‘one-and-done’ nature of CAR-T infusions provide meaningful improvements in quality of life, and that the active cancer at hand is “a much larger threat than a hypothetical cancer years later.”
In many cases, patients may only have months to live without CAR-T therapy and will have already had multiple prior lines of therapy, therefore the CAR-T treatment itself may provide time for the secondary primary cancers from any of the treatments to emerge, as experts have noted.
“One has to be alive to be diagnosed with a secondary primary malignancy, and it’s thus very possible that CAR-T may be creating a type of ‘immortal time bias’ wherein patients live long enough to experience the unfortunate sequelae of their previous therapies,” Dr. Banerjee explained in an interview.
Nevertheless, the potential for substantial improvements in quality of life with CAR-T therapy compared with traditional treatments addresses a top priority for patients, he added.
“For most patients with [for instance], myeloma, the ability of CAR-T to put them rapidly into a deep remission without the need for maintenance is an unheard-of potential for them,” Dr. Banerjee said.
“In multiple myeloma, no CAR-T therapy has (yet) demonstrated an overall survival benefit — but I think the substantial quality-of-life benefit stands by itself as a big reason why patients continue to prefer CAR-T.”
Keep Patients In Touch with CAR T Centers
In light of the concerns regarding the secondary malignancies, Dr. Banerjee underscored that CAR-T patients should be kept in close touch with centers that have CAR-T treatment expertise.
With most patients followed primarily at community practices where CAR-T therapy is not administered, “I’d strongly encourage my colleagues in community practices to refer all eligible patients to a CAR-T-capable center for evaluation regardless of what their risk of post-CAR-T secondary primary malignancies may be,” Dr. Banerjee urged.
“Based on the evidence we have currently, which includes the FDA’s updated information, there are many more unknowns about this potential secondary primary malignancy risk than knowns,” he said. “This is of course a much more nuanced issue than any one package insert can convey, and CAR-T experts at treating centers can have these conversations at length with eligible patients who are nervous about these recent updates.”
Dr. Ruella disclosed that he holds patents related to CD19 CAR T cells, as well as relationships with NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scailyte, Bayer, AbClon, Oxford NanoImaging, CURIOX, and Beckman Coulter, and he was the scientific founder of viTToria Biotherapeutics. Dr. Banerjee reported ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
Testosterone Replacement Shows No Benefit in Diabetes Prevention
Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.
“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.
The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.
Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.
But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.
“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.
In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.
The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.
For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).
There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.
The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”
However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.
The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.
“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
Study ‘Overcomes Limitations of Prior Studies’
In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”
Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.
“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.
She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”
Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”
This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
A version of this article appeared on Medscape.com.
Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.
“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.
The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.
Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.
But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.
“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.
In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.
The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.
For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).
There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.
The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”
However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.
The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.
“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
Study ‘Overcomes Limitations of Prior Studies’
In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”
Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.
“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.
She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”
Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”
This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
A version of this article appeared on Medscape.com.
Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.
“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.
The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.
Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.
But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.
“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.
In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.
The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.
For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).
There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.
The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”
However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.
The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.
“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
Study ‘Overcomes Limitations of Prior Studies’
In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”
Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.
“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.
She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”
Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”
This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
A version of this article appeared on Medscape.com.
SGLT2 Inhibitors Reduce Kidney Stone Risk in Type 2 Diabetes
People with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2) inhibitors show a significantly reduced risk of developing kidney stones compared with those treated with other commonly used diabetes drugs.
“To our knowledge, this study is the first and largest to assess the association between SGLT2 inhibitors use and risk of nephrolithiasis [kidney stones] in patients with type 2 diabetes in routine US clinical practice,” said the authors of the study, published in JAMA Internal Medicine.
they wrote.
The prevalence of kidney stones has been on the rise, and the problem is especially relevant to those with type 2 diabetes, which is known to have an increased risk of kidney stones, potentially causing severe pain and leading to kidney function decline.
With SGLT2 inhibitors showing renoprotective, in addition to cardiovascular benefits, first author Julie Paik, MD, MPH, an associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics and the Division of Renal (Kidney) Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues conducted an active comparator cohort study using data from three nationwide databases on patients with type 2 diabetes in routine clinical practice.
In the study’s two arms of propensity score-matched patients, 358,203 pairs of patients with type 2 diabetes were matched 1:1 to either those who were new users of SGLT2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), with patients in those groups having a mean age of 61 and being about 51% female.
In addition, 331,028 pairs matched new SGLT2 inhibitor users 1:1 with didpeptidyl peptidase-4 (DPP4) inhibitor users, who also had a mean age of about 61.5 years and were about 47% female.
Over a median follow-up of 192 days, those treated with SGLT2 inhibitors had about a 31% significantly lower risk of kidney stones than GLP-1RA users (14.9 vs 21.3 events per 1000 person-years; hazard ratio [HR], 0.69).
And the SGLT2 group also had a 26% lower kidney stone risk vs DPP4 inhibitor users (14.6 vs 19.9 events per 1000 person-years; HR, 0.74).
There were no differences in the results with either groups of pairs based on sex, race, ethnicity, a history of chronic kidney disease, or obesity.
Of note, the magnitude of the risk reduction observed with SGLT2 inhibitors was greater in adults aged < 70 years than in those aged ≥ 70 years (HR, 0.85; P for interaction < .001).
The age-related difference could possibly be due to changes in stone composition that occurs with aging, which may influence SGLT2 inhibitor response, Dr Paik told this news organization.
“However, we did not have information on stone composition in our study.”
In the study, patients were taking, on average, more than two antidiabetic medications upon entrance to the study, with 13% taking thiazides and 12% taking loop diuretics. In addition, approximately half of patients discontinued SGLT2 inhibitors (52.6%) and DPP4 inhibitors (53.2%).
However, the results remained consistent after adjusting for those factors, Dr. Paik noted.
Mechanisms: Urinary Citrate Excretion?
Among key possible explanations for the lower risk of kidney stones with SGLT2 inhibitors is that the drugs have increased urinary citrate excretion, with one study showing a nearly 50% increase in urinary citrate excretion among patients treated with empagliflozin vs placebo over 4 weeks and other studies also showing similar increases.
“This increased urinary citrate excretion may play a pivotal role in decreasing stone risk by inhibiting supersaturation and crystallization of calcium crystals,” the authors explained.
In addition, the urinary citrate excretion could further play a role by “forming complexes with calcium and thus lowering urinary calcium concentration, and raising urinary pH, thereby reducing the risk of uric acid stones,” they added.
SGLT inhibitors’ anti-inflammatory effects could also reduce stone formation by “suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation,” the authors noted.
Ultimately, however, “while we found a lower risk of kidney stones in our study, we don’t fully understand how they lower the risk,” Dr. Paik said. The potential explanations “remain to be studied further.”
Either way, “the risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes,” Dr. Paik said.
The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, the National Institute of Aging the Patient-Centered Outcomes Research Institute, the US Food and Drug Administration, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
A version of this article appeared on Medscape.com .
People with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2) inhibitors show a significantly reduced risk of developing kidney stones compared with those treated with other commonly used diabetes drugs.
“To our knowledge, this study is the first and largest to assess the association between SGLT2 inhibitors use and risk of nephrolithiasis [kidney stones] in patients with type 2 diabetes in routine US clinical practice,” said the authors of the study, published in JAMA Internal Medicine.
they wrote.
The prevalence of kidney stones has been on the rise, and the problem is especially relevant to those with type 2 diabetes, which is known to have an increased risk of kidney stones, potentially causing severe pain and leading to kidney function decline.
With SGLT2 inhibitors showing renoprotective, in addition to cardiovascular benefits, first author Julie Paik, MD, MPH, an associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics and the Division of Renal (Kidney) Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues conducted an active comparator cohort study using data from three nationwide databases on patients with type 2 diabetes in routine clinical practice.
In the study’s two arms of propensity score-matched patients, 358,203 pairs of patients with type 2 diabetes were matched 1:1 to either those who were new users of SGLT2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), with patients in those groups having a mean age of 61 and being about 51% female.
In addition, 331,028 pairs matched new SGLT2 inhibitor users 1:1 with didpeptidyl peptidase-4 (DPP4) inhibitor users, who also had a mean age of about 61.5 years and were about 47% female.
Over a median follow-up of 192 days, those treated with SGLT2 inhibitors had about a 31% significantly lower risk of kidney stones than GLP-1RA users (14.9 vs 21.3 events per 1000 person-years; hazard ratio [HR], 0.69).
And the SGLT2 group also had a 26% lower kidney stone risk vs DPP4 inhibitor users (14.6 vs 19.9 events per 1000 person-years; HR, 0.74).
There were no differences in the results with either groups of pairs based on sex, race, ethnicity, a history of chronic kidney disease, or obesity.
Of note, the magnitude of the risk reduction observed with SGLT2 inhibitors was greater in adults aged < 70 years than in those aged ≥ 70 years (HR, 0.85; P for interaction < .001).
The age-related difference could possibly be due to changes in stone composition that occurs with aging, which may influence SGLT2 inhibitor response, Dr Paik told this news organization.
“However, we did not have information on stone composition in our study.”
In the study, patients were taking, on average, more than two antidiabetic medications upon entrance to the study, with 13% taking thiazides and 12% taking loop diuretics. In addition, approximately half of patients discontinued SGLT2 inhibitors (52.6%) and DPP4 inhibitors (53.2%).
However, the results remained consistent after adjusting for those factors, Dr. Paik noted.
Mechanisms: Urinary Citrate Excretion?
Among key possible explanations for the lower risk of kidney stones with SGLT2 inhibitors is that the drugs have increased urinary citrate excretion, with one study showing a nearly 50% increase in urinary citrate excretion among patients treated with empagliflozin vs placebo over 4 weeks and other studies also showing similar increases.
“This increased urinary citrate excretion may play a pivotal role in decreasing stone risk by inhibiting supersaturation and crystallization of calcium crystals,” the authors explained.
In addition, the urinary citrate excretion could further play a role by “forming complexes with calcium and thus lowering urinary calcium concentration, and raising urinary pH, thereby reducing the risk of uric acid stones,” they added.
SGLT inhibitors’ anti-inflammatory effects could also reduce stone formation by “suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation,” the authors noted.
Ultimately, however, “while we found a lower risk of kidney stones in our study, we don’t fully understand how they lower the risk,” Dr. Paik said. The potential explanations “remain to be studied further.”
Either way, “the risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes,” Dr. Paik said.
The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, the National Institute of Aging the Patient-Centered Outcomes Research Institute, the US Food and Drug Administration, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
A version of this article appeared on Medscape.com .
People with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2) inhibitors show a significantly reduced risk of developing kidney stones compared with those treated with other commonly used diabetes drugs.
“To our knowledge, this study is the first and largest to assess the association between SGLT2 inhibitors use and risk of nephrolithiasis [kidney stones] in patients with type 2 diabetes in routine US clinical practice,” said the authors of the study, published in JAMA Internal Medicine.
they wrote.
The prevalence of kidney stones has been on the rise, and the problem is especially relevant to those with type 2 diabetes, which is known to have an increased risk of kidney stones, potentially causing severe pain and leading to kidney function decline.
With SGLT2 inhibitors showing renoprotective, in addition to cardiovascular benefits, first author Julie Paik, MD, MPH, an associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics and the Division of Renal (Kidney) Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues conducted an active comparator cohort study using data from three nationwide databases on patients with type 2 diabetes in routine clinical practice.
In the study’s two arms of propensity score-matched patients, 358,203 pairs of patients with type 2 diabetes were matched 1:1 to either those who were new users of SGLT2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), with patients in those groups having a mean age of 61 and being about 51% female.
In addition, 331,028 pairs matched new SGLT2 inhibitor users 1:1 with didpeptidyl peptidase-4 (DPP4) inhibitor users, who also had a mean age of about 61.5 years and were about 47% female.
Over a median follow-up of 192 days, those treated with SGLT2 inhibitors had about a 31% significantly lower risk of kidney stones than GLP-1RA users (14.9 vs 21.3 events per 1000 person-years; hazard ratio [HR], 0.69).
And the SGLT2 group also had a 26% lower kidney stone risk vs DPP4 inhibitor users (14.6 vs 19.9 events per 1000 person-years; HR, 0.74).
There were no differences in the results with either groups of pairs based on sex, race, ethnicity, a history of chronic kidney disease, or obesity.
Of note, the magnitude of the risk reduction observed with SGLT2 inhibitors was greater in adults aged < 70 years than in those aged ≥ 70 years (HR, 0.85; P for interaction < .001).
The age-related difference could possibly be due to changes in stone composition that occurs with aging, which may influence SGLT2 inhibitor response, Dr Paik told this news organization.
“However, we did not have information on stone composition in our study.”
In the study, patients were taking, on average, more than two antidiabetic medications upon entrance to the study, with 13% taking thiazides and 12% taking loop diuretics. In addition, approximately half of patients discontinued SGLT2 inhibitors (52.6%) and DPP4 inhibitors (53.2%).
However, the results remained consistent after adjusting for those factors, Dr. Paik noted.
Mechanisms: Urinary Citrate Excretion?
Among key possible explanations for the lower risk of kidney stones with SGLT2 inhibitors is that the drugs have increased urinary citrate excretion, with one study showing a nearly 50% increase in urinary citrate excretion among patients treated with empagliflozin vs placebo over 4 weeks and other studies also showing similar increases.
“This increased urinary citrate excretion may play a pivotal role in decreasing stone risk by inhibiting supersaturation and crystallization of calcium crystals,” the authors explained.
In addition, the urinary citrate excretion could further play a role by “forming complexes with calcium and thus lowering urinary calcium concentration, and raising urinary pH, thereby reducing the risk of uric acid stones,” they added.
SGLT inhibitors’ anti-inflammatory effects could also reduce stone formation by “suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation,” the authors noted.
Ultimately, however, “while we found a lower risk of kidney stones in our study, we don’t fully understand how they lower the risk,” Dr. Paik said. The potential explanations “remain to be studied further.”
Either way, “the risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes,” Dr. Paik said.
The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, the National Institute of Aging the Patient-Centered Outcomes Research Institute, the US Food and Drug Administration, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
A version of this article appeared on Medscape.com .
FROM JAMA INTERNAL MEDICINE
Stockholm3 Prostate Test Bests PSA for Prostate Cancer Risk in North America
The Stockholm3 (A3P Biomedical) multiparametic blood test has shown accuracy in assessing the risk of prostate cancer, exceeding that of the standard prostate-specific antigen (PSA)-based test, in Swedish patients.
“The Stockholm3 outperformed the PSA test overall and in every subcohort, with an impressive reduction of unnecessary biopsies of 40% to 50%, while maintaining relative sensitivity,” first author Scott E. Eggener, MD, said in presenting the findings at the ASCO Genitourinary Cancers Symposium. The test “has attractive characteristics in a diverse cohort, including within various racial and ethnic subgroups,” added Dr. Eggener, professor of surgery and radiology at the University of Chicago.
While the PSA test, the standard-of-care in prostate cancer risk assessment, reduces mortality, the test is known to have a risk for false positive results, leading to unnecessary prostate biopsies, as well as overdiagnosis of low-risk prostate cancers, Dr. Eggener explained in his talk.
Randomized trials do show “fewer men die from prostate cancer with screening [with PSA testing], however, the likelihood of unnecessarily finding out about a cancer, undergoing treatment, and exposure to potential treatment-related side effects is significantly higher,” Dr. Eggener said in a interview.
The Stockholm3 clinical diagnostic prostate cancer test, which has been used in Sweden and Norway since 2017, was validated in a sample of nearly 60,000 men in the STHLM3 study (doi: 10.1016/S1470-2045[15]00361-7), which was published in The Lancet Oncology in December 2015. That study showed significant improvement over PSA alone detection of prostate cancers with a Gleason score of at least 7 (P < .0001), Dr. Eggener explained.
The test combines five plasma protein markers, including total and free PSA, PSP94, GDF-15 and KLK2, along with 101 genetic markers and clinical patient data, including age, previous biopsy results and family history.
Because the Stockholm3 test was validated in a Swedish population cohort, evidence on the accuracy of the test in other racial and ethnic populations is lacking, the authors noted in the abstract.
Study Methods and Results
To further investigate, Dr. Eggener and his colleagues conducted the prospective SEPTA trial, involving 2,129 men with no known prostate cancer but clinical indications for prostate biopsy, who were referred for prostate biopsy at 17 North American sites between 2019 and 2023.
Among the men, 24% were self-identified as African American/Black; 46% were White/Caucasian; 14% were Hispanic/Latina; and 16% were Asian. The men’s median age was 63; their median PSA value was 6.1 ng/mL, according to the abstract.
Of the patients, 16% received magnetic resonance imaging (MRI)-targeted biopsies and 20% had prior benign biopsies, the abstract notes.
Biopsy results showed that clinically significant prostate cancer, defined as International Society of Urological Pathology (ISUP) Gleason Grade group ≥ 2, was detected in 29% of patients, with 14% having ISUP 1 cancer and 57% of cases having been benign, according to the abstract.
Overall detection rates of grade 2 or higher were 37% for African American/Black, 28% for White/Caucasian, 29% for Hispanic/Latino, and 21% Asian.
In terms of sensitivity of the two tests, the Stockholm3 (cut-point of ≥ 15) was noninferior compared with the traditional PSA cut-point of ≥ 4 ng/mL (relative sensitivity 0.95).
Results were consistent across ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70), the abstract authors reported.
Compared with the use of the PSA test’s cut-point of ≥ 4 ng/mL, the use of Stockholm3’s cut-point of ≥ 15 or higher would have reduced unnecessary biopsies by 45% overall, including by 46% among Asian and Black/African American patients, by 53% in Hispanic patients and 42% in White patients, according to the abstract.
Overall, “utilization of Stockholm3 improves the net benefit:harm ratio of PSA screening by identifying nearly all men with Gleason Grade 2 or higher, while minimizing the number of men undergoing biopsy who show no cancer or an indolent cancer (Gleason Grade 1),” Dr. Eggener said in an interview.
Stockholm3 Expected to be Available in U.S. This Year
The test, which has been available in Sweden since 2018, is expected to become commercially available in the United States in early 2024. Dr. Eggener noted that “cost of the test hasn’t been finalized, but will be considerably more expensive than PSA, which is very cheap.”
Commenting on the findings, Bradley McGregor, MD, of the Dana Farber Cancer Institute and an ASCO oncology expert, noted that “ultimately, the goal [of prostate screening] is to be able to better decide when a biopsy is going to yield a clinically relevant prostate cancer, [and] this study gives us some insight of the use of the Stockholm3 tool in a more diverse population.
“How the tool will be utilized in the clinic and in guidelines is something that is a work in progress,” he added. “But I think this provides some reassurances that this will have implications beyond just the homogeneous populations in the original studies.”
Dr. McGregor noted that considerations of the issue of cost should be weighed against the potential costs involved in unnecessary biopsies and a host of other costs that can arise with an inaccurate risk assessment.
“If there is a way to avoid those costs and help us have more confidence in the prostate test results and intervene at an earlier stage, I think that’s exciting,” he said.
Dr. Eggener has consulted for A3P Biomedical but had no financial relationship with the company to disclose.
The Stockholm3 (A3P Biomedical) multiparametic blood test has shown accuracy in assessing the risk of prostate cancer, exceeding that of the standard prostate-specific antigen (PSA)-based test, in Swedish patients.
“The Stockholm3 outperformed the PSA test overall and in every subcohort, with an impressive reduction of unnecessary biopsies of 40% to 50%, while maintaining relative sensitivity,” first author Scott E. Eggener, MD, said in presenting the findings at the ASCO Genitourinary Cancers Symposium. The test “has attractive characteristics in a diverse cohort, including within various racial and ethnic subgroups,” added Dr. Eggener, professor of surgery and radiology at the University of Chicago.
While the PSA test, the standard-of-care in prostate cancer risk assessment, reduces mortality, the test is known to have a risk for false positive results, leading to unnecessary prostate biopsies, as well as overdiagnosis of low-risk prostate cancers, Dr. Eggener explained in his talk.
Randomized trials do show “fewer men die from prostate cancer with screening [with PSA testing], however, the likelihood of unnecessarily finding out about a cancer, undergoing treatment, and exposure to potential treatment-related side effects is significantly higher,” Dr. Eggener said in a interview.
The Stockholm3 clinical diagnostic prostate cancer test, which has been used in Sweden and Norway since 2017, was validated in a sample of nearly 60,000 men in the STHLM3 study (doi: 10.1016/S1470-2045[15]00361-7), which was published in The Lancet Oncology in December 2015. That study showed significant improvement over PSA alone detection of prostate cancers with a Gleason score of at least 7 (P < .0001), Dr. Eggener explained.
The test combines five plasma protein markers, including total and free PSA, PSP94, GDF-15 and KLK2, along with 101 genetic markers and clinical patient data, including age, previous biopsy results and family history.
Because the Stockholm3 test was validated in a Swedish population cohort, evidence on the accuracy of the test in other racial and ethnic populations is lacking, the authors noted in the abstract.
Study Methods and Results
To further investigate, Dr. Eggener and his colleagues conducted the prospective SEPTA trial, involving 2,129 men with no known prostate cancer but clinical indications for prostate biopsy, who were referred for prostate biopsy at 17 North American sites between 2019 and 2023.
Among the men, 24% were self-identified as African American/Black; 46% were White/Caucasian; 14% were Hispanic/Latina; and 16% were Asian. The men’s median age was 63; their median PSA value was 6.1 ng/mL, according to the abstract.
Of the patients, 16% received magnetic resonance imaging (MRI)-targeted biopsies and 20% had prior benign biopsies, the abstract notes.
Biopsy results showed that clinically significant prostate cancer, defined as International Society of Urological Pathology (ISUP) Gleason Grade group ≥ 2, was detected in 29% of patients, with 14% having ISUP 1 cancer and 57% of cases having been benign, according to the abstract.
Overall detection rates of grade 2 or higher were 37% for African American/Black, 28% for White/Caucasian, 29% for Hispanic/Latino, and 21% Asian.
In terms of sensitivity of the two tests, the Stockholm3 (cut-point of ≥ 15) was noninferior compared with the traditional PSA cut-point of ≥ 4 ng/mL (relative sensitivity 0.95).
Results were consistent across ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70), the abstract authors reported.
Compared with the use of the PSA test’s cut-point of ≥ 4 ng/mL, the use of Stockholm3’s cut-point of ≥ 15 or higher would have reduced unnecessary biopsies by 45% overall, including by 46% among Asian and Black/African American patients, by 53% in Hispanic patients and 42% in White patients, according to the abstract.
Overall, “utilization of Stockholm3 improves the net benefit:harm ratio of PSA screening by identifying nearly all men with Gleason Grade 2 or higher, while minimizing the number of men undergoing biopsy who show no cancer or an indolent cancer (Gleason Grade 1),” Dr. Eggener said in an interview.
Stockholm3 Expected to be Available in U.S. This Year
The test, which has been available in Sweden since 2018, is expected to become commercially available in the United States in early 2024. Dr. Eggener noted that “cost of the test hasn’t been finalized, but will be considerably more expensive than PSA, which is very cheap.”
Commenting on the findings, Bradley McGregor, MD, of the Dana Farber Cancer Institute and an ASCO oncology expert, noted that “ultimately, the goal [of prostate screening] is to be able to better decide when a biopsy is going to yield a clinically relevant prostate cancer, [and] this study gives us some insight of the use of the Stockholm3 tool in a more diverse population.
“How the tool will be utilized in the clinic and in guidelines is something that is a work in progress,” he added. “But I think this provides some reassurances that this will have implications beyond just the homogeneous populations in the original studies.”
Dr. McGregor noted that considerations of the issue of cost should be weighed against the potential costs involved in unnecessary biopsies and a host of other costs that can arise with an inaccurate risk assessment.
“If there is a way to avoid those costs and help us have more confidence in the prostate test results and intervene at an earlier stage, I think that’s exciting,” he said.
Dr. Eggener has consulted for A3P Biomedical but had no financial relationship with the company to disclose.
The Stockholm3 (A3P Biomedical) multiparametic blood test has shown accuracy in assessing the risk of prostate cancer, exceeding that of the standard prostate-specific antigen (PSA)-based test, in Swedish patients.
“The Stockholm3 outperformed the PSA test overall and in every subcohort, with an impressive reduction of unnecessary biopsies of 40% to 50%, while maintaining relative sensitivity,” first author Scott E. Eggener, MD, said in presenting the findings at the ASCO Genitourinary Cancers Symposium. The test “has attractive characteristics in a diverse cohort, including within various racial and ethnic subgroups,” added Dr. Eggener, professor of surgery and radiology at the University of Chicago.
While the PSA test, the standard-of-care in prostate cancer risk assessment, reduces mortality, the test is known to have a risk for false positive results, leading to unnecessary prostate biopsies, as well as overdiagnosis of low-risk prostate cancers, Dr. Eggener explained in his talk.
Randomized trials do show “fewer men die from prostate cancer with screening [with PSA testing], however, the likelihood of unnecessarily finding out about a cancer, undergoing treatment, and exposure to potential treatment-related side effects is significantly higher,” Dr. Eggener said in a interview.
The Stockholm3 clinical diagnostic prostate cancer test, which has been used in Sweden and Norway since 2017, was validated in a sample of nearly 60,000 men in the STHLM3 study (doi: 10.1016/S1470-2045[15]00361-7), which was published in The Lancet Oncology in December 2015. That study showed significant improvement over PSA alone detection of prostate cancers with a Gleason score of at least 7 (P < .0001), Dr. Eggener explained.
The test combines five plasma protein markers, including total and free PSA, PSP94, GDF-15 and KLK2, along with 101 genetic markers and clinical patient data, including age, previous biopsy results and family history.
Because the Stockholm3 test was validated in a Swedish population cohort, evidence on the accuracy of the test in other racial and ethnic populations is lacking, the authors noted in the abstract.
Study Methods and Results
To further investigate, Dr. Eggener and his colleagues conducted the prospective SEPTA trial, involving 2,129 men with no known prostate cancer but clinical indications for prostate biopsy, who were referred for prostate biopsy at 17 North American sites between 2019 and 2023.
Among the men, 24% were self-identified as African American/Black; 46% were White/Caucasian; 14% were Hispanic/Latina; and 16% were Asian. The men’s median age was 63; their median PSA value was 6.1 ng/mL, according to the abstract.
Of the patients, 16% received magnetic resonance imaging (MRI)-targeted biopsies and 20% had prior benign biopsies, the abstract notes.
Biopsy results showed that clinically significant prostate cancer, defined as International Society of Urological Pathology (ISUP) Gleason Grade group ≥ 2, was detected in 29% of patients, with 14% having ISUP 1 cancer and 57% of cases having been benign, according to the abstract.
Overall detection rates of grade 2 or higher were 37% for African American/Black, 28% for White/Caucasian, 29% for Hispanic/Latino, and 21% Asian.
In terms of sensitivity of the two tests, the Stockholm3 (cut-point of ≥ 15) was noninferior compared with the traditional PSA cut-point of ≥ 4 ng/mL (relative sensitivity 0.95).
Results were consistent across ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70), the abstract authors reported.
Compared with the use of the PSA test’s cut-point of ≥ 4 ng/mL, the use of Stockholm3’s cut-point of ≥ 15 or higher would have reduced unnecessary biopsies by 45% overall, including by 46% among Asian and Black/African American patients, by 53% in Hispanic patients and 42% in White patients, according to the abstract.
Overall, “utilization of Stockholm3 improves the net benefit:harm ratio of PSA screening by identifying nearly all men with Gleason Grade 2 or higher, while minimizing the number of men undergoing biopsy who show no cancer or an indolent cancer (Gleason Grade 1),” Dr. Eggener said in an interview.
Stockholm3 Expected to be Available in U.S. This Year
The test, which has been available in Sweden since 2018, is expected to become commercially available in the United States in early 2024. Dr. Eggener noted that “cost of the test hasn’t been finalized, but will be considerably more expensive than PSA, which is very cheap.”
Commenting on the findings, Bradley McGregor, MD, of the Dana Farber Cancer Institute and an ASCO oncology expert, noted that “ultimately, the goal [of prostate screening] is to be able to better decide when a biopsy is going to yield a clinically relevant prostate cancer, [and] this study gives us some insight of the use of the Stockholm3 tool in a more diverse population.
“How the tool will be utilized in the clinic and in guidelines is something that is a work in progress,” he added. “But I think this provides some reassurances that this will have implications beyond just the homogeneous populations in the original studies.”
Dr. McGregor noted that considerations of the issue of cost should be weighed against the potential costs involved in unnecessary biopsies and a host of other costs that can arise with an inaccurate risk assessment.
“If there is a way to avoid those costs and help us have more confidence in the prostate test results and intervene at an earlier stage, I think that’s exciting,” he said.
Dr. Eggener has consulted for A3P Biomedical but had no financial relationship with the company to disclose.
FROM ASCO GU 2024
ctDNA Clearance Improves Prediction of Relapse Risk in Urothelial Cancer
In ongoing efforts to better understand the predictive value of circulating tumor DNA (ctDNA) in cancer treatment response, new research shows ctDNA clearance following neoadjuvant treatment of muscle-invasive urothelial cancer is a better predictor of the risk of relapse than a 50% reduction in ctDNA variant allele frequency (VAF).
The combination of ctDNA with other baseline biomarkers shows further accuracy in predicting treatment response, the study also shows.
Matthew Nicholas Young, MD, of Barts Cancer Institute, London, presented the research at the ASCO Genitourinary Cancers Symposium.
“We found that ctDNA and tissue-based biomarkers improved biomarker accuracy,” Dr. Young, first author of the study, said at the meeting.
Furthermore, “ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse,” the authors said in their abstract.
“This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint,” they wrote.
Dr. Young and his colleagues have previously shown ctDNA clearance to be an important predictive marker of treatment response or relapse.
To better understand the predictive value in combination with other biomarkers, as well as whether a reduction in ctDNA variant allele frequency could be used as a surrogate predictor of relapse compared with ctDNA clearance, the authors conducted an exploratory biomarker analysis of the phase 2, multicenter ABACUS trial.
Methods and Results
In the study, 95 patients with inoperable, muscle-invasive urothelial cancer who were either not eligible for or refused neoadjuvant cisplatin-based chemotherapy, each received two cycles of atezolizumab, followed by radical cystectomy.
Previously published results show the study met its primary endpoint of a pathological complete response (pCR) of 31%, and the 2-year disease-free survival and overall survival rates were 68% and 77%, respectively.
Of the 95 patients, 40 had sequential DNA analysis that could be evaluated in the current analysis; 43% of those patients achieved a pCR, while 20% experienced a relapse.
At baseline, 63% of patients were ctDNA-positive, and after treatment, 8% achieved ctDNA clearance, while 40% had a ctDNA response of a 50% VAF reduction.
All patients who had ctDNA clearance achieved pCR and none relapsed. In comparison, 30% of patients with a 50% VAF reduction experienced relapse and only 40% achieved pCR.
In terms of correlations with baseline biomarkers, the combination of ctDNA with activated T cells was significantly associated with outcomes (P = .02), as was the combination with PDL-1 status (P = .004).
However, combination with tumor mutation burden, already weak as a predictive biomarker, remained weak when combined with ctDNA status (P = .2), Dr. Young reported.
In terms of baseline expression of ctDNA, patients who were positive at baseline showed an increase in innate and adaptive immune signaling, in a profile aligning with increased PD-L1 at baseline in ctDNA-positive patients.
In addition, decreased immune signaling was observed in ctDNA-positive patients who relapsed.
Results May Be ‘Hypothesis-Generating’
Asked during the session whether the results imply that patients with no detectable ctDNA prior to the start of therapy may not need or benefit from neoadjuvant therapy, Dr. Young said the small sample size of ctDNA patients in the study was an important limitation.
“I think [the results] are hypothesis-generating, as we know that some patients will not benefit from neoadjuvant therapy and the goal of this work is to try to identify patterns among those who may not need treatment,” he said.
Of the patients with ctDNA analysis, “only those who were ctDNA-positive at baseline relapsed, [as well as] those who were ctDNA-positive following cystectomy, so I think [the possibility that a lack of detectable ctDNA prior to the start of therapy could suggest that the patient may not need or benefit from neoadjuvant therapy] is an interesting hypothesis that has come from this work,” Dr. Young said.
Overall, the findings show that, “in ctDNA-positive patients, increased immune signals appear to be associated with better outcomes with atezolizumab,” he concluded.
“Combining immune and circulating biomarkers may be required to accurately predict response to therapy,” Dr. Young added.
The ABACUS trial was supported by Roche.
In ongoing efforts to better understand the predictive value of circulating tumor DNA (ctDNA) in cancer treatment response, new research shows ctDNA clearance following neoadjuvant treatment of muscle-invasive urothelial cancer is a better predictor of the risk of relapse than a 50% reduction in ctDNA variant allele frequency (VAF).
The combination of ctDNA with other baseline biomarkers shows further accuracy in predicting treatment response, the study also shows.
Matthew Nicholas Young, MD, of Barts Cancer Institute, London, presented the research at the ASCO Genitourinary Cancers Symposium.
“We found that ctDNA and tissue-based biomarkers improved biomarker accuracy,” Dr. Young, first author of the study, said at the meeting.
Furthermore, “ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse,” the authors said in their abstract.
“This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint,” they wrote.
Dr. Young and his colleagues have previously shown ctDNA clearance to be an important predictive marker of treatment response or relapse.
To better understand the predictive value in combination with other biomarkers, as well as whether a reduction in ctDNA variant allele frequency could be used as a surrogate predictor of relapse compared with ctDNA clearance, the authors conducted an exploratory biomarker analysis of the phase 2, multicenter ABACUS trial.
Methods and Results
In the study, 95 patients with inoperable, muscle-invasive urothelial cancer who were either not eligible for or refused neoadjuvant cisplatin-based chemotherapy, each received two cycles of atezolizumab, followed by radical cystectomy.
Previously published results show the study met its primary endpoint of a pathological complete response (pCR) of 31%, and the 2-year disease-free survival and overall survival rates were 68% and 77%, respectively.
Of the 95 patients, 40 had sequential DNA analysis that could be evaluated in the current analysis; 43% of those patients achieved a pCR, while 20% experienced a relapse.
At baseline, 63% of patients were ctDNA-positive, and after treatment, 8% achieved ctDNA clearance, while 40% had a ctDNA response of a 50% VAF reduction.
All patients who had ctDNA clearance achieved pCR and none relapsed. In comparison, 30% of patients with a 50% VAF reduction experienced relapse and only 40% achieved pCR.
In terms of correlations with baseline biomarkers, the combination of ctDNA with activated T cells was significantly associated with outcomes (P = .02), as was the combination with PDL-1 status (P = .004).
However, combination with tumor mutation burden, already weak as a predictive biomarker, remained weak when combined with ctDNA status (P = .2), Dr. Young reported.
In terms of baseline expression of ctDNA, patients who were positive at baseline showed an increase in innate and adaptive immune signaling, in a profile aligning with increased PD-L1 at baseline in ctDNA-positive patients.
In addition, decreased immune signaling was observed in ctDNA-positive patients who relapsed.
Results May Be ‘Hypothesis-Generating’
Asked during the session whether the results imply that patients with no detectable ctDNA prior to the start of therapy may not need or benefit from neoadjuvant therapy, Dr. Young said the small sample size of ctDNA patients in the study was an important limitation.
“I think [the results] are hypothesis-generating, as we know that some patients will not benefit from neoadjuvant therapy and the goal of this work is to try to identify patterns among those who may not need treatment,” he said.
Of the patients with ctDNA analysis, “only those who were ctDNA-positive at baseline relapsed, [as well as] those who were ctDNA-positive following cystectomy, so I think [the possibility that a lack of detectable ctDNA prior to the start of therapy could suggest that the patient may not need or benefit from neoadjuvant therapy] is an interesting hypothesis that has come from this work,” Dr. Young said.
Overall, the findings show that, “in ctDNA-positive patients, increased immune signals appear to be associated with better outcomes with atezolizumab,” he concluded.
“Combining immune and circulating biomarkers may be required to accurately predict response to therapy,” Dr. Young added.
The ABACUS trial was supported by Roche.
In ongoing efforts to better understand the predictive value of circulating tumor DNA (ctDNA) in cancer treatment response, new research shows ctDNA clearance following neoadjuvant treatment of muscle-invasive urothelial cancer is a better predictor of the risk of relapse than a 50% reduction in ctDNA variant allele frequency (VAF).
The combination of ctDNA with other baseline biomarkers shows further accuracy in predicting treatment response, the study also shows.
Matthew Nicholas Young, MD, of Barts Cancer Institute, London, presented the research at the ASCO Genitourinary Cancers Symposium.
“We found that ctDNA and tissue-based biomarkers improved biomarker accuracy,” Dr. Young, first author of the study, said at the meeting.
Furthermore, “ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse,” the authors said in their abstract.
“This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint,” they wrote.
Dr. Young and his colleagues have previously shown ctDNA clearance to be an important predictive marker of treatment response or relapse.
To better understand the predictive value in combination with other biomarkers, as well as whether a reduction in ctDNA variant allele frequency could be used as a surrogate predictor of relapse compared with ctDNA clearance, the authors conducted an exploratory biomarker analysis of the phase 2, multicenter ABACUS trial.
Methods and Results
In the study, 95 patients with inoperable, muscle-invasive urothelial cancer who were either not eligible for or refused neoadjuvant cisplatin-based chemotherapy, each received two cycles of atezolizumab, followed by radical cystectomy.
Previously published results show the study met its primary endpoint of a pathological complete response (pCR) of 31%, and the 2-year disease-free survival and overall survival rates were 68% and 77%, respectively.
Of the 95 patients, 40 had sequential DNA analysis that could be evaluated in the current analysis; 43% of those patients achieved a pCR, while 20% experienced a relapse.
At baseline, 63% of patients were ctDNA-positive, and after treatment, 8% achieved ctDNA clearance, while 40% had a ctDNA response of a 50% VAF reduction.
All patients who had ctDNA clearance achieved pCR and none relapsed. In comparison, 30% of patients with a 50% VAF reduction experienced relapse and only 40% achieved pCR.
In terms of correlations with baseline biomarkers, the combination of ctDNA with activated T cells was significantly associated with outcomes (P = .02), as was the combination with PDL-1 status (P = .004).
However, combination with tumor mutation burden, already weak as a predictive biomarker, remained weak when combined with ctDNA status (P = .2), Dr. Young reported.
In terms of baseline expression of ctDNA, patients who were positive at baseline showed an increase in innate and adaptive immune signaling, in a profile aligning with increased PD-L1 at baseline in ctDNA-positive patients.
In addition, decreased immune signaling was observed in ctDNA-positive patients who relapsed.
Results May Be ‘Hypothesis-Generating’
Asked during the session whether the results imply that patients with no detectable ctDNA prior to the start of therapy may not need or benefit from neoadjuvant therapy, Dr. Young said the small sample size of ctDNA patients in the study was an important limitation.
“I think [the results] are hypothesis-generating, as we know that some patients will not benefit from neoadjuvant therapy and the goal of this work is to try to identify patterns among those who may not need treatment,” he said.
Of the patients with ctDNA analysis, “only those who were ctDNA-positive at baseline relapsed, [as well as] those who were ctDNA-positive following cystectomy, so I think [the possibility that a lack of detectable ctDNA prior to the start of therapy could suggest that the patient may not need or benefit from neoadjuvant therapy] is an interesting hypothesis that has come from this work,” Dr. Young said.
Overall, the findings show that, “in ctDNA-positive patients, increased immune signals appear to be associated with better outcomes with atezolizumab,” he concluded.
“Combining immune and circulating biomarkers may be required to accurately predict response to therapy,” Dr. Young added.
The ABACUS trial was supported by Roche.
FROM ASCO GU 2024
T-ALL: Cranial Radiotherapy Yields Little Benefit
“Overall, comparison of these cohorts provides a strong indication that CRT provides minimal benefit to patients with CNS-3 disease at diagnosis,” first author Ajay Vora, MD, a consultant hematologist with Great Ormond Street Hospital, in London, and his colleagues report in a research letter published recently in Blood Advances.
“Given the high rates of neurocognitive impairment and secondary CNS malignancies, we believe strong consideration should be given to eliminating CRT in first-line treatment for all patients with T-ALL,” they wrote.
More aggressive than B-cell ALL, T-ALL is characterized by a higher likelihood of infiltration of the CNS at diagnosis, which increases the risk of relapse after treatment.
Until recently, treatment of T-ALL long entailed CNS-directed therapy using prophylactic CRT. Now, however, due to the risks of significant toxicity, including neurocognitive defects and secondary cancers, CRT is usually either omitted or limited to key subgroups, such as those with CNS-3 disease. As an alternative, intrathecal chemotherapy is used, the authors explain.
In a 2023 study evaluating the consecutive Children’s Oncology Group (COG) AALL0434 and AALL1231 phase 3 trials of 2,164 patients with T-ALL, patients with CNS-3 at diagnosis were found to have worse outcomes, compared with CNS-1 and 2.
Importantly, the outcomes in both of those two trials were similar, despite the use of CRT in more than 90% of patients in the AALL0434 trial--but in only 10% of patients AALL1231 trial (mainly those with CNS-3 and at high-risk). These outcomes suggested that CRT can safely be eliminated for CNS-1 and 2 patients.
With CRT used in both trials among patients with CNS-3, conclusions about eliminating CRT among those patients could not be drawn. However, with other large groups (including the Dutch Childhood Oncology Group), eliminating CRT in the frontline treatment of all patients with T-ALL, including those with CNS-3, is what Dr. Vora and colleagues sought to further investigate.
For the current study, they evaluated outcomes in the UKALL2003 and UKALL2011 trials conducted by the UK National Cancer Research Institute, in which CRT was eliminated for all patients — including those with CNS-3 — and compared them with the COG AALL0434 and AALL1231 trials.
In the UK trials, involving 665 patients with T-ALL aged 1 to 24, treatment included a dexamethasone-based backbone chemotherapy consisting of a 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation, interim maintenance, delayed intensification, and maintenance therapy, with the treatment stratified based on morphological early response and minimal residual disease at the end of induction.
While the UKALL2003 trial initially recommended CRT for patients with CNS-3, that practice ended in 2009, and CNS-directed therapy subsequently consisted of intrathecal methotrexate (MTX) at regular intervals throughout treatment. Additional weekly intrathecal MTX treatments were recommended throughout induction for patients with CNS-3.
In the UKALL2011 trial, the weekly intrathecal MTX treatments were recommended for patients with CNS-2, as well as CNS-3.
Overall, among those with CNS data available, 557 patients had CNS-1 (87.4%), 44 CNS-2 (6.9%), and 36 CNS-3 (5.7%).
For the outcomes of 4-year cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) in the combined cohort of the 2 UK trials, there were no significant differences between CNS-1, 2 or 3 groups.
Specifically, the mean rates of 4-year CIR in the CNS-1, 2, and 3 groups were 13.6%, 25.9% and 24.6%, respectively (P = .241); mean EFS rates were 82.9%, 74.1% and 77.8% (P = .623), and OS rates were 88.6%, 80.9% and 91.8%, (P = .453).
“Most importantly, outcomes are not significantly different for the patients with CNS-3, despite omission of CRT in the UK cohort,” the authors underscored.
Comparatively, in the cohort of the 2 COG trials, there were significant differences based on CNS status for 4-year CIR (P = .0002); EFS (P = .0004) and OS (P = .005).
The 4-year relapse rates among those with CNS-3 in the UK cohort were slightly higher compared with those in the COG cohort (24.6% UK vs 17.9%, COG). However, the difference did not translate to poorer long-term survival in the UK cohort (91.8% vs 82.7%, respectively).
Those findings are consistent with a previous meta-analysis that Dr. Vora and his colleagues conducted of more than 16,000 patients with mainly B-cell ALL, which showed that CRT reduced the risk of isolated and combined CNS relapse in patients with CNS-3. However, that risk had no impact on EFS and OS.
Of note, patients in the UK cohort with CNS-2 had worse outcomes compared with the COG group, with double the rate of relapse and lower EFS and OS. However, the authors speculate that factors including a lower proportion of patients with CNS-2 in the UK cohort and differences in methodologies may explain those different outcomes and may preclude their generalizability to other groups.
Overall, “these findings corroborate those of earlier studies that CRT has marginal, if any benefit, for any sub-group of ALL, especially as part of contemporary treatment,” Dr. Vora said in an interview.
In terms of therapies that do appear to make a difference in the treatment of CNS-3, Dr. Vora noted that the addition of nelarabine in the COG AALL0434 trial showed “remarkable benefit” in the CNS-3 group, with a 93.1% rate of disease-free survival in those patients versus 70.2% without nelarabine.
Importantly, those patients did also receive CRT. However, Dr. Vora and colleagues underscore that “the improvement is impressive and raises the question of whether nelarabine would have a similar beneficial effect in the absence of CRT.”
In an editorial published with the COG trials, Josep-Maria Ribera, MD, of the Josep Carreras Leukemia Research Institute, in Barcelona, Spain, agrees that “better approaches clearly are needed to treat CNS-3 T-ALL, especially if omission of CRT is a priority.”
Noting the improvements observed with nelarabine, as well as Capizzi escalating-dose methotrexate (C-MTX), and dexamethasone in reducing the risk of CNS relapse, he speculates that “it is possible that the additional use of C-MTX and induction dexamethasone could eliminate the need for CRT in these patients.”
The authors and Dr. Ribera had no disclosures to report.
“Overall, comparison of these cohorts provides a strong indication that CRT provides minimal benefit to patients with CNS-3 disease at diagnosis,” first author Ajay Vora, MD, a consultant hematologist with Great Ormond Street Hospital, in London, and his colleagues report in a research letter published recently in Blood Advances.
“Given the high rates of neurocognitive impairment and secondary CNS malignancies, we believe strong consideration should be given to eliminating CRT in first-line treatment for all patients with T-ALL,” they wrote.
More aggressive than B-cell ALL, T-ALL is characterized by a higher likelihood of infiltration of the CNS at diagnosis, which increases the risk of relapse after treatment.
Until recently, treatment of T-ALL long entailed CNS-directed therapy using prophylactic CRT. Now, however, due to the risks of significant toxicity, including neurocognitive defects and secondary cancers, CRT is usually either omitted or limited to key subgroups, such as those with CNS-3 disease. As an alternative, intrathecal chemotherapy is used, the authors explain.
In a 2023 study evaluating the consecutive Children’s Oncology Group (COG) AALL0434 and AALL1231 phase 3 trials of 2,164 patients with T-ALL, patients with CNS-3 at diagnosis were found to have worse outcomes, compared with CNS-1 and 2.
Importantly, the outcomes in both of those two trials were similar, despite the use of CRT in more than 90% of patients in the AALL0434 trial--but in only 10% of patients AALL1231 trial (mainly those with CNS-3 and at high-risk). These outcomes suggested that CRT can safely be eliminated for CNS-1 and 2 patients.
With CRT used in both trials among patients with CNS-3, conclusions about eliminating CRT among those patients could not be drawn. However, with other large groups (including the Dutch Childhood Oncology Group), eliminating CRT in the frontline treatment of all patients with T-ALL, including those with CNS-3, is what Dr. Vora and colleagues sought to further investigate.
For the current study, they evaluated outcomes in the UKALL2003 and UKALL2011 trials conducted by the UK National Cancer Research Institute, in which CRT was eliminated for all patients — including those with CNS-3 — and compared them with the COG AALL0434 and AALL1231 trials.
In the UK trials, involving 665 patients with T-ALL aged 1 to 24, treatment included a dexamethasone-based backbone chemotherapy consisting of a 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation, interim maintenance, delayed intensification, and maintenance therapy, with the treatment stratified based on morphological early response and minimal residual disease at the end of induction.
While the UKALL2003 trial initially recommended CRT for patients with CNS-3, that practice ended in 2009, and CNS-directed therapy subsequently consisted of intrathecal methotrexate (MTX) at regular intervals throughout treatment. Additional weekly intrathecal MTX treatments were recommended throughout induction for patients with CNS-3.
In the UKALL2011 trial, the weekly intrathecal MTX treatments were recommended for patients with CNS-2, as well as CNS-3.
Overall, among those with CNS data available, 557 patients had CNS-1 (87.4%), 44 CNS-2 (6.9%), and 36 CNS-3 (5.7%).
For the outcomes of 4-year cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) in the combined cohort of the 2 UK trials, there were no significant differences between CNS-1, 2 or 3 groups.
Specifically, the mean rates of 4-year CIR in the CNS-1, 2, and 3 groups were 13.6%, 25.9% and 24.6%, respectively (P = .241); mean EFS rates were 82.9%, 74.1% and 77.8% (P = .623), and OS rates were 88.6%, 80.9% and 91.8%, (P = .453).
“Most importantly, outcomes are not significantly different for the patients with CNS-3, despite omission of CRT in the UK cohort,” the authors underscored.
Comparatively, in the cohort of the 2 COG trials, there were significant differences based on CNS status for 4-year CIR (P = .0002); EFS (P = .0004) and OS (P = .005).
The 4-year relapse rates among those with CNS-3 in the UK cohort were slightly higher compared with those in the COG cohort (24.6% UK vs 17.9%, COG). However, the difference did not translate to poorer long-term survival in the UK cohort (91.8% vs 82.7%, respectively).
Those findings are consistent with a previous meta-analysis that Dr. Vora and his colleagues conducted of more than 16,000 patients with mainly B-cell ALL, which showed that CRT reduced the risk of isolated and combined CNS relapse in patients with CNS-3. However, that risk had no impact on EFS and OS.
Of note, patients in the UK cohort with CNS-2 had worse outcomes compared with the COG group, with double the rate of relapse and lower EFS and OS. However, the authors speculate that factors including a lower proportion of patients with CNS-2 in the UK cohort and differences in methodologies may explain those different outcomes and may preclude their generalizability to other groups.
Overall, “these findings corroborate those of earlier studies that CRT has marginal, if any benefit, for any sub-group of ALL, especially as part of contemporary treatment,” Dr. Vora said in an interview.
In terms of therapies that do appear to make a difference in the treatment of CNS-3, Dr. Vora noted that the addition of nelarabine in the COG AALL0434 trial showed “remarkable benefit” in the CNS-3 group, with a 93.1% rate of disease-free survival in those patients versus 70.2% without nelarabine.
Importantly, those patients did also receive CRT. However, Dr. Vora and colleagues underscore that “the improvement is impressive and raises the question of whether nelarabine would have a similar beneficial effect in the absence of CRT.”
In an editorial published with the COG trials, Josep-Maria Ribera, MD, of the Josep Carreras Leukemia Research Institute, in Barcelona, Spain, agrees that “better approaches clearly are needed to treat CNS-3 T-ALL, especially if omission of CRT is a priority.”
Noting the improvements observed with nelarabine, as well as Capizzi escalating-dose methotrexate (C-MTX), and dexamethasone in reducing the risk of CNS relapse, he speculates that “it is possible that the additional use of C-MTX and induction dexamethasone could eliminate the need for CRT in these patients.”
The authors and Dr. Ribera had no disclosures to report.
“Overall, comparison of these cohorts provides a strong indication that CRT provides minimal benefit to patients with CNS-3 disease at diagnosis,” first author Ajay Vora, MD, a consultant hematologist with Great Ormond Street Hospital, in London, and his colleagues report in a research letter published recently in Blood Advances.
“Given the high rates of neurocognitive impairment and secondary CNS malignancies, we believe strong consideration should be given to eliminating CRT in first-line treatment for all patients with T-ALL,” they wrote.
More aggressive than B-cell ALL, T-ALL is characterized by a higher likelihood of infiltration of the CNS at diagnosis, which increases the risk of relapse after treatment.
Until recently, treatment of T-ALL long entailed CNS-directed therapy using prophylactic CRT. Now, however, due to the risks of significant toxicity, including neurocognitive defects and secondary cancers, CRT is usually either omitted or limited to key subgroups, such as those with CNS-3 disease. As an alternative, intrathecal chemotherapy is used, the authors explain.
In a 2023 study evaluating the consecutive Children’s Oncology Group (COG) AALL0434 and AALL1231 phase 3 trials of 2,164 patients with T-ALL, patients with CNS-3 at diagnosis were found to have worse outcomes, compared with CNS-1 and 2.
Importantly, the outcomes in both of those two trials were similar, despite the use of CRT in more than 90% of patients in the AALL0434 trial--but in only 10% of patients AALL1231 trial (mainly those with CNS-3 and at high-risk). These outcomes suggested that CRT can safely be eliminated for CNS-1 and 2 patients.
With CRT used in both trials among patients with CNS-3, conclusions about eliminating CRT among those patients could not be drawn. However, with other large groups (including the Dutch Childhood Oncology Group), eliminating CRT in the frontline treatment of all patients with T-ALL, including those with CNS-3, is what Dr. Vora and colleagues sought to further investigate.
For the current study, they evaluated outcomes in the UKALL2003 and UKALL2011 trials conducted by the UK National Cancer Research Institute, in which CRT was eliminated for all patients — including those with CNS-3 — and compared them with the COG AALL0434 and AALL1231 trials.
In the UK trials, involving 665 patients with T-ALL aged 1 to 24, treatment included a dexamethasone-based backbone chemotherapy consisting of a 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation, interim maintenance, delayed intensification, and maintenance therapy, with the treatment stratified based on morphological early response and minimal residual disease at the end of induction.
While the UKALL2003 trial initially recommended CRT for patients with CNS-3, that practice ended in 2009, and CNS-directed therapy subsequently consisted of intrathecal methotrexate (MTX) at regular intervals throughout treatment. Additional weekly intrathecal MTX treatments were recommended throughout induction for patients with CNS-3.
In the UKALL2011 trial, the weekly intrathecal MTX treatments were recommended for patients with CNS-2, as well as CNS-3.
Overall, among those with CNS data available, 557 patients had CNS-1 (87.4%), 44 CNS-2 (6.9%), and 36 CNS-3 (5.7%).
For the outcomes of 4-year cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) in the combined cohort of the 2 UK trials, there were no significant differences between CNS-1, 2 or 3 groups.
Specifically, the mean rates of 4-year CIR in the CNS-1, 2, and 3 groups were 13.6%, 25.9% and 24.6%, respectively (P = .241); mean EFS rates were 82.9%, 74.1% and 77.8% (P = .623), and OS rates were 88.6%, 80.9% and 91.8%, (P = .453).
“Most importantly, outcomes are not significantly different for the patients with CNS-3, despite omission of CRT in the UK cohort,” the authors underscored.
Comparatively, in the cohort of the 2 COG trials, there were significant differences based on CNS status for 4-year CIR (P = .0002); EFS (P = .0004) and OS (P = .005).
The 4-year relapse rates among those with CNS-3 in the UK cohort were slightly higher compared with those in the COG cohort (24.6% UK vs 17.9%, COG). However, the difference did not translate to poorer long-term survival in the UK cohort (91.8% vs 82.7%, respectively).
Those findings are consistent with a previous meta-analysis that Dr. Vora and his colleagues conducted of more than 16,000 patients with mainly B-cell ALL, which showed that CRT reduced the risk of isolated and combined CNS relapse in patients with CNS-3. However, that risk had no impact on EFS and OS.
Of note, patients in the UK cohort with CNS-2 had worse outcomes compared with the COG group, with double the rate of relapse and lower EFS and OS. However, the authors speculate that factors including a lower proportion of patients with CNS-2 in the UK cohort and differences in methodologies may explain those different outcomes and may preclude their generalizability to other groups.
Overall, “these findings corroborate those of earlier studies that CRT has marginal, if any benefit, for any sub-group of ALL, especially as part of contemporary treatment,” Dr. Vora said in an interview.
In terms of therapies that do appear to make a difference in the treatment of CNS-3, Dr. Vora noted that the addition of nelarabine in the COG AALL0434 trial showed “remarkable benefit” in the CNS-3 group, with a 93.1% rate of disease-free survival in those patients versus 70.2% without nelarabine.
Importantly, those patients did also receive CRT. However, Dr. Vora and colleagues underscore that “the improvement is impressive and raises the question of whether nelarabine would have a similar beneficial effect in the absence of CRT.”
In an editorial published with the COG trials, Josep-Maria Ribera, MD, of the Josep Carreras Leukemia Research Institute, in Barcelona, Spain, agrees that “better approaches clearly are needed to treat CNS-3 T-ALL, especially if omission of CRT is a priority.”
Noting the improvements observed with nelarabine, as well as Capizzi escalating-dose methotrexate (C-MTX), and dexamethasone in reducing the risk of CNS relapse, he speculates that “it is possible that the additional use of C-MTX and induction dexamethasone could eliminate the need for CRT in these patients.”
The authors and Dr. Ribera had no disclosures to report.
FROM BLOOD ADVANCES
Are Post-Meal Insulin Surges Beneficial?
Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.
“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.
“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”
The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.
Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.
As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Dr. Retnakaran told this news organization.
However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.
Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.
To investigate the issue in a longitudinal context, Dr. Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.
The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.
Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).
However, those trends were also associated with progressively improved beta cell function (P < .001).
After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).
The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.
Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).
“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Dr. Retnakaran told this news organization. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”
While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.
“This evidence should help push back concern around the postprandial insulin spike,” Dr. Retnakaran said.
Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told this news organization.
However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.
“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”
A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.
Nevertheless, “I think this is an interesting and important study,” Dr. Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”
The authors and Dr. Johnson had no disclosures to report.
A version of this article appeared on Medscape.com.
Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.
“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.
“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”
The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.
Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.
As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Dr. Retnakaran told this news organization.
However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.
Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.
To investigate the issue in a longitudinal context, Dr. Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.
The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.
Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).
However, those trends were also associated with progressively improved beta cell function (P < .001).
After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).
The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.
Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).
“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Dr. Retnakaran told this news organization. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”
While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.
“This evidence should help push back concern around the postprandial insulin spike,” Dr. Retnakaran said.
Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told this news organization.
However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.
“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”
A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.
Nevertheless, “I think this is an interesting and important study,” Dr. Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”
The authors and Dr. Johnson had no disclosures to report.
A version of this article appeared on Medscape.com.
Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.
“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.
“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”
The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.
Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.
As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Dr. Retnakaran told this news organization.
However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.
Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.
To investigate the issue in a longitudinal context, Dr. Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.
The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.
Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).
However, those trends were also associated with progressively improved beta cell function (P < .001).
After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).
The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.
Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).
“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Dr. Retnakaran told this news organization. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”
While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.
“This evidence should help push back concern around the postprandial insulin spike,” Dr. Retnakaran said.
Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told this news organization.
However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.
“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”
A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.
Nevertheless, “I think this is an interesting and important study,” Dr. Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”
The authors and Dr. Johnson had no disclosures to report.
A version of this article appeared on Medscape.com.
ALL: Asparaginase Tx Boosts Survival in AYA Patients
“These findings of a large cohort of adolescents and young adults treated at a variety of U.S. centers confirm the findings of the clinical trial and also provide confidence that patients remaining on this regimen have very excellent 3-year outcomes,” senior author Lori S. Muffly, MD, associate professor of medicine at Stanford University in the Division of Blood and Marrow Transplantation and Cellular Therapy, in Stanford, California, said in an interview.
The study was presented at the American Society of Hematology annual meeting. In the Cancer and Leukemia Group B 10403 trial, the intensive asparaginase pediatric regimen, used in the adult oncology treatment setting, showed benefits in the adolescent and young adult population, with a 3-year event-free survival (EFS) rate of 59% and an overall survival rate of 73%.
Based on the results, the regimen has gained widespread utilization in the United States. However, evidence of the therapy’s safety and efficacy in real-world practice, outside of the controlled clinical trial setting, has been lacking.
To investigate, first author Dr. Muffly, along with coauthor Brandon DaSilva, MD, and colleagues at Stanford University School of Medicine conducted a retrospective analysis of 101 adolescent and young adult patients aged 17 to 40 with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL (B-ALL) or T-cell ALL (T-ALL).
The patients had been treated with the C10403 regimen off-trial at five U.S. centers between October 2012 and July 2020.
The study excluded Ph-positive or Burkitt-type ALL patients, in addition to those who were previously treated, with the exception of treatment with hydroxyurea, steroids, one dose of single-agent therapy, or rituximab for CD20-positive B-ALL. Of the patients, about half, 54%, were between the ages of 20 and 29; 69% were male and 55% were White. Most patients (70%) had B-cell immunophenotype, and among them, 49% had CD20 expression.
Forty percent of patients had normal karyotype; 3% were hypodiploid, 7% were KMT2a-rearranged, and 30% of the 27 patients assessed had Ph-like ALL. CNS involvement was present at diagnosis among 20% (9% with CNS2, 11% with CNS3) and 14% of patients had a mediastinal mass.
Of 71 patients with B-ALL, 16 (23%) received at least one dose of rituximab.
Among the 101 patients who started induction with C10403, 72 (71%) completed induction and continued to consolidation; 51 (50%) continued beyond consolidation, while only 31 (31%) completed the entire C10403 regimen through the end of maintenance.
For the primary outcomes, overall, the rate of induction response, defined as achieving <5% blasts on bone marrow by the end of induction or extended induction, was 91% of whom 54% were measurable residual disease [MRD]-negative (threshold of at least 10–4).
The co-primary endpoint of 3-year event-free survival was 65% and 3-year overall survival was 82.7%.
Two deaths occurred (2%) among patients who were in remission and still receiving treatment.
Overall, 44 patients (44%) were taken off C10403 while in complete remission, including 20 (20%) to receive an allogeneic hematopoietic cell transplant (HCT), 23 (23%) to receive non-HCT alternative treatments including Hyper-CVAD or blinatumomab, and 1 (1%) for patient preference.
Dr. Muffly noted that the 31% of treatment completion is about the same as that seen on the original C10403 trial.
“In clinical practice, there are a variety of reasons that these patients came off therapy — probably the most common reason is for MRD-directed therapy, such as with blinatumomab.”
“We are currently analyzing the results of the patients who came off therapy relative to those who stayed on therapy which will be interesting.”
The slightly higher real-world 3-year EFS and OS (65% and 82.7%, respectively) compared with the outcomes in the clinical trial (59% and 73%, respectively), were “very encouraging,” Dr. Muffly noted.
“A lot has changed and improved in B-ALL for adolescent/young adults since this trial closed to enrollment over 10 years ago,” she explained.
“We have better MRD methods, MRD-directed therapies, and a variety of targeted immunotherapies being used in a variety of ways,” Dr. Muffly said. “The overall outcomes for adolescent/young adult ALL patients are improving and we can see that in this data set.”
Commenting on the study, Catherine Bollard, MD, a pediatric oncologist at Children’s National Hospital in Washington, DC, noted that the study’s retrospective nature is “definitely a major caveat that needs to be considered when evaluating the impact of the data.”
Regarding the relatively low rate of regimen completion, Dr. Bollard said, “I do think the pros still outweigh the cons. But getting patients into a deep complete remission and then evaluating their outcomes after consolidation with HCT or alternative therapy is certainly an important consideration and needs to be studied further in a larger cohort.”
Overall, however, “this ‘real world’ experience validates the use of this regimen outside of the clinical trial setting,” she said.
Dr. Muffly and Dr. Bollard had no disclosures to report. Dr. Bollard is the editor-in-chief of ASH’s journal, Blood Advances.
“These findings of a large cohort of adolescents and young adults treated at a variety of U.S. centers confirm the findings of the clinical trial and also provide confidence that patients remaining on this regimen have very excellent 3-year outcomes,” senior author Lori S. Muffly, MD, associate professor of medicine at Stanford University in the Division of Blood and Marrow Transplantation and Cellular Therapy, in Stanford, California, said in an interview.
The study was presented at the American Society of Hematology annual meeting. In the Cancer and Leukemia Group B 10403 trial, the intensive asparaginase pediatric regimen, used in the adult oncology treatment setting, showed benefits in the adolescent and young adult population, with a 3-year event-free survival (EFS) rate of 59% and an overall survival rate of 73%.
Based on the results, the regimen has gained widespread utilization in the United States. However, evidence of the therapy’s safety and efficacy in real-world practice, outside of the controlled clinical trial setting, has been lacking.
To investigate, first author Dr. Muffly, along with coauthor Brandon DaSilva, MD, and colleagues at Stanford University School of Medicine conducted a retrospective analysis of 101 adolescent and young adult patients aged 17 to 40 with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL (B-ALL) or T-cell ALL (T-ALL).
The patients had been treated with the C10403 regimen off-trial at five U.S. centers between October 2012 and July 2020.
The study excluded Ph-positive or Burkitt-type ALL patients, in addition to those who were previously treated, with the exception of treatment with hydroxyurea, steroids, one dose of single-agent therapy, or rituximab for CD20-positive B-ALL. Of the patients, about half, 54%, were between the ages of 20 and 29; 69% were male and 55% were White. Most patients (70%) had B-cell immunophenotype, and among them, 49% had CD20 expression.
Forty percent of patients had normal karyotype; 3% were hypodiploid, 7% were KMT2a-rearranged, and 30% of the 27 patients assessed had Ph-like ALL. CNS involvement was present at diagnosis among 20% (9% with CNS2, 11% with CNS3) and 14% of patients had a mediastinal mass.
Of 71 patients with B-ALL, 16 (23%) received at least one dose of rituximab.
Among the 101 patients who started induction with C10403, 72 (71%) completed induction and continued to consolidation; 51 (50%) continued beyond consolidation, while only 31 (31%) completed the entire C10403 regimen through the end of maintenance.
For the primary outcomes, overall, the rate of induction response, defined as achieving <5% blasts on bone marrow by the end of induction or extended induction, was 91% of whom 54% were measurable residual disease [MRD]-negative (threshold of at least 10–4).
The co-primary endpoint of 3-year event-free survival was 65% and 3-year overall survival was 82.7%.
Two deaths occurred (2%) among patients who were in remission and still receiving treatment.
Overall, 44 patients (44%) were taken off C10403 while in complete remission, including 20 (20%) to receive an allogeneic hematopoietic cell transplant (HCT), 23 (23%) to receive non-HCT alternative treatments including Hyper-CVAD or blinatumomab, and 1 (1%) for patient preference.
Dr. Muffly noted that the 31% of treatment completion is about the same as that seen on the original C10403 trial.
“In clinical practice, there are a variety of reasons that these patients came off therapy — probably the most common reason is for MRD-directed therapy, such as with blinatumomab.”
“We are currently analyzing the results of the patients who came off therapy relative to those who stayed on therapy which will be interesting.”
The slightly higher real-world 3-year EFS and OS (65% and 82.7%, respectively) compared with the outcomes in the clinical trial (59% and 73%, respectively), were “very encouraging,” Dr. Muffly noted.
“A lot has changed and improved in B-ALL for adolescent/young adults since this trial closed to enrollment over 10 years ago,” she explained.
“We have better MRD methods, MRD-directed therapies, and a variety of targeted immunotherapies being used in a variety of ways,” Dr. Muffly said. “The overall outcomes for adolescent/young adult ALL patients are improving and we can see that in this data set.”
Commenting on the study, Catherine Bollard, MD, a pediatric oncologist at Children’s National Hospital in Washington, DC, noted that the study’s retrospective nature is “definitely a major caveat that needs to be considered when evaluating the impact of the data.”
Regarding the relatively low rate of regimen completion, Dr. Bollard said, “I do think the pros still outweigh the cons. But getting patients into a deep complete remission and then evaluating their outcomes after consolidation with HCT or alternative therapy is certainly an important consideration and needs to be studied further in a larger cohort.”
Overall, however, “this ‘real world’ experience validates the use of this regimen outside of the clinical trial setting,” she said.
Dr. Muffly and Dr. Bollard had no disclosures to report. Dr. Bollard is the editor-in-chief of ASH’s journal, Blood Advances.
“These findings of a large cohort of adolescents and young adults treated at a variety of U.S. centers confirm the findings of the clinical trial and also provide confidence that patients remaining on this regimen have very excellent 3-year outcomes,” senior author Lori S. Muffly, MD, associate professor of medicine at Stanford University in the Division of Blood and Marrow Transplantation and Cellular Therapy, in Stanford, California, said in an interview.
The study was presented at the American Society of Hematology annual meeting. In the Cancer and Leukemia Group B 10403 trial, the intensive asparaginase pediatric regimen, used in the adult oncology treatment setting, showed benefits in the adolescent and young adult population, with a 3-year event-free survival (EFS) rate of 59% and an overall survival rate of 73%.
Based on the results, the regimen has gained widespread utilization in the United States. However, evidence of the therapy’s safety and efficacy in real-world practice, outside of the controlled clinical trial setting, has been lacking.
To investigate, first author Dr. Muffly, along with coauthor Brandon DaSilva, MD, and colleagues at Stanford University School of Medicine conducted a retrospective analysis of 101 adolescent and young adult patients aged 17 to 40 with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL (B-ALL) or T-cell ALL (T-ALL).
The patients had been treated with the C10403 regimen off-trial at five U.S. centers between October 2012 and July 2020.
The study excluded Ph-positive or Burkitt-type ALL patients, in addition to those who were previously treated, with the exception of treatment with hydroxyurea, steroids, one dose of single-agent therapy, or rituximab for CD20-positive B-ALL. Of the patients, about half, 54%, were between the ages of 20 and 29; 69% were male and 55% were White. Most patients (70%) had B-cell immunophenotype, and among them, 49% had CD20 expression.
Forty percent of patients had normal karyotype; 3% were hypodiploid, 7% were KMT2a-rearranged, and 30% of the 27 patients assessed had Ph-like ALL. CNS involvement was present at diagnosis among 20% (9% with CNS2, 11% with CNS3) and 14% of patients had a mediastinal mass.
Of 71 patients with B-ALL, 16 (23%) received at least one dose of rituximab.
Among the 101 patients who started induction with C10403, 72 (71%) completed induction and continued to consolidation; 51 (50%) continued beyond consolidation, while only 31 (31%) completed the entire C10403 regimen through the end of maintenance.
For the primary outcomes, overall, the rate of induction response, defined as achieving <5% blasts on bone marrow by the end of induction or extended induction, was 91% of whom 54% were measurable residual disease [MRD]-negative (threshold of at least 10–4).
The co-primary endpoint of 3-year event-free survival was 65% and 3-year overall survival was 82.7%.
Two deaths occurred (2%) among patients who were in remission and still receiving treatment.
Overall, 44 patients (44%) were taken off C10403 while in complete remission, including 20 (20%) to receive an allogeneic hematopoietic cell transplant (HCT), 23 (23%) to receive non-HCT alternative treatments including Hyper-CVAD or blinatumomab, and 1 (1%) for patient preference.
Dr. Muffly noted that the 31% of treatment completion is about the same as that seen on the original C10403 trial.
“In clinical practice, there are a variety of reasons that these patients came off therapy — probably the most common reason is for MRD-directed therapy, such as with blinatumomab.”
“We are currently analyzing the results of the patients who came off therapy relative to those who stayed on therapy which will be interesting.”
The slightly higher real-world 3-year EFS and OS (65% and 82.7%, respectively) compared with the outcomes in the clinical trial (59% and 73%, respectively), were “very encouraging,” Dr. Muffly noted.
“A lot has changed and improved in B-ALL for adolescent/young adults since this trial closed to enrollment over 10 years ago,” she explained.
“We have better MRD methods, MRD-directed therapies, and a variety of targeted immunotherapies being used in a variety of ways,” Dr. Muffly said. “The overall outcomes for adolescent/young adult ALL patients are improving and we can see that in this data set.”
Commenting on the study, Catherine Bollard, MD, a pediatric oncologist at Children’s National Hospital in Washington, DC, noted that the study’s retrospective nature is “definitely a major caveat that needs to be considered when evaluating the impact of the data.”
Regarding the relatively low rate of regimen completion, Dr. Bollard said, “I do think the pros still outweigh the cons. But getting patients into a deep complete remission and then evaluating their outcomes after consolidation with HCT or alternative therapy is certainly an important consideration and needs to be studied further in a larger cohort.”
Overall, however, “this ‘real world’ experience validates the use of this regimen outside of the clinical trial setting,” she said.
Dr. Muffly and Dr. Bollard had no disclosures to report. Dr. Bollard is the editor-in-chief of ASH’s journal, Blood Advances.
FROM ASH 2023
Children who are overweight at risk for chronic kidney disease
TOPLINE
, with the association, though weaker, still significant among those who do not develop type 2 diabetes or hypertension, in a large cohort study.
METHODOLOGY
- The study included data on 593,660 adolescents aged 16-20, born after January 1, 1975, who had medical assessments as part of mandatory military service in Israel.
- The mean age at study entry was 17.2 and 54.5% were male.
- Early CKD was defined as stage 1 to 2 CKD with moderately or severely increased albuminuria, with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher.
- The study excluded those with kidney pathology, albuminuria, hypertension, dysglycemia, or missing blood pressure or BMI data.
- Participants were followed up until early CKD onset, death, the last day insured, or August 23, 2020.
TAKEAWAY
- With a mean follow-up of 13.4 years, 1963 adolescents (0.3%) overall developed early chronic kidney disease. Among males, an increased risk of developing CKD was observed with a high-normal BMI in adolescence (hazard ratio [HR], 1.8); with overweight BMI (HR, 4.0); with mild obesity (HR, 6.7); and severe obesity (HR, 9.4).
- Among females, the increased risk was also observed with high-normal BMI (HR 1.4); overweight (HR, 2.3); mild obesity (HR, 2.7); and severe obesity (HR, 4.3).
- In excluding those who developed diabetes or hypertension, the overall rate of early CKD in the cohort was 0.2%.
- For males without diabetes or hypertension, the adjusted HR for early CKD with high-normal weight was 1.2; for overweight, HR 1.6; for mild obesity, HR 2.2; and for severe obesity, HR 2.7.
- For females without diabetes or hypertension, the corresponding increased risk for early CKD was HR 1.2 for high-normal BMI; HR 1.8 for overweight; 1.5 for mild obesity and 2.3 for severe obesity.
IN PRACTICE
“These findings suggest that adolescent obesity is a major risk factor for early CKD in young adulthood; this underscores the importance of mitigating adolescent obesity rates and managing risk factors for kidney disease in adolescents with high BMI,” the authors report.
“The association was evident even in persons with high-normal BMI in adolescence, was more pronounced in men, and appeared before the age of 30 years,” they say.
“Given the increasing obesity rates among adolescents, our findings are a harbinger of the potentially preventable increasing burden of CKD and subsequent cardiovascular disease.”
SOURCE
The study was conducted by first author Avishai M. Tsur, MD, of the Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan, Israel and Department of Military Medicine, Hebrew University of Jerusalem Faculty of Medicine, Jerusalem, Israel, and colleagues. The study was published online in JAMA Pediatrics.
LIMITATIONS
The study lacked longitudinal data on clinical and lifestyle factors, including stress, diet and physical activity. While adolescents were screened using urine dipstick, a lack of serum creatinine measurements could have missed some adolescents with reduced eGFR at the study entry. The generalizability of the results is limited by the lack of people from West Africa and East Asia in the study population.
DISCLOSURES
Coauthor Josef Coresh, MD, reported receiving grants from the National Institutes of Health outside the submitted work. No other disclosures were reported.
A version of this article appeared on Medscape.com.
TOPLINE
, with the association, though weaker, still significant among those who do not develop type 2 diabetes or hypertension, in a large cohort study.
METHODOLOGY
- The study included data on 593,660 adolescents aged 16-20, born after January 1, 1975, who had medical assessments as part of mandatory military service in Israel.
- The mean age at study entry was 17.2 and 54.5% were male.
- Early CKD was defined as stage 1 to 2 CKD with moderately or severely increased albuminuria, with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher.
- The study excluded those with kidney pathology, albuminuria, hypertension, dysglycemia, or missing blood pressure or BMI data.
- Participants were followed up until early CKD onset, death, the last day insured, or August 23, 2020.
TAKEAWAY
- With a mean follow-up of 13.4 years, 1963 adolescents (0.3%) overall developed early chronic kidney disease. Among males, an increased risk of developing CKD was observed with a high-normal BMI in adolescence (hazard ratio [HR], 1.8); with overweight BMI (HR, 4.0); with mild obesity (HR, 6.7); and severe obesity (HR, 9.4).
- Among females, the increased risk was also observed with high-normal BMI (HR 1.4); overweight (HR, 2.3); mild obesity (HR, 2.7); and severe obesity (HR, 4.3).
- In excluding those who developed diabetes or hypertension, the overall rate of early CKD in the cohort was 0.2%.
- For males without diabetes or hypertension, the adjusted HR for early CKD with high-normal weight was 1.2; for overweight, HR 1.6; for mild obesity, HR 2.2; and for severe obesity, HR 2.7.
- For females without diabetes or hypertension, the corresponding increased risk for early CKD was HR 1.2 for high-normal BMI; HR 1.8 for overweight; 1.5 for mild obesity and 2.3 for severe obesity.
IN PRACTICE
“These findings suggest that adolescent obesity is a major risk factor for early CKD in young adulthood; this underscores the importance of mitigating adolescent obesity rates and managing risk factors for kidney disease in adolescents with high BMI,” the authors report.
“The association was evident even in persons with high-normal BMI in adolescence, was more pronounced in men, and appeared before the age of 30 years,” they say.
“Given the increasing obesity rates among adolescents, our findings are a harbinger of the potentially preventable increasing burden of CKD and subsequent cardiovascular disease.”
SOURCE
The study was conducted by first author Avishai M. Tsur, MD, of the Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan, Israel and Department of Military Medicine, Hebrew University of Jerusalem Faculty of Medicine, Jerusalem, Israel, and colleagues. The study was published online in JAMA Pediatrics.
LIMITATIONS
The study lacked longitudinal data on clinical and lifestyle factors, including stress, diet and physical activity. While adolescents were screened using urine dipstick, a lack of serum creatinine measurements could have missed some adolescents with reduced eGFR at the study entry. The generalizability of the results is limited by the lack of people from West Africa and East Asia in the study population.
DISCLOSURES
Coauthor Josef Coresh, MD, reported receiving grants from the National Institutes of Health outside the submitted work. No other disclosures were reported.
A version of this article appeared on Medscape.com.
TOPLINE
, with the association, though weaker, still significant among those who do not develop type 2 diabetes or hypertension, in a large cohort study.
METHODOLOGY
- The study included data on 593,660 adolescents aged 16-20, born after January 1, 1975, who had medical assessments as part of mandatory military service in Israel.
- The mean age at study entry was 17.2 and 54.5% were male.
- Early CKD was defined as stage 1 to 2 CKD with moderately or severely increased albuminuria, with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher.
- The study excluded those with kidney pathology, albuminuria, hypertension, dysglycemia, or missing blood pressure or BMI data.
- Participants were followed up until early CKD onset, death, the last day insured, or August 23, 2020.
TAKEAWAY
- With a mean follow-up of 13.4 years, 1963 adolescents (0.3%) overall developed early chronic kidney disease. Among males, an increased risk of developing CKD was observed with a high-normal BMI in adolescence (hazard ratio [HR], 1.8); with overweight BMI (HR, 4.0); with mild obesity (HR, 6.7); and severe obesity (HR, 9.4).
- Among females, the increased risk was also observed with high-normal BMI (HR 1.4); overweight (HR, 2.3); mild obesity (HR, 2.7); and severe obesity (HR, 4.3).
- In excluding those who developed diabetes or hypertension, the overall rate of early CKD in the cohort was 0.2%.
- For males without diabetes or hypertension, the adjusted HR for early CKD with high-normal weight was 1.2; for overweight, HR 1.6; for mild obesity, HR 2.2; and for severe obesity, HR 2.7.
- For females without diabetes or hypertension, the corresponding increased risk for early CKD was HR 1.2 for high-normal BMI; HR 1.8 for overweight; 1.5 for mild obesity and 2.3 for severe obesity.
IN PRACTICE
“These findings suggest that adolescent obesity is a major risk factor for early CKD in young adulthood; this underscores the importance of mitigating adolescent obesity rates and managing risk factors for kidney disease in adolescents with high BMI,” the authors report.
“The association was evident even in persons with high-normal BMI in adolescence, was more pronounced in men, and appeared before the age of 30 years,” they say.
“Given the increasing obesity rates among adolescents, our findings are a harbinger of the potentially preventable increasing burden of CKD and subsequent cardiovascular disease.”
SOURCE
The study was conducted by first author Avishai M. Tsur, MD, of the Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan, Israel and Department of Military Medicine, Hebrew University of Jerusalem Faculty of Medicine, Jerusalem, Israel, and colleagues. The study was published online in JAMA Pediatrics.
LIMITATIONS
The study lacked longitudinal data on clinical and lifestyle factors, including stress, diet and physical activity. While adolescents were screened using urine dipstick, a lack of serum creatinine measurements could have missed some adolescents with reduced eGFR at the study entry. The generalizability of the results is limited by the lack of people from West Africa and East Asia in the study population.
DISCLOSURES
Coauthor Josef Coresh, MD, reported receiving grants from the National Institutes of Health outside the submitted work. No other disclosures were reported.
A version of this article appeared on Medscape.com.
Anti-Rheumatic Drugs Linked to Reduced Thyroid Disease Incidence
TOPLINE:
Patients with rheumatoid arthritis (RA) in a large Swedish population cohort show a reduced incidence of autoimmune thyroid diseases, such as hypothyroidism or hyperthyroidism, after being diagnosed with RA, with the effect being more pronounced among those treated with disease-modifying anti-rheumatic drugs (DMARDs), particularly TNF-inhibitors.
Although DMARDs are commonly used in the treatment of RA, the drugs are rarely used to treat autoimmune thyroid diseases. The new results support theories raised in previous smaller studies that DMARDs could have a protective effect against thyroid disease.
METHODOLOGY:
- The study involved 13,731 patients with new-onset RA who were listed in the Swedish Rheumatology Quality Register between 2006 and 2018.
- The patients were matched for sex, age, and residential area with up to five reference individuals in the general population of 63,201 comparators.
- Overall, patients with RA were 64.7% female, with a mean age of 59. They were followed up with their matched comparators until the development of autoimmune thyroid disease, death, emigration, or the end of the study period, December 2019.
- The relative risks of autoimmune thyroid disease following a diagnosis of RA and with treatment with DMARDs were compared with those risks in the general population.
- Participants with a non-autoimmune cause for thyroxine prescription were excluded, as were those with an autoimmune thyroid disease at the time of RA diagnosis.
TAKEAWAY:
- Following their RA diagnosis, 321 (2.3%) of patients developed an autoimmune thyroid disease, compared with 1838 (2.9%) in the general population comparators, representing an incidence of 3.7 vs 4.6 per 1000 person-years (hazard ratio [HR], 0.81).
- The lower incidence of autoimmune thyroid disease was more pronounced with longer RA duration. For instance, at 10-14 years after an RA diagnosis, the incidence was 2.9 vs. 4.5 autoimmune thyroid disease events per 1000 person-years, respectively (HR, 0.64).
- The decreased risk of incident autoimmune thyroid disease among RA patients compared with the general population was strongest among patients treated with biologic DMARDs (bDMARD), with an HR of 0.54.
- The reduced incidence of autoimmune thyroid disease with bDMARD use was most pronounced among users of TNF-inhibitors (HR, 0.67).
- The lower incidence of autoimmune thyroid disease following a diagnosis of RA contrasts with previous studies showing an increased risk for thyroid disease associated with RA.
- However, the decreased risk of thyroid disease following bDMARD treatment supports the theory that immunomodulatory treatment could also have an effect of blunting the inflammatory processes that can lead to overt clinical autoimmune thyroid disease.
IN PRACTICE:
“To our knowledge, no previous study has investigated whether the risk of new-onset autoimmune thyroid disease is affected by RA treatment in early RA,” the authors report.
“Our results demonstrate that compared to the general population, patients with RA treated with bDMARDs, TNF-inhibitors in particular, are at decreased risk of developing autoimmune thyroid disease, a finding that calls for replication and may open for drug-repurposing studies,” they note.
SOURCE:
The study was conducted by first author Kristin Waldenlind, PhD, of the Department of Medicine, Solna, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden, and colleagues. It was published online November 27 in the Journal of Internal Medicine.
LIMITATIONS:
The study lacked details on participants’ thyroid autoantibody and hormone levels.
The presence of autoimmune thyroid disease was determined based on prescriptions for thyroxine, hence the authors cannot exclude the possibility of a lower threshold for thyroxine prescription among patients treated with DMARDs.
Information was not available on potential risk factors for RA and autoimmune thyroid disease that might have introduced confounding, such as smoking or obesity.
DISCLOSURES:
The study received funding from the Swedish Research Council, the Swedish Heart Lung Foundation, Vinnova, and Region Stockholm/Karolinska Institutet (ALF). The authors’ disclosures are detailed in the published study.
A version of this article appeared on Medscape.com.
TOPLINE:
Patients with rheumatoid arthritis (RA) in a large Swedish population cohort show a reduced incidence of autoimmune thyroid diseases, such as hypothyroidism or hyperthyroidism, after being diagnosed with RA, with the effect being more pronounced among those treated with disease-modifying anti-rheumatic drugs (DMARDs), particularly TNF-inhibitors.
Although DMARDs are commonly used in the treatment of RA, the drugs are rarely used to treat autoimmune thyroid diseases. The new results support theories raised in previous smaller studies that DMARDs could have a protective effect against thyroid disease.
METHODOLOGY:
- The study involved 13,731 patients with new-onset RA who were listed in the Swedish Rheumatology Quality Register between 2006 and 2018.
- The patients were matched for sex, age, and residential area with up to five reference individuals in the general population of 63,201 comparators.
- Overall, patients with RA were 64.7% female, with a mean age of 59. They were followed up with their matched comparators until the development of autoimmune thyroid disease, death, emigration, or the end of the study period, December 2019.
- The relative risks of autoimmune thyroid disease following a diagnosis of RA and with treatment with DMARDs were compared with those risks in the general population.
- Participants with a non-autoimmune cause for thyroxine prescription were excluded, as were those with an autoimmune thyroid disease at the time of RA diagnosis.
TAKEAWAY:
- Following their RA diagnosis, 321 (2.3%) of patients developed an autoimmune thyroid disease, compared with 1838 (2.9%) in the general population comparators, representing an incidence of 3.7 vs 4.6 per 1000 person-years (hazard ratio [HR], 0.81).
- The lower incidence of autoimmune thyroid disease was more pronounced with longer RA duration. For instance, at 10-14 years after an RA diagnosis, the incidence was 2.9 vs. 4.5 autoimmune thyroid disease events per 1000 person-years, respectively (HR, 0.64).
- The decreased risk of incident autoimmune thyroid disease among RA patients compared with the general population was strongest among patients treated with biologic DMARDs (bDMARD), with an HR of 0.54.
- The reduced incidence of autoimmune thyroid disease with bDMARD use was most pronounced among users of TNF-inhibitors (HR, 0.67).
- The lower incidence of autoimmune thyroid disease following a diagnosis of RA contrasts with previous studies showing an increased risk for thyroid disease associated with RA.
- However, the decreased risk of thyroid disease following bDMARD treatment supports the theory that immunomodulatory treatment could also have an effect of blunting the inflammatory processes that can lead to overt clinical autoimmune thyroid disease.
IN PRACTICE:
“To our knowledge, no previous study has investigated whether the risk of new-onset autoimmune thyroid disease is affected by RA treatment in early RA,” the authors report.
“Our results demonstrate that compared to the general population, patients with RA treated with bDMARDs, TNF-inhibitors in particular, are at decreased risk of developing autoimmune thyroid disease, a finding that calls for replication and may open for drug-repurposing studies,” they note.
SOURCE:
The study was conducted by first author Kristin Waldenlind, PhD, of the Department of Medicine, Solna, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden, and colleagues. It was published online November 27 in the Journal of Internal Medicine.
LIMITATIONS:
The study lacked details on participants’ thyroid autoantibody and hormone levels.
The presence of autoimmune thyroid disease was determined based on prescriptions for thyroxine, hence the authors cannot exclude the possibility of a lower threshold for thyroxine prescription among patients treated with DMARDs.
Information was not available on potential risk factors for RA and autoimmune thyroid disease that might have introduced confounding, such as smoking or obesity.
DISCLOSURES:
The study received funding from the Swedish Research Council, the Swedish Heart Lung Foundation, Vinnova, and Region Stockholm/Karolinska Institutet (ALF). The authors’ disclosures are detailed in the published study.
A version of this article appeared on Medscape.com.
TOPLINE:
Patients with rheumatoid arthritis (RA) in a large Swedish population cohort show a reduced incidence of autoimmune thyroid diseases, such as hypothyroidism or hyperthyroidism, after being diagnosed with RA, with the effect being more pronounced among those treated with disease-modifying anti-rheumatic drugs (DMARDs), particularly TNF-inhibitors.
Although DMARDs are commonly used in the treatment of RA, the drugs are rarely used to treat autoimmune thyroid diseases. The new results support theories raised in previous smaller studies that DMARDs could have a protective effect against thyroid disease.
METHODOLOGY:
- The study involved 13,731 patients with new-onset RA who were listed in the Swedish Rheumatology Quality Register between 2006 and 2018.
- The patients were matched for sex, age, and residential area with up to five reference individuals in the general population of 63,201 comparators.
- Overall, patients with RA were 64.7% female, with a mean age of 59. They were followed up with their matched comparators until the development of autoimmune thyroid disease, death, emigration, or the end of the study period, December 2019.
- The relative risks of autoimmune thyroid disease following a diagnosis of RA and with treatment with DMARDs were compared with those risks in the general population.
- Participants with a non-autoimmune cause for thyroxine prescription were excluded, as were those with an autoimmune thyroid disease at the time of RA diagnosis.
TAKEAWAY:
- Following their RA diagnosis, 321 (2.3%) of patients developed an autoimmune thyroid disease, compared with 1838 (2.9%) in the general population comparators, representing an incidence of 3.7 vs 4.6 per 1000 person-years (hazard ratio [HR], 0.81).
- The lower incidence of autoimmune thyroid disease was more pronounced with longer RA duration. For instance, at 10-14 years after an RA diagnosis, the incidence was 2.9 vs. 4.5 autoimmune thyroid disease events per 1000 person-years, respectively (HR, 0.64).
- The decreased risk of incident autoimmune thyroid disease among RA patients compared with the general population was strongest among patients treated with biologic DMARDs (bDMARD), with an HR of 0.54.
- The reduced incidence of autoimmune thyroid disease with bDMARD use was most pronounced among users of TNF-inhibitors (HR, 0.67).
- The lower incidence of autoimmune thyroid disease following a diagnosis of RA contrasts with previous studies showing an increased risk for thyroid disease associated with RA.
- However, the decreased risk of thyroid disease following bDMARD treatment supports the theory that immunomodulatory treatment could also have an effect of blunting the inflammatory processes that can lead to overt clinical autoimmune thyroid disease.
IN PRACTICE:
“To our knowledge, no previous study has investigated whether the risk of new-onset autoimmune thyroid disease is affected by RA treatment in early RA,” the authors report.
“Our results demonstrate that compared to the general population, patients with RA treated with bDMARDs, TNF-inhibitors in particular, are at decreased risk of developing autoimmune thyroid disease, a finding that calls for replication and may open for drug-repurposing studies,” they note.
SOURCE:
The study was conducted by first author Kristin Waldenlind, PhD, of the Department of Medicine, Solna, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden, and colleagues. It was published online November 27 in the Journal of Internal Medicine.
LIMITATIONS:
The study lacked details on participants’ thyroid autoantibody and hormone levels.
The presence of autoimmune thyroid disease was determined based on prescriptions for thyroxine, hence the authors cannot exclude the possibility of a lower threshold for thyroxine prescription among patients treated with DMARDs.
Information was not available on potential risk factors for RA and autoimmune thyroid disease that might have introduced confounding, such as smoking or obesity.
DISCLOSURES:
The study received funding from the Swedish Research Council, the Swedish Heart Lung Foundation, Vinnova, and Region Stockholm/Karolinska Institutet (ALF). The authors’ disclosures are detailed in the published study.
A version of this article appeared on Medscape.com.