Hematology News

Marstacimab, a novel, investigational monoclonal antibody, shows long-term safety and efficacy in the prevention of bleeding events in patients with hemophilia A as well as B without inhibitors, potentially adding to the toolbox for hemophilia A and representing a first of its kind therapy for hemophilia B.

“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.

“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.

Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.

The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.

If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.

The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.

Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.

Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.

Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.

With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.

In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.

In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.

The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.

The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.

Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.

The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.

The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.

Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.

“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.

Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.

Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”

Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”

Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”

And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”

The marstacimab long-term extension study is designed to extend to 7 years of follow-up.

The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.

Marstacimab, a novel, investigational monoclonal antibody, shows long-term safety and efficacy in the prevention of bleeding events in patients with hemophilia A as well as B without inhibitors, potentially adding to the toolbox for hemophilia A and representing a first of its kind therapy for hemophilia B.

“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.

“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.

Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.

The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.

If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.

The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.

Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.

Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.

Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.

With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.

In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.

In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.

The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.

The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.

Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.

The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.

The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.

Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.

“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.

Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.

Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”

Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”

Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”

And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”

The marstacimab long-term extension study is designed to extend to 7 years of follow-up.

The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.

Marstacimab, a novel, investigational monoclonal antibody, shows long-term safety and efficacy in the prevention of bleeding events in patients with hemophilia A as well as B without inhibitors, potentially adding to the toolbox for hemophilia A and representing a first of its kind therapy for hemophilia B.

“In the long-term extension study treatment with marstacimab demonstrates sustained or improved efficacy for treated and total annualized bleeding rates (ABR) in adults and adolescents with hemophilia A or hemophilia B in this data set of patients without inhibitors,” first author Shamsah Kazani, MD, of Pfizer, Cambridge, Massachusetts, said in presenting the findings at the 2024 annual meeting of the European Hematology Association (EHA) in Madrid.

“The majority of the patients from the pivotal study chose to transition into the long-term extension, and we are finding that these patients are highly compliant with their weekly marstacimab dose, with more than 98% compliance,” Dr. Kazani said.

Marstacimab targets the tissue factor pathway inhibitor, a natural anticoagulation protein that prevents the formation of blood clots, and is administered as a once-weekly subcutaneous injection.

The therapy has been granted fast-track and orphan drug status in the United States, in addition to orphan drug status in the European Union for the prevention of hemophilia bleeding episodes.

If approved, the therapy would become the first once-weekly subcutaneous therapy for either hemophilia A or B. Emicizumab, which also is administered subcutaneously, is only approved to prevent or reduce bleeding in hemophilia A.

The latest findings are from an interim analysis of a long-term extension study involving 107 of 116 patients who were in the non-inhibitor cohort in the pivotal BASIS trial. Data from that trial, involving patients aged 12-75 previously showed favorable outcomes in the non-inhibitor cohort receiving marstacimab, and a cohort of patients with inhibitors is ongoing.

Participants entering the extension study were continuing on 150-mg subcutaneous doses of marstacimab, which had been administered in the BASIS study for 12 months after a loading dose of 300 mg.

Of the patients, 89 (83%) were adult and 18 (17%) were adolescents. Overall, they had a mean age of 29 years; 83 (76%) patients had hemophilia A, while 24 (22.4%) had hemophilia B.

Prior to switching to marstacimab treatment, 32 patients had been treated with factor replacement therapy on demand, while 75 received the therapy as routine prophylaxis.

With a mean additional duration of follow-up of 12.5 months in the extension study (range, 1-23.1 months), the overall rate of compliance was very high, at 98.9%.

In the pivotal and extension studies combined, 21% of patients had their marstacimab dose increased from 150 mg to 300 mg weekly, which was an option if patients had 2 or more spontaneous bleeds in a major joint while on the 150-mg dose.

In the hemophilia A and B groups combined, those previously treated with on-demand factor replacement therapy (n = 33) had substantial reductions in estimated ABR for treated bleeds from the baseline of 38.0 prior to initiating marstacimab, to 3.2 after 12 months of the treatment in the trial (P < .001).That reduction was sustained at an ABR of 3.7 after the mean additional 12.5 months in the extension study.

The corresponding estimated ABR rates in the routine prophylaxis group (n = 83) were 7.9 at baseline, 5.1 at the end of the trial, and 2.8 in the extension study analysis interim cutoff.

The authors then further stratified the results based on hemophilia A or B groups: Among patients with hemophilia A (n = 26), the on-demand subgroup had a baseline ABR of 40.6, which dropped substantially to just 3.6 after 12 months on marstacimab in the pivotal trial and was sustained at 5.3 in the extension study.

Similar trends were observed in the hemophilia A group who received routine prophylaxis (n = 65), with an ABR of 9.2 at baseline; 5.3 after the trial, and 3.1 at the extension study interim.

The trends were similar among those with hemophilia B, albeit with lower numbers of patients, consistent with hemophilia B being more rare.

The mean ABR at baseline in the on-demand group of those patients (n = 7) was 28.7, which was reduced to just 1.7 after the 12-months of active marstacimab treatment and sustained at 1.8 by the interim analysis of the extension study.

Of hemophilia B patients previously on routine prophylaxis (n = 18), the mean ABR at baseline was 3.3 and was at 4.7 at the end of the trial. The rate declined to 2.3 in the extension phase.

“We see that these trends of improvement with marstacimab are sustained into the long-term extension study, both in the on-demand group and in the routine prophylaxis groups,” Dr. Kazani said.

Importantly, she noted that marstacimab continued to be well tolerated and safe in the long-term extension study, with no reports of thromboembolic events, which had been a concern with the drug.

Commenting on the study, Margaret Ragni, MD, MPH, a professor of medicine and clinical and translational research in the Division of Hematology/Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, noted that marstacimab could represent an important addition in the prevention of bleeds in hemophilia. “[If marstacimab is approved], hemophilia B patients [will] have a drug that can be given subcutaneously weekly to rebalance hemostasis, reducing bleeds, just as hemophilia A patients have with emicizumab.”

Dr. Ragni underscored, however, that caveats include the important point that “neither [marstacimab nor emicizumab] treats bleeds. For that, standard factor replacement therapy or bypass for inhibitors, would be required.”

Also, “a limitation with marstacimab is the lack of weight-dependent dosing. All use one dose [however, in the studies they did use 150 mg or 300 mg]. ... Furthermore, emicizumab can be given weekly, biweekly, or monthly, while that [variation in dosing] is not yet studied with marstacimab.”

And while no thromboembolic events occurred during the trial, Dr. Ragni underscored that “longer-term follow-up is needed.”

The marstacimab long-term extension study is designed to extend to 7 years of follow-up.

The study was sponsored by Pfizer, and Dr. Kazani is an employee of Pfizer. Dr. Ragni reported no disclosures.

MONTREAL – Levels of neurofilament light chain (Nfl) may be a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN), new research suggests.

Investigators found Nfl levels increased in cancer patients following a first infusion of the medication paclitaxel and corresponded to neuropathy severity 6-12 months post-treatment, suggesting the blood protein may provide an early CIPN biomarker.

“Nfl after a single cycle could detect axonal degeneration,” said lead investigator Masarra Joda, a researcher and PhD candidate at the University of Sydney in Australia. She added that “quantification of Nfl may provide a clinically useful marker of emerging neurotoxicity in patients vulnerable to CIPN.”

The findings were presented at the Peripheral Nerve Society (PNS) 2024 annual meeting.
 

Common, Burdensome Side Effect

A common side effect of chemotherapy, CIPN manifests as sensory neuropathy and causes degeneration of the peripheral axons. A protein biomarker of axonal degeneration, Nfl has previously been investigated as a way of identifying patients at risk of CIPN.

The goal of the current study was to identify the potential link between Nfl with neurophysiological markers of axon degeneration in patients receiving the neurotoxin chemotherapy paclitaxel.

The study included 93 cancer patients. All were assessed at the beginning, middle, and end of treatment. CIPN was assessed using blood samples of Nfl and the Total Neuropathy Score (TNS), the Common Terminology Criteria for Adverse Events (CTCAE) neuropathy scale, and patient-reported measures using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy Module (EORTC-CIPN20).

Axonal degeneration was measured with neurophysiological tests including sural nerve compound sensory action potential (CSAP) for the lower limbs, and sensory median nerve CSAP, as well as stimulus threshold testing, for the upper limbs. 

Almost all of study participants (97%) were female. The majority (66%) had breast cancer and 30% had gynecological cancer. Most (73%) were receiving a weekly regimen of paclitaxel, and the remainder were treated with taxanes plus platinum once every 3 weeks. By the end of treatment, 82% of the patients had developed CIPN, which was mild in 44% and moderate/severe in 38%. 

Nfl levels increased significantly from baseline to after the first dose of chemotherapy (P < .001), “highlighting that nerve damage occurs from the very beginning of treatment,” senior investigator Susanna Park, PhD, told this news organization. 

In addition, “patients with higher Nfl levels after a single paclitaxel treatment had greater neuropathy at the end of treatment (higher EORTC scores [P ≤ .026], and higher TNS scores [P ≤ .00]),” added Dr. Park, who is associate professor at the University of Sydney.

“Importantly, we also looked at long-term outcomes beyond the end of chemotherapy, because chronic neuropathy produces a significant burden in cancer survivors,” said Dr. Park. 

“Among a total of 44 patients who completed the 6- to 12-month post-treatment follow-up, NfL levels after a single treatment were linked to severity of nerve damage quantified with neurophysiological tests, and greater Nfl levels at mid-treatment were correlated with worse patient and neurologically graded neuropathy at 6-12 months.”

Dr. Park said the results suggest that NfL may provide a biomarker of long-term axon damage and that Nfl assays “may enable clinicians to evaluate the risk of long-term toxicity early during paclitaxel treatment to hopefully provide clinically significant information to guide better treatment titration.” 

Currently, she said, CIPN is a prominent cause of dose reduction and early chemotherapy cessation. 

“For example, in early breast cancer around 25% of patients experience a dose reduction due to the severity of neuropathy symptoms.” But, she said, “there is no standardized way of identifying which patients are at risk of long-term neuropathy and therefore, may benefit more from dose reduction. In this setting, a biomarker such as Nfl could provide oncologists with more information about the risk of long-term toxicity and take that into account in dose decision-making.” 

For some cancers, she added, there are multiple potential therapy options.

“A biomarker such as NfL could assist in determining risk-benefit profile in terms of switching to alternate therapies. However, further studies will be needed to fully define the utility of NfL as a biomarker of paclitaxel neuropathy.” 
 

Promising Research

Commenting on the research for this news organization, Maryam Lustberg, MD, associate professor, director of the Center for Breast Cancer at Smilow Cancer Hospital and Yale Cancer Center, and chief of Breast Medical Oncology at Yale Cancer Center, in New Haven, Connecticut, said the study “builds on a body of work previously reported by others showing that neurofilament light chains as detected in the blood can be associated with early signs of neurotoxic injury.” 

She added that the research “is promising, since existing clinical and patient-reported measures tend to under-detect chemotherapy-induced neuropathy until more permanent injury might have occurred.” 

Dr. Lustberg, who is immediate past president of the Multinational Association of Supportive Care in Cancer, said future studies are needed before Nfl testing can be implemented in routine practice, but that “early detection will allow earlier initiation of supportive care strategies such as physical therapy and exercise, as well as dose modifications, which may be helpful for preventing permanent damage and improving quality of life.” 

The investigators and Dr. Lustberg report no relevant financial relationships.

A version of this article appeared on Medscape.com.

MONTREAL – Levels of neurofilament light chain (Nfl) may be a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN), new research suggests.

Investigators found Nfl levels increased in cancer patients following a first infusion of the medication paclitaxel and corresponded to neuropathy severity 6-12 months post-treatment, suggesting the blood protein may provide an early CIPN biomarker.

“Nfl after a single cycle could detect axonal degeneration,” said lead investigator Masarra Joda, a researcher and PhD candidate at the University of Sydney in Australia. She added that “quantification of Nfl may provide a clinically useful marker of emerging neurotoxicity in patients vulnerable to CIPN.”

The findings were presented at the Peripheral Nerve Society (PNS) 2024 annual meeting.
 

Common, Burdensome Side Effect

A common side effect of chemotherapy, CIPN manifests as sensory neuropathy and causes degeneration of the peripheral axons. A protein biomarker of axonal degeneration, Nfl has previously been investigated as a way of identifying patients at risk of CIPN.

The goal of the current study was to identify the potential link between Nfl with neurophysiological markers of axon degeneration in patients receiving the neurotoxin chemotherapy paclitaxel.

The study included 93 cancer patients. All were assessed at the beginning, middle, and end of treatment. CIPN was assessed using blood samples of Nfl and the Total Neuropathy Score (TNS), the Common Terminology Criteria for Adverse Events (CTCAE) neuropathy scale, and patient-reported measures using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy Module (EORTC-CIPN20).

Axonal degeneration was measured with neurophysiological tests including sural nerve compound sensory action potential (CSAP) for the lower limbs, and sensory median nerve CSAP, as well as stimulus threshold testing, for the upper limbs. 

Almost all of study participants (97%) were female. The majority (66%) had breast cancer and 30% had gynecological cancer. Most (73%) were receiving a weekly regimen of paclitaxel, and the remainder were treated with taxanes plus platinum once every 3 weeks. By the end of treatment, 82% of the patients had developed CIPN, which was mild in 44% and moderate/severe in 38%. 

Nfl levels increased significantly from baseline to after the first dose of chemotherapy (P < .001), “highlighting that nerve damage occurs from the very beginning of treatment,” senior investigator Susanna Park, PhD, told this news organization. 

In addition, “patients with higher Nfl levels after a single paclitaxel treatment had greater neuropathy at the end of treatment (higher EORTC scores [P ≤ .026], and higher TNS scores [P ≤ .00]),” added Dr. Park, who is associate professor at the University of Sydney.

“Importantly, we also looked at long-term outcomes beyond the end of chemotherapy, because chronic neuropathy produces a significant burden in cancer survivors,” said Dr. Park. 

“Among a total of 44 patients who completed the 6- to 12-month post-treatment follow-up, NfL levels after a single treatment were linked to severity of nerve damage quantified with neurophysiological tests, and greater Nfl levels at mid-treatment were correlated with worse patient and neurologically graded neuropathy at 6-12 months.”

Dr. Park said the results suggest that NfL may provide a biomarker of long-term axon damage and that Nfl assays “may enable clinicians to evaluate the risk of long-term toxicity early during paclitaxel treatment to hopefully provide clinically significant information to guide better treatment titration.” 

Currently, she said, CIPN is a prominent cause of dose reduction and early chemotherapy cessation. 

“For example, in early breast cancer around 25% of patients experience a dose reduction due to the severity of neuropathy symptoms.” But, she said, “there is no standardized way of identifying which patients are at risk of long-term neuropathy and therefore, may benefit more from dose reduction. In this setting, a biomarker such as Nfl could provide oncologists with more information about the risk of long-term toxicity and take that into account in dose decision-making.” 

For some cancers, she added, there are multiple potential therapy options.

“A biomarker such as NfL could assist in determining risk-benefit profile in terms of switching to alternate therapies. However, further studies will be needed to fully define the utility of NfL as a biomarker of paclitaxel neuropathy.” 
 

Promising Research

Commenting on the research for this news organization, Maryam Lustberg, MD, associate professor, director of the Center for Breast Cancer at Smilow Cancer Hospital and Yale Cancer Center, and chief of Breast Medical Oncology at Yale Cancer Center, in New Haven, Connecticut, said the study “builds on a body of work previously reported by others showing that neurofilament light chains as detected in the blood can be associated with early signs of neurotoxic injury.” 

She added that the research “is promising, since existing clinical and patient-reported measures tend to under-detect chemotherapy-induced neuropathy until more permanent injury might have occurred.” 

Dr. Lustberg, who is immediate past president of the Multinational Association of Supportive Care in Cancer, said future studies are needed before Nfl testing can be implemented in routine practice, but that “early detection will allow earlier initiation of supportive care strategies such as physical therapy and exercise, as well as dose modifications, which may be helpful for preventing permanent damage and improving quality of life.” 

The investigators and Dr. Lustberg report no relevant financial relationships.

A version of this article appeared on Medscape.com.

MONTREAL – Levels of neurofilament light chain (Nfl) may be a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN), new research suggests.

Investigators found Nfl levels increased in cancer patients following a first infusion of the medication paclitaxel and corresponded to neuropathy severity 6-12 months post-treatment, suggesting the blood protein may provide an early CIPN biomarker.

“Nfl after a single cycle could detect axonal degeneration,” said lead investigator Masarra Joda, a researcher and PhD candidate at the University of Sydney in Australia. She added that “quantification of Nfl may provide a clinically useful marker of emerging neurotoxicity in patients vulnerable to CIPN.”

The findings were presented at the Peripheral Nerve Society (PNS) 2024 annual meeting.
 

Common, Burdensome Side Effect

A common side effect of chemotherapy, CIPN manifests as sensory neuropathy and causes degeneration of the peripheral axons. A protein biomarker of axonal degeneration, Nfl has previously been investigated as a way of identifying patients at risk of CIPN.

The goal of the current study was to identify the potential link between Nfl with neurophysiological markers of axon degeneration in patients receiving the neurotoxin chemotherapy paclitaxel.

The study included 93 cancer patients. All were assessed at the beginning, middle, and end of treatment. CIPN was assessed using blood samples of Nfl and the Total Neuropathy Score (TNS), the Common Terminology Criteria for Adverse Events (CTCAE) neuropathy scale, and patient-reported measures using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy Module (EORTC-CIPN20).

Axonal degeneration was measured with neurophysiological tests including sural nerve compound sensory action potential (CSAP) for the lower limbs, and sensory median nerve CSAP, as well as stimulus threshold testing, for the upper limbs. 

Almost all of study participants (97%) were female. The majority (66%) had breast cancer and 30% had gynecological cancer. Most (73%) were receiving a weekly regimen of paclitaxel, and the remainder were treated with taxanes plus platinum once every 3 weeks. By the end of treatment, 82% of the patients had developed CIPN, which was mild in 44% and moderate/severe in 38%. 

Nfl levels increased significantly from baseline to after the first dose of chemotherapy (P < .001), “highlighting that nerve damage occurs from the very beginning of treatment,” senior investigator Susanna Park, PhD, told this news organization. 

In addition, “patients with higher Nfl levels after a single paclitaxel treatment had greater neuropathy at the end of treatment (higher EORTC scores [P ≤ .026], and higher TNS scores [P ≤ .00]),” added Dr. Park, who is associate professor at the University of Sydney.

“Importantly, we also looked at long-term outcomes beyond the end of chemotherapy, because chronic neuropathy produces a significant burden in cancer survivors,” said Dr. Park. 

“Among a total of 44 patients who completed the 6- to 12-month post-treatment follow-up, NfL levels after a single treatment were linked to severity of nerve damage quantified with neurophysiological tests, and greater Nfl levels at mid-treatment were correlated with worse patient and neurologically graded neuropathy at 6-12 months.”

Dr. Park said the results suggest that NfL may provide a biomarker of long-term axon damage and that Nfl assays “may enable clinicians to evaluate the risk of long-term toxicity early during paclitaxel treatment to hopefully provide clinically significant information to guide better treatment titration.” 

Currently, she said, CIPN is a prominent cause of dose reduction and early chemotherapy cessation. 

“For example, in early breast cancer around 25% of patients experience a dose reduction due to the severity of neuropathy symptoms.” But, she said, “there is no standardized way of identifying which patients are at risk of long-term neuropathy and therefore, may benefit more from dose reduction. In this setting, a biomarker such as Nfl could provide oncologists with more information about the risk of long-term toxicity and take that into account in dose decision-making.” 

For some cancers, she added, there are multiple potential therapy options.

“A biomarker such as NfL could assist in determining risk-benefit profile in terms of switching to alternate therapies. However, further studies will be needed to fully define the utility of NfL as a biomarker of paclitaxel neuropathy.” 
 

Promising Research

Commenting on the research for this news organization, Maryam Lustberg, MD, associate professor, director of the Center for Breast Cancer at Smilow Cancer Hospital and Yale Cancer Center, and chief of Breast Medical Oncology at Yale Cancer Center, in New Haven, Connecticut, said the study “builds on a body of work previously reported by others showing that neurofilament light chains as detected in the blood can be associated with early signs of neurotoxic injury.” 

She added that the research “is promising, since existing clinical and patient-reported measures tend to under-detect chemotherapy-induced neuropathy until more permanent injury might have occurred.” 

Dr. Lustberg, who is immediate past president of the Multinational Association of Supportive Care in Cancer, said future studies are needed before Nfl testing can be implemented in routine practice, but that “early detection will allow earlier initiation of supportive care strategies such as physical therapy and exercise, as well as dose modifications, which may be helpful for preventing permanent damage and improving quality of life.” 

The investigators and Dr. Lustberg report no relevant financial relationships.

A version of this article appeared on Medscape.com.

The Centers for Medicare & Medicaid Services (CMS) has announced the conclusion of a program that provided billions in early Medicare payments to those affected by the Change Healthcare/UnitedHealth Group cyberattack last winter. The Accelerated and Advance Payment program, which began in early March to assist hospitals and practices facing significant reimbursement delays, will stop accepting applications after July 12, 2024.

CMS reported that the program advanced more than $2.55 billion in Medicare payments to > 4200 Part A providers, including hospitals, and more than $717.18 million in payments to Part B suppliers such as physicians, nonphysician practitioners, and durable medical equipment suppliers.

According to CMS, the Medicare billing system is now functioning properly, and 96% of the early payments have been recovered. The advances were to represent ≤ 30 days of typical claims payments in a 3-month period of 2023, with full repayment expected within 90 days through “automatic recoupment from Medicare claims” — no extensions allowed.

The agency took a victory lap regarding its response. “In the face of one of the most widespread cyberattacks on the US health care industry, CMS promptly took action to get providers and suppliers access to the funds they needed to continue providing patients with vital care,” CMS Administrator Chiquita Brooks-LaSure said in a statement. “Our efforts helped minimize the disruptive fallout from this incident, and we will remain vigilant to be ready to address future events.”

Ongoing Concerns from Health Care Organizations

Ben Teicher, an American Hospital Association spokesman, said that the organization hopes that CMS will be responsive if there’s more need for action after the advance payment program expires. The organization represents about 5000 hospitals, health care systems, and other providers.

“Our members report that the aftereffects of this event will likely be felt throughout the remainder of the year,” he said. According to Teicher, hospitals remain concerned about their ability to process claims and appeal denials, the safety of reconnecting to cyber services, and access to information needed to bill patients and reconcile payments.

In addition, hospitals are concerned about “financial support to mitigate the considerable costs incurred as a result of the cyberattack,” he said.

Charlene MacDonald, executive vice-president of public affairs at the Federation of American Hospitals, which represents more than 1000 for-profit hospitals, sent a statement to this news organization that said some providers “are still feeling the effects of care denials and delays caused by insurer inaction.

“We appreciate that the Administration acted within its authority to support providers during this unprecedented crisis and blunt these devastating impacts, especially because a vast majority of managed care companies failed to step up to the plate,” she said. “It is now time to shift our focus to holding plans accountable for using tactics to delay and deny needed patient care.”

Cyberattack Impact and Response

The ransom-based cyberattack against Change Healthcare/UnitedHealth Group targeted an electronic data interchange clearing house processing payer reimbursement systems, disrupting cash flows at hospitals and medical practices, and affecting patient access to prescriptions and life-saving therapy.

Change Healthcare — part of the UnitedHealth Group subsidiary Optum — processes half of all medical claims, according to a Department of Justice lawsuit. The American Hospital Association described the cyberattack as “the most significant and consequential incident of its kind” in US history.

By late March, UnitedHealth Group said nearly all medical and pharmacy claims were processing properly, while a deputy secretary of the US Department of Health & Human Services told clinicians that officials were focusing on the last group of clinicians who were facing cash-flow problems.

Still, a senior advisor with CMS told providers at that time that “we have heard from so many providers over the last several weeks who are really struggling to make ends meet right now or who are worried that they will not be able to make payroll in the weeks to come.”

Randy Dotinga is a freelance health/medical reporter and board member of the Association of Health Care Journalists.

A version of this article appeared on Medscape.com.

The Centers for Medicare & Medicaid Services (CMS) has announced the conclusion of a program that provided billions in early Medicare payments to those affected by the Change Healthcare/UnitedHealth Group cyberattack last winter. The Accelerated and Advance Payment program, which began in early March to assist hospitals and practices facing significant reimbursement delays, will stop accepting applications after July 12, 2024.

CMS reported that the program advanced more than $2.55 billion in Medicare payments to > 4200 Part A providers, including hospitals, and more than $717.18 million in payments to Part B suppliers such as physicians, nonphysician practitioners, and durable medical equipment suppliers.

According to CMS, the Medicare billing system is now functioning properly, and 96% of the early payments have been recovered. The advances were to represent ≤ 30 days of typical claims payments in a 3-month period of 2023, with full repayment expected within 90 days through “automatic recoupment from Medicare claims” — no extensions allowed.

The agency took a victory lap regarding its response. “In the face of one of the most widespread cyberattacks on the US health care industry, CMS promptly took action to get providers and suppliers access to the funds they needed to continue providing patients with vital care,” CMS Administrator Chiquita Brooks-LaSure said in a statement. “Our efforts helped minimize the disruptive fallout from this incident, and we will remain vigilant to be ready to address future events.”

Ongoing Concerns from Health Care Organizations

Ben Teicher, an American Hospital Association spokesman, said that the organization hopes that CMS will be responsive if there’s more need for action after the advance payment program expires. The organization represents about 5000 hospitals, health care systems, and other providers.

“Our members report that the aftereffects of this event will likely be felt throughout the remainder of the year,” he said. According to Teicher, hospitals remain concerned about their ability to process claims and appeal denials, the safety of reconnecting to cyber services, and access to information needed to bill patients and reconcile payments.

In addition, hospitals are concerned about “financial support to mitigate the considerable costs incurred as a result of the cyberattack,” he said.

Charlene MacDonald, executive vice-president of public affairs at the Federation of American Hospitals, which represents more than 1000 for-profit hospitals, sent a statement to this news organization that said some providers “are still feeling the effects of care denials and delays caused by insurer inaction.

“We appreciate that the Administration acted within its authority to support providers during this unprecedented crisis and blunt these devastating impacts, especially because a vast majority of managed care companies failed to step up to the plate,” she said. “It is now time to shift our focus to holding plans accountable for using tactics to delay and deny needed patient care.”

Cyberattack Impact and Response

The ransom-based cyberattack against Change Healthcare/UnitedHealth Group targeted an electronic data interchange clearing house processing payer reimbursement systems, disrupting cash flows at hospitals and medical practices, and affecting patient access to prescriptions and life-saving therapy.

Change Healthcare — part of the UnitedHealth Group subsidiary Optum — processes half of all medical claims, according to a Department of Justice lawsuit. The American Hospital Association described the cyberattack as “the most significant and consequential incident of its kind” in US history.

By late March, UnitedHealth Group said nearly all medical and pharmacy claims were processing properly, while a deputy secretary of the US Department of Health & Human Services told clinicians that officials were focusing on the last group of clinicians who were facing cash-flow problems.

Still, a senior advisor with CMS told providers at that time that “we have heard from so many providers over the last several weeks who are really struggling to make ends meet right now or who are worried that they will not be able to make payroll in the weeks to come.”

Randy Dotinga is a freelance health/medical reporter and board member of the Association of Health Care Journalists.

A version of this article appeared on Medscape.com.

The Centers for Medicare & Medicaid Services (CMS) has announced the conclusion of a program that provided billions in early Medicare payments to those affected by the Change Healthcare/UnitedHealth Group cyberattack last winter. The Accelerated and Advance Payment program, which began in early March to assist hospitals and practices facing significant reimbursement delays, will stop accepting applications after July 12, 2024.

CMS reported that the program advanced more than $2.55 billion in Medicare payments to > 4200 Part A providers, including hospitals, and more than $717.18 million in payments to Part B suppliers such as physicians, nonphysician practitioners, and durable medical equipment suppliers.

According to CMS, the Medicare billing system is now functioning properly, and 96% of the early payments have been recovered. The advances were to represent ≤ 30 days of typical claims payments in a 3-month period of 2023, with full repayment expected within 90 days through “automatic recoupment from Medicare claims” — no extensions allowed.

The agency took a victory lap regarding its response. “In the face of one of the most widespread cyberattacks on the US health care industry, CMS promptly took action to get providers and suppliers access to the funds they needed to continue providing patients with vital care,” CMS Administrator Chiquita Brooks-LaSure said in a statement. “Our efforts helped minimize the disruptive fallout from this incident, and we will remain vigilant to be ready to address future events.”

Ongoing Concerns from Health Care Organizations

Ben Teicher, an American Hospital Association spokesman, said that the organization hopes that CMS will be responsive if there’s more need for action after the advance payment program expires. The organization represents about 5000 hospitals, health care systems, and other providers.

“Our members report that the aftereffects of this event will likely be felt throughout the remainder of the year,” he said. According to Teicher, hospitals remain concerned about their ability to process claims and appeal denials, the safety of reconnecting to cyber services, and access to information needed to bill patients and reconcile payments.

In addition, hospitals are concerned about “financial support to mitigate the considerable costs incurred as a result of the cyberattack,” he said.

Charlene MacDonald, executive vice-president of public affairs at the Federation of American Hospitals, which represents more than 1000 for-profit hospitals, sent a statement to this news organization that said some providers “are still feeling the effects of care denials and delays caused by insurer inaction.

“We appreciate that the Administration acted within its authority to support providers during this unprecedented crisis and blunt these devastating impacts, especially because a vast majority of managed care companies failed to step up to the plate,” she said. “It is now time to shift our focus to holding plans accountable for using tactics to delay and deny needed patient care.”

Cyberattack Impact and Response

The ransom-based cyberattack against Change Healthcare/UnitedHealth Group targeted an electronic data interchange clearing house processing payer reimbursement systems, disrupting cash flows at hospitals and medical practices, and affecting patient access to prescriptions and life-saving therapy.

Change Healthcare — part of the UnitedHealth Group subsidiary Optum — processes half of all medical claims, according to a Department of Justice lawsuit. The American Hospital Association described the cyberattack as “the most significant and consequential incident of its kind” in US history.

By late March, UnitedHealth Group said nearly all medical and pharmacy claims were processing properly, while a deputy secretary of the US Department of Health & Human Services told clinicians that officials were focusing on the last group of clinicians who were facing cash-flow problems.

Still, a senior advisor with CMS told providers at that time that “we have heard from so many providers over the last several weeks who are really struggling to make ends meet right now or who are worried that they will not be able to make payroll in the weeks to come.”

Randy Dotinga is a freelance health/medical reporter and board member of the Association of Health Care Journalists.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Andrew N. Wilner, MD: My guest today is Dr. Jose Merino, editor in chief of the Neurology family of journals and professor of neurology and co-vice chair of education at Georgetown University in Washington, DC.

Our program today is a follow-up of Dr. Merino’s presentation at the recent American Academy of Neurology meeting in Denver, Colorado. Along with two other panelists, Dr. Merino discussed the role of open-access publication and the dangers of predatory journals. 

Jose G. Merino, MD, MPhil: Thank you for having me here. It’s a pleasure.
 

Open Access Defined

Dr. Wilner: I remember when publication in neurology was pretty straightforward. It was either the green journal or the blue journal, but things have certainly changed. I think one topic that is not clear to everyone is this concept of open access. Could you define that for us? 

Dr. Merino: Sure. Open access is a mode of publication that fosters more open or accessible science. The idea of open access is that it combines two main elements. One is that the papers that are published become immediately available to anybody with an internet connection anywhere in the world without any restrictions. 

The second important element from open access, which makes it different from other models we can talk about, is the fact that the authors retain the copyright of their work, but they give the journal and readers a license to use, reproduce, and modify the content.

This is different, for example, from instances where we have funder mandates. For example, NIH papers have to become available 6 months after publication, so they’re available to everybody but not immediately. 

Then copyright is retained, in the case of NIH employees, for example, by the government or by the journals themselves. The two elements of open access, I think, are immediate access to the material and the fact that it’s published with a Creative Commons license. 

Dr. Wilner: I remember that when a journal article was published, say, in Neurology, if you didn’t have a subscription to Neurology, you went to the library that hopefully had a subscription.

If they didn’t have it, you would write to the author and say, “Hey, I heard you have this great paper because the abstract was out there. Could you send me a reprint?” Has that whole universe evaporated? 

Dr. Merino: It depends on how the paper is published. For example, in Neurology, some of the research we publish is open access. Basically, if you have an internet connection, you can access the paper.

That’s the case for papers published in our wholly open-access journals in the Neurology family like Neurology Neuroimmunology & Neuroinflammation, Neurology Genetics, or Neurology Education. 

For other papers that are published in Neurology, not under open access, there is a paywall. For some of them, the paywall comes down after a few months based on funder mandates and so on. As I was mentioning, the NIH-funded papers are available 6 months later. 

In the first 6 months, you may have to go to your library, and if your library has a subscription, you can download it directly. [This is also true for] those that always stay behind the paywall, where you have to have a subscription or your library has to have a subscription.
 

Is Pay to Publish a Red Flag?

Dr. Wilner: I’m a professional writer. With any luck, when I write something, I get paid to write it. There’s been a long tradition in academic medicine that when you submit an article to, say, Neurology, you don’t get paid as an author for the publication. Your reward is the honor of it being published. 

Neurology supports itself in various ways, including advertising and so on. That’s been the contract: free publication for work that merits it, and the journal survives on its own. 

With open access, one of the things that’s happened is that — and I’ve published open access myself — is that I get a notification that I need to pay to have my article that I’ve slaved over published. Explain that, please. 

Dr. Merino: This is the issue with open access. As I mentioned, the paper gets published. You’re giving the journal a license to publish it. You’re retaining the copyright of your work. That means that the journal cannot make money or support itself by just publishing open access because they belong to you. 

Typically, open-access journals are not in print and don’t have much in terms of advertising. The contract is you’re giving me a license to publish it, but it’s your journal, so you’re paying a fee for the journal expenses to basically produce your paper. That’s what’s happening with open access. 

That’s been recognized with many funders, for example, with NIH funding or many of the European funders, they’re including open-access fees as part of their funding for research. Now, of course, this doesn’t help if you’re not a funded researcher or if you’re a fellow who’s doing work and so on. 

Typically, most journals will have waived fees or lower fees for these situations. The reason for the open-access fee is the fact that you’re retaining the copyright. You’re not giving it to the journal who can then use it to generate its revenue for supporting itself, the editorial staff, and so on. 

Dr. Wilner: This idea of charging for publication has created a satellite business of what are called predatory journals. How does one know if the open-access journal that I’m submitting to is really just in the business of wanting my $300 or my $900 to get published? How do I know if that’s a reasonable place to publish? 
 

Predatory Journals

Dr. Merino: That’s a big challenge that has come with this whole idea of open access and the fact that now, many journals are online only, so you’re no longer seeing a physical copy. That has given rise to the predatory journals. 

The predatory journal, by definition, is a journal that claims to be open access. They’ll take your paper and publish it, but they don’t provide all the other services that you would typically expect from the fact that you’re paying an open-access fee. This includes getting appropriate peer review, production of the manuscript, and long-term curation and storage of the manuscript. 

Many predatory journals will take your open-access fee, accept any paper that you submit, regardless of the quality, because they’re charging the fees for that. They don’t send it to real peer review, and then in a few months, the journal disappears so there’s no way for anybody to actually find your paper anymore. 

There are certain checklists. Dr. David Moher at the University of Toronto has produced some work trying to help us identify predatory journals. 

One thing I typically suggest to people who ask me this question is: Have you ever heard of this journal before? Does the journal have a track record? How far back does the story of the journal go? Is it supported by a publisher that you know? Do you know anybody who has published there? Is it something you can easily access?

If in doubt, always ask your friendly medical librarian. There used to be lists that were kept in terms of predatory journals that were being constantly updated, but those had to be shut down. As far as I understand, there were legal issues in terms of how things got on that list. 

I think that overall, if you’ve heard of it, if it’s relevant, if it’s known in your field, and if your librarian knows it, it’s probably a good legitimate open-access journal. There are many very good legitimate open-access journals. 

I mentioned the two that we have in our family, but all the other major journals have their own open-access journal within their family. There are some, like BMC or PLOS, that are completely open-access and legitimate journals. 
 

Impact Factor

Dr. Wilner: What about impact factor? Many journals boast about their impact factor. I’m not sure how to interpret that number. 

Dr. Merino: Impact factor is very interesting. The impact factor was developed by medical librarians to try to identify the journals they should be subscribing to. It’s a measure of the average citations to an average paper in the journal. 

It doesn’t tell you about specific papers. It tells you, on average, how many of the papers in this journal get cited so many times. It’s calculated by the number of articles that were cited divided by the number of articles that were published. Journals that publish many papers, like Neurology, have a hard time bringing up their impact factor beyond a certain level. 

Similarly, very small journals with one or two very highly cited papers have a very high impact factor. It’s being used as a measure, perhaps inappropriately, of how good or how reputable a journal is. We all say we don’t care about journal impact factors, but we all know our journal impact factor and we used to know it to three decimals. Now, they changed the system, and there’s only one decimal point, which makes more sense. 

This is more important, for example, for authors when deciding where to submit papers. I know that in some countries, particularly in Europe, the impact factor of the journal where you publish has an impact on your promotion decisions. 

I would say what’s even more important than the impact factor, is to say, “Well, is this the journal that fits the scope of my paper? Is this the journal that reaches the audience that I want to reach when I write my paper?” 

There are some papers, for example, that are very influential. The impact factor just captures citations. There are some papers that are very influential that may not get cited very often. There may be papers that change clinical practice. 

If you read a paper that tells you that you should be changing how you treat your patients with myasthenia based on this paper, that may not get cited. It’s a very clinically focused paper, but it’s probably more impactful than one that gets cited very much in some respect, or they make it to public policy decisions, and so on. 

I think it’s important to look more at the audience and the journal scope when you submit your papers. 

Dr. Wilner: One other technical question. The journals also say they’re indexed in PubMed or Google Scholar. If I want to publish my paper and I want it indexed where the right people are going to find it, where does it need to be indexed? 

Dr. Merino: I grew up using Index Medicus, MedlinePlus, and the Library of Science. I still do. If I need to find something, I go to PubMed. Ideally, papers are listed in MedlinePlus or can be found in PubMed. They’re not the same thing, but you can find them through them. 

That would be an important thing. Nowadays, a lot more people are using Google Scholar or Google just to identify papers. It may be a little bit less relevant, but it’s still a measure of the quality of the journal before they get indexed in some of these. For example, if you get listed in MedlinePlus, it has gone through certain quality checks by the index itself to see whether they would accept the journal or not. That’s something you want to check.

Typically, most of the large journals or the journals you and I know about are listed in more than one place, right? They’re listed in Scopus and Web of Science. They’re listed in MedlinePlus and so on. Again, if you’re submitting your paper, go somewhere where you know the journal and you’ve heard about it. 

Dr. Wilner: I’m not going to ask you about artificial intelligence. We can do that another time. I want to ask something closer to me, which is this question of publish or perish. 

There seems to be, in academics, more emphasis on the number of papers that one has published rather than their quality. How does a younger academician or one who really needs to publish cope with that? 

Dr. Merino: Many people are writing up research that may not be relevant or that may not be high quality just because you need to have a long list of papers to get promoted, for example, if you’re an academician. 

Doug Altman, who was a very influential person in the field quality of not only medical statistics but also medical publishing, had the idea that we need less research, but we need better research. 

We often receive papers where you say, well, what’s the rationale behind the question in this paper? It’s like they had a large amount of data and were trying to squeeze as much as they could out of that. I think, as a young academician, the important thing to think about is whether it is an important question that matters to you and to the field, from whatever perspective, whether it’s going to advance research, advance clinical care, or have public policy implications. 

Is this one where the answer will be important no matter what the answer is? If you’re thinking of that, your work will be well recognized, people will know you, and you’ll get invited to collaborate. I think that’s the most important thing rather than just churning out a large number of papers. 

The productivity will come from the fact that you start by saying, let me ask something that’s really meaningful to me and to the field, with a good question and using strong research methodology. 

Dr. Wilner: Thanks for that, Dr. Merino. I think that’s very valuable for all of us. This has been a great discussion. Do you have any final comments before we wrap up? 

Dr. Merino: I want to encourage people to continue reading medical journals all the time and submitting to us, again, good research and important questions with robust methodology. That’s what we’re looking for in Neurology and most serious medical journals.
 

Dr. Wilner is an associate professor of neurology at the University of Tennessee Health Science Center, Memphis. Dr. Merino is a professor in the department of neurology at Georgetown University Medical Center, Washington, DC. Dr. Wilner reported conflicts of interest with Accordant Health Services and Lulu Publishing. Dr. Merino reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Andrew N. Wilner, MD: My guest today is Dr. Jose Merino, editor in chief of the Neurology family of journals and professor of neurology and co-vice chair of education at Georgetown University in Washington, DC.

Our program today is a follow-up of Dr. Merino’s presentation at the recent American Academy of Neurology meeting in Denver, Colorado. Along with two other panelists, Dr. Merino discussed the role of open-access publication and the dangers of predatory journals. 

Jose G. Merino, MD, MPhil: Thank you for having me here. It’s a pleasure.
 

Open Access Defined

Dr. Wilner: I remember when publication in neurology was pretty straightforward. It was either the green journal or the blue journal, but things have certainly changed. I think one topic that is not clear to everyone is this concept of open access. Could you define that for us? 

Dr. Merino: Sure. Open access is a mode of publication that fosters more open or accessible science. The idea of open access is that it combines two main elements. One is that the papers that are published become immediately available to anybody with an internet connection anywhere in the world without any restrictions. 

The second important element from open access, which makes it different from other models we can talk about, is the fact that the authors retain the copyright of their work, but they give the journal and readers a license to use, reproduce, and modify the content.

This is different, for example, from instances where we have funder mandates. For example, NIH papers have to become available 6 months after publication, so they’re available to everybody but not immediately. 

Then copyright is retained, in the case of NIH employees, for example, by the government or by the journals themselves. The two elements of open access, I think, are immediate access to the material and the fact that it’s published with a Creative Commons license. 

Dr. Wilner: I remember that when a journal article was published, say, in Neurology, if you didn’t have a subscription to Neurology, you went to the library that hopefully had a subscription.

If they didn’t have it, you would write to the author and say, “Hey, I heard you have this great paper because the abstract was out there. Could you send me a reprint?” Has that whole universe evaporated? 

Dr. Merino: It depends on how the paper is published. For example, in Neurology, some of the research we publish is open access. Basically, if you have an internet connection, you can access the paper.

That’s the case for papers published in our wholly open-access journals in the Neurology family like Neurology Neuroimmunology & Neuroinflammation, Neurology Genetics, or Neurology Education. 

For other papers that are published in Neurology, not under open access, there is a paywall. For some of them, the paywall comes down after a few months based on funder mandates and so on. As I was mentioning, the NIH-funded papers are available 6 months later. 

In the first 6 months, you may have to go to your library, and if your library has a subscription, you can download it directly. [This is also true for] those that always stay behind the paywall, where you have to have a subscription or your library has to have a subscription.
 

Is Pay to Publish a Red Flag?

Dr. Wilner: I’m a professional writer. With any luck, when I write something, I get paid to write it. There’s been a long tradition in academic medicine that when you submit an article to, say, Neurology, you don’t get paid as an author for the publication. Your reward is the honor of it being published. 

Neurology supports itself in various ways, including advertising and so on. That’s been the contract: free publication for work that merits it, and the journal survives on its own. 

With open access, one of the things that’s happened is that — and I’ve published open access myself — is that I get a notification that I need to pay to have my article that I’ve slaved over published. Explain that, please. 

Dr. Merino: This is the issue with open access. As I mentioned, the paper gets published. You’re giving the journal a license to publish it. You’re retaining the copyright of your work. That means that the journal cannot make money or support itself by just publishing open access because they belong to you. 

Typically, open-access journals are not in print and don’t have much in terms of advertising. The contract is you’re giving me a license to publish it, but it’s your journal, so you’re paying a fee for the journal expenses to basically produce your paper. That’s what’s happening with open access. 

That’s been recognized with many funders, for example, with NIH funding or many of the European funders, they’re including open-access fees as part of their funding for research. Now, of course, this doesn’t help if you’re not a funded researcher or if you’re a fellow who’s doing work and so on. 

Typically, most journals will have waived fees or lower fees for these situations. The reason for the open-access fee is the fact that you’re retaining the copyright. You’re not giving it to the journal who can then use it to generate its revenue for supporting itself, the editorial staff, and so on. 

Dr. Wilner: This idea of charging for publication has created a satellite business of what are called predatory journals. How does one know if the open-access journal that I’m submitting to is really just in the business of wanting my $300 or my $900 to get published? How do I know if that’s a reasonable place to publish? 
 

Predatory Journals

Dr. Merino: That’s a big challenge that has come with this whole idea of open access and the fact that now, many journals are online only, so you’re no longer seeing a physical copy. That has given rise to the predatory journals. 

The predatory journal, by definition, is a journal that claims to be open access. They’ll take your paper and publish it, but they don’t provide all the other services that you would typically expect from the fact that you’re paying an open-access fee. This includes getting appropriate peer review, production of the manuscript, and long-term curation and storage of the manuscript. 

Many predatory journals will take your open-access fee, accept any paper that you submit, regardless of the quality, because they’re charging the fees for that. They don’t send it to real peer review, and then in a few months, the journal disappears so there’s no way for anybody to actually find your paper anymore. 

There are certain checklists. Dr. David Moher at the University of Toronto has produced some work trying to help us identify predatory journals. 

One thing I typically suggest to people who ask me this question is: Have you ever heard of this journal before? Does the journal have a track record? How far back does the story of the journal go? Is it supported by a publisher that you know? Do you know anybody who has published there? Is it something you can easily access?

If in doubt, always ask your friendly medical librarian. There used to be lists that were kept in terms of predatory journals that were being constantly updated, but those had to be shut down. As far as I understand, there were legal issues in terms of how things got on that list. 

I think that overall, if you’ve heard of it, if it’s relevant, if it’s known in your field, and if your librarian knows it, it’s probably a good legitimate open-access journal. There are many very good legitimate open-access journals. 

I mentioned the two that we have in our family, but all the other major journals have their own open-access journal within their family. There are some, like BMC or PLOS, that are completely open-access and legitimate journals. 
 

Impact Factor

Dr. Wilner: What about impact factor? Many journals boast about their impact factor. I’m not sure how to interpret that number. 

Dr. Merino: Impact factor is very interesting. The impact factor was developed by medical librarians to try to identify the journals they should be subscribing to. It’s a measure of the average citations to an average paper in the journal. 

It doesn’t tell you about specific papers. It tells you, on average, how many of the papers in this journal get cited so many times. It’s calculated by the number of articles that were cited divided by the number of articles that were published. Journals that publish many papers, like Neurology, have a hard time bringing up their impact factor beyond a certain level. 

Similarly, very small journals with one or two very highly cited papers have a very high impact factor. It’s being used as a measure, perhaps inappropriately, of how good or how reputable a journal is. We all say we don’t care about journal impact factors, but we all know our journal impact factor and we used to know it to three decimals. Now, they changed the system, and there’s only one decimal point, which makes more sense. 

This is more important, for example, for authors when deciding where to submit papers. I know that in some countries, particularly in Europe, the impact factor of the journal where you publish has an impact on your promotion decisions. 

I would say what’s even more important than the impact factor, is to say, “Well, is this the journal that fits the scope of my paper? Is this the journal that reaches the audience that I want to reach when I write my paper?” 

There are some papers, for example, that are very influential. The impact factor just captures citations. There are some papers that are very influential that may not get cited very often. There may be papers that change clinical practice. 

If you read a paper that tells you that you should be changing how you treat your patients with myasthenia based on this paper, that may not get cited. It’s a very clinically focused paper, but it’s probably more impactful than one that gets cited very much in some respect, or they make it to public policy decisions, and so on. 

I think it’s important to look more at the audience and the journal scope when you submit your papers. 

Dr. Wilner: One other technical question. The journals also say they’re indexed in PubMed or Google Scholar. If I want to publish my paper and I want it indexed where the right people are going to find it, where does it need to be indexed? 

Dr. Merino: I grew up using Index Medicus, MedlinePlus, and the Library of Science. I still do. If I need to find something, I go to PubMed. Ideally, papers are listed in MedlinePlus or can be found in PubMed. They’re not the same thing, but you can find them through them. 

That would be an important thing. Nowadays, a lot more people are using Google Scholar or Google just to identify papers. It may be a little bit less relevant, but it’s still a measure of the quality of the journal before they get indexed in some of these. For example, if you get listed in MedlinePlus, it has gone through certain quality checks by the index itself to see whether they would accept the journal or not. That’s something you want to check.

Typically, most of the large journals or the journals you and I know about are listed in more than one place, right? They’re listed in Scopus and Web of Science. They’re listed in MedlinePlus and so on. Again, if you’re submitting your paper, go somewhere where you know the journal and you’ve heard about it. 

Dr. Wilner: I’m not going to ask you about artificial intelligence. We can do that another time. I want to ask something closer to me, which is this question of publish or perish. 

There seems to be, in academics, more emphasis on the number of papers that one has published rather than their quality. How does a younger academician or one who really needs to publish cope with that? 

Dr. Merino: Many people are writing up research that may not be relevant or that may not be high quality just because you need to have a long list of papers to get promoted, for example, if you’re an academician. 

Doug Altman, who was a very influential person in the field quality of not only medical statistics but also medical publishing, had the idea that we need less research, but we need better research. 

We often receive papers where you say, well, what’s the rationale behind the question in this paper? It’s like they had a large amount of data and were trying to squeeze as much as they could out of that. I think, as a young academician, the important thing to think about is whether it is an important question that matters to you and to the field, from whatever perspective, whether it’s going to advance research, advance clinical care, or have public policy implications. 

Is this one where the answer will be important no matter what the answer is? If you’re thinking of that, your work will be well recognized, people will know you, and you’ll get invited to collaborate. I think that’s the most important thing rather than just churning out a large number of papers. 

The productivity will come from the fact that you start by saying, let me ask something that’s really meaningful to me and to the field, with a good question and using strong research methodology. 

Dr. Wilner: Thanks for that, Dr. Merino. I think that’s very valuable for all of us. This has been a great discussion. Do you have any final comments before we wrap up? 

Dr. Merino: I want to encourage people to continue reading medical journals all the time and submitting to us, again, good research and important questions with robust methodology. That’s what we’re looking for in Neurology and most serious medical journals.
 

Dr. Wilner is an associate professor of neurology at the University of Tennessee Health Science Center, Memphis. Dr. Merino is a professor in the department of neurology at Georgetown University Medical Center, Washington, DC. Dr. Wilner reported conflicts of interest with Accordant Health Services and Lulu Publishing. Dr. Merino reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Andrew N. Wilner, MD: My guest today is Dr. Jose Merino, editor in chief of the Neurology family of journals and professor of neurology and co-vice chair of education at Georgetown University in Washington, DC.

Our program today is a follow-up of Dr. Merino’s presentation at the recent American Academy of Neurology meeting in Denver, Colorado. Along with two other panelists, Dr. Merino discussed the role of open-access publication and the dangers of predatory journals. 

Jose G. Merino, MD, MPhil: Thank you for having me here. It’s a pleasure.
 

Open Access Defined

Dr. Wilner: I remember when publication in neurology was pretty straightforward. It was either the green journal or the blue journal, but things have certainly changed. I think one topic that is not clear to everyone is this concept of open access. Could you define that for us? 

Dr. Merino: Sure. Open access is a mode of publication that fosters more open or accessible science. The idea of open access is that it combines two main elements. One is that the papers that are published become immediately available to anybody with an internet connection anywhere in the world without any restrictions. 

The second important element from open access, which makes it different from other models we can talk about, is the fact that the authors retain the copyright of their work, but they give the journal and readers a license to use, reproduce, and modify the content.

This is different, for example, from instances where we have funder mandates. For example, NIH papers have to become available 6 months after publication, so they’re available to everybody but not immediately. 

Then copyright is retained, in the case of NIH employees, for example, by the government or by the journals themselves. The two elements of open access, I think, are immediate access to the material and the fact that it’s published with a Creative Commons license. 

Dr. Wilner: I remember that when a journal article was published, say, in Neurology, if you didn’t have a subscription to Neurology, you went to the library that hopefully had a subscription.

If they didn’t have it, you would write to the author and say, “Hey, I heard you have this great paper because the abstract was out there. Could you send me a reprint?” Has that whole universe evaporated? 

Dr. Merino: It depends on how the paper is published. For example, in Neurology, some of the research we publish is open access. Basically, if you have an internet connection, you can access the paper.

That’s the case for papers published in our wholly open-access journals in the Neurology family like Neurology Neuroimmunology & Neuroinflammation, Neurology Genetics, or Neurology Education. 

For other papers that are published in Neurology, not under open access, there is a paywall. For some of them, the paywall comes down after a few months based on funder mandates and so on. As I was mentioning, the NIH-funded papers are available 6 months later. 

In the first 6 months, you may have to go to your library, and if your library has a subscription, you can download it directly. [This is also true for] those that always stay behind the paywall, where you have to have a subscription or your library has to have a subscription.
 

Is Pay to Publish a Red Flag?

Dr. Wilner: I’m a professional writer. With any luck, when I write something, I get paid to write it. There’s been a long tradition in academic medicine that when you submit an article to, say, Neurology, you don’t get paid as an author for the publication. Your reward is the honor of it being published. 

Neurology supports itself in various ways, including advertising and so on. That’s been the contract: free publication for work that merits it, and the journal survives on its own. 

With open access, one of the things that’s happened is that — and I’ve published open access myself — is that I get a notification that I need to pay to have my article that I’ve slaved over published. Explain that, please. 

Dr. Merino: This is the issue with open access. As I mentioned, the paper gets published. You’re giving the journal a license to publish it. You’re retaining the copyright of your work. That means that the journal cannot make money or support itself by just publishing open access because they belong to you. 

Typically, open-access journals are not in print and don’t have much in terms of advertising. The contract is you’re giving me a license to publish it, but it’s your journal, so you’re paying a fee for the journal expenses to basically produce your paper. That’s what’s happening with open access. 

That’s been recognized with many funders, for example, with NIH funding or many of the European funders, they’re including open-access fees as part of their funding for research. Now, of course, this doesn’t help if you’re not a funded researcher or if you’re a fellow who’s doing work and so on. 

Typically, most journals will have waived fees or lower fees for these situations. The reason for the open-access fee is the fact that you’re retaining the copyright. You’re not giving it to the journal who can then use it to generate its revenue for supporting itself, the editorial staff, and so on. 

Dr. Wilner: This idea of charging for publication has created a satellite business of what are called predatory journals. How does one know if the open-access journal that I’m submitting to is really just in the business of wanting my $300 or my $900 to get published? How do I know if that’s a reasonable place to publish? 
 

Predatory Journals

Dr. Merino: That’s a big challenge that has come with this whole idea of open access and the fact that now, many journals are online only, so you’re no longer seeing a physical copy. That has given rise to the predatory journals. 

The predatory journal, by definition, is a journal that claims to be open access. They’ll take your paper and publish it, but they don’t provide all the other services that you would typically expect from the fact that you’re paying an open-access fee. This includes getting appropriate peer review, production of the manuscript, and long-term curation and storage of the manuscript. 

Many predatory journals will take your open-access fee, accept any paper that you submit, regardless of the quality, because they’re charging the fees for that. They don’t send it to real peer review, and then in a few months, the journal disappears so there’s no way for anybody to actually find your paper anymore. 

There are certain checklists. Dr. David Moher at the University of Toronto has produced some work trying to help us identify predatory journals. 

One thing I typically suggest to people who ask me this question is: Have you ever heard of this journal before? Does the journal have a track record? How far back does the story of the journal go? Is it supported by a publisher that you know? Do you know anybody who has published there? Is it something you can easily access?

If in doubt, always ask your friendly medical librarian. There used to be lists that were kept in terms of predatory journals that were being constantly updated, but those had to be shut down. As far as I understand, there were legal issues in terms of how things got on that list. 

I think that overall, if you’ve heard of it, if it’s relevant, if it’s known in your field, and if your librarian knows it, it’s probably a good legitimate open-access journal. There are many very good legitimate open-access journals. 

I mentioned the two that we have in our family, but all the other major journals have their own open-access journal within their family. There are some, like BMC or PLOS, that are completely open-access and legitimate journals. 
 

Impact Factor

Dr. Wilner: What about impact factor? Many journals boast about their impact factor. I’m not sure how to interpret that number. 

Dr. Merino: Impact factor is very interesting. The impact factor was developed by medical librarians to try to identify the journals they should be subscribing to. It’s a measure of the average citations to an average paper in the journal. 

It doesn’t tell you about specific papers. It tells you, on average, how many of the papers in this journal get cited so many times. It’s calculated by the number of articles that were cited divided by the number of articles that were published. Journals that publish many papers, like Neurology, have a hard time bringing up their impact factor beyond a certain level. 

Similarly, very small journals with one or two very highly cited papers have a very high impact factor. It’s being used as a measure, perhaps inappropriately, of how good or how reputable a journal is. We all say we don’t care about journal impact factors, but we all know our journal impact factor and we used to know it to three decimals. Now, they changed the system, and there’s only one decimal point, which makes more sense. 

This is more important, for example, for authors when deciding where to submit papers. I know that in some countries, particularly in Europe, the impact factor of the journal where you publish has an impact on your promotion decisions. 

I would say what’s even more important than the impact factor, is to say, “Well, is this the journal that fits the scope of my paper? Is this the journal that reaches the audience that I want to reach when I write my paper?” 

There are some papers, for example, that are very influential. The impact factor just captures citations. There are some papers that are very influential that may not get cited very often. There may be papers that change clinical practice. 

If you read a paper that tells you that you should be changing how you treat your patients with myasthenia based on this paper, that may not get cited. It’s a very clinically focused paper, but it’s probably more impactful than one that gets cited very much in some respect, or they make it to public policy decisions, and so on. 

I think it’s important to look more at the audience and the journal scope when you submit your papers. 

Dr. Wilner: One other technical question. The journals also say they’re indexed in PubMed or Google Scholar. If I want to publish my paper and I want it indexed where the right people are going to find it, where does it need to be indexed? 

Dr. Merino: I grew up using Index Medicus, MedlinePlus, and the Library of Science. I still do. If I need to find something, I go to PubMed. Ideally, papers are listed in MedlinePlus or can be found in PubMed. They’re not the same thing, but you can find them through them. 

That would be an important thing. Nowadays, a lot more people are using Google Scholar or Google just to identify papers. It may be a little bit less relevant, but it’s still a measure of the quality of the journal before they get indexed in some of these. For example, if you get listed in MedlinePlus, it has gone through certain quality checks by the index itself to see whether they would accept the journal or not. That’s something you want to check.

Typically, most of the large journals or the journals you and I know about are listed in more than one place, right? They’re listed in Scopus and Web of Science. They’re listed in MedlinePlus and so on. Again, if you’re submitting your paper, go somewhere where you know the journal and you’ve heard about it. 

Dr. Wilner: I’m not going to ask you about artificial intelligence. We can do that another time. I want to ask something closer to me, which is this question of publish or perish. 

There seems to be, in academics, more emphasis on the number of papers that one has published rather than their quality. How does a younger academician or one who really needs to publish cope with that? 

Dr. Merino: Many people are writing up research that may not be relevant or that may not be high quality just because you need to have a long list of papers to get promoted, for example, if you’re an academician. 

Doug Altman, who was a very influential person in the field quality of not only medical statistics but also medical publishing, had the idea that we need less research, but we need better research. 

We often receive papers where you say, well, what’s the rationale behind the question in this paper? It’s like they had a large amount of data and were trying to squeeze as much as they could out of that. I think, as a young academician, the important thing to think about is whether it is an important question that matters to you and to the field, from whatever perspective, whether it’s going to advance research, advance clinical care, or have public policy implications. 

Is this one where the answer will be important no matter what the answer is? If you’re thinking of that, your work will be well recognized, people will know you, and you’ll get invited to collaborate. I think that’s the most important thing rather than just churning out a large number of papers. 

The productivity will come from the fact that you start by saying, let me ask something that’s really meaningful to me and to the field, with a good question and using strong research methodology. 

Dr. Wilner: Thanks for that, Dr. Merino. I think that’s very valuable for all of us. This has been a great discussion. Do you have any final comments before we wrap up? 

Dr. Merino: I want to encourage people to continue reading medical journals all the time and submitting to us, again, good research and important questions with robust methodology. That’s what we’re looking for in Neurology and most serious medical journals.
 

Dr. Wilner is an associate professor of neurology at the University of Tennessee Health Science Center, Memphis. Dr. Merino is a professor in the department of neurology at Georgetown University Medical Center, Washington, DC. Dr. Wilner reported conflicts of interest with Accordant Health Services and Lulu Publishing. Dr. Merino reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

When he completed his fellowship at Fox Chase Cancer Center in Philadelphia, Moshe Chasky, MD, joined a small five-person practice that rented space from the city’s Jefferson Hospital in Philadelphia. The arrangement seemed to work well for the hospital and the small practice, which remained independent.

Within 10 years, the hospital sought to buy the practice, Alliance Cancer Specialists.

But the oncologists at Alliance did not want to join Jefferson.

The hospital eventually entered into an exclusive agreement with its own medical group to provide inpatient oncology/hematology services at three Jefferson Health–Northeast hospitals and stripped Dr. Chasky and his colleagues of their privileges at those facilities, Medscape Medical News reported last year.

The Alliance story is a familiar one for independent community oncology practices, said Jeff Patton, MD, CEO of OneOncology, a management services organization.

A 2020 report from the Community Oncology Alliance (COA), for instance, tracked mergers, acquisitions, and closures in the community oncology setting and found the number of practices acquired by hospitals, known as vertical integration, nearly tripled from 2010 to 2020.

“Some hospitals are pretty predatory in their approach,” Dr. Patton said. If hospitals have their own oncology program, “they’ll employ the referring doctors and then discourage them or prevent them from referring patients to our independent practices that are not owned by the hospital.”

Still, in the face of growing pressure to join hospitals, some community oncology practices are finding ways to survive and maintain their independence.
 

A Growing Trend

The latest data continue to show a clear trend: Consolidation in oncology is on the rise.

A 2024 study revealed that the pace of consolidation seems to be increasing.

The analysis found that, between 2015 and 2022, the number of medical oncologists increased by 14% and the number of medical oncologists per practice increased by 40%, while the number of practices decreased by 18%.

While about 44% of practices remain independent, the percentage of medical oncologists working in practices with more than 25 clinicians has increased from 34% in 2015 to 44% in 2022. By 2022, the largest 102 practices in the United States employed more than 40% of all medical oncologists.

“The rate of consolidation seems to be rapid,” study coauthor Parsa Erfani, MD, an internal medicine resident at Brigham & Women’s Hospital, Boston, explained.

Consolidation appears to breed more consolidation. The researchers found, for instance, that markets with greater hospital consolidation and more hospital beds per capita were more likely to undergo consolidation in oncology.

Consolidation may be higher in these markets “because hospitals or health systems are buying up oncology practices or conversely because oncology practices are merging to compete more effectively with larger hospitals in the area,” Dr. Erfani told this news organization.

Mergers among independent practices, known as horizontal integration, have also been on the rise, according to the 2020 COA report. These mergers can help counter pressures from hospitals seeking to acquire community practices as well as prevent practices and their clinics from closing.

Although Dr. Erfani’s research wasn’t designed to determine the factors behind consolidation, he and his colleagues point to the Affordable Care Act (ACA) and the federal 340B Drug Pricing Program as potential drivers of this trend.

The ACA encouraged consolidation as a way to improve efficiency and created the need for ever-larger information systems to collect and report quality data. But these data collection and reporting requirements have become increasingly difficult for smaller practices to take on.

The 340B Program, however, may be a bigger contributing factor to consolidation. Created in 1992, the 340B Program allows qualifying hospitals and clinics that treat low-income and uninsured patients to buy outpatient prescription drugs at a 25%-50% discount.

Hospitals seeking to capitalize on the margins possible under the 340B Program will “buy all the referring physicians in a market so that the medical oncology group is left with little choice but to sell to the hospital,” said Dr. Patton.

“Those 340B dollars are worth a lot to hospitals,” said David A. Eagle, MD, a hematologist/oncologist with New York Cancer & Blood Specialists and past president of COA. The program “creates an appetite for nonprofit hospitals to want to grow their medical oncology programs,” he told this news organization.

Declining Medicare reimbursement has also hit independent practices hard.

Over the past 15 years, compared with inflation, physicians have gotten “a pay rate decrease from Medicare,” said Dr. Patton. Payers have followed that lead and tried to cut pay for clinicians, especially those who do not have market share, he said. Paying them less is “disingenuous knowing that our costs of providing care are going up,” he said.
 

Less Access, Higher Costs, Worse Care?

Many studies have demonstrated that, when hospitals become behemoths in a given market, healthcare costs go up.

“There are robust data showing that consolidation increases healthcare costs by reducing competition, including in oncology,” wrote Dr. Erfani and colleagues.

Oncology practices that are owned by hospitals bill facility fees for outpatient chemotherapy treatment, adding another layer of cost, the researchers explained, citing a 2019 Health Economics study.

Another analysis, published in 2020, found that hospital prices for the top 37 infused cancer drugs averaged 86% more per unit than the price charged by physician offices. Hospital outpatient departments charged even more, on average, for drugs — 128% more for nivolumab and 428% more for fluorouracil, for instance.

In their 2024 analysis, Dr. Erfani and colleagues also found that increased hospital market concentration was associated with worse quality of care, across all assessed patient satisfaction measures, and may result in worse access to care as well.

Overall, these consolidation “trends have important implications for cancer care cost, quality, and access,” the authors concluded.
 

Navigating the Consolidation Trend

In the face of mounting pressure to join hospitals, community oncology practices have typically relied on horizontal mergers to maintain their independence. An increasing number of practices, however, are now turning to another strategy: Management services organizations.

According to some oncologists, a core benefit of joining a management services organization is their community practices can maintain autonomy, hold on to referrals, and benefit from access to a wider network of peers and recently approved treatments such as chimeric antigen receptor T-cell therapies.

In these arrangements, the management company also provides business assistance to practices, including help with billing and collection, payer negotiations, supply chain issues, and credentialing, as well as recruiting, hiring, and marketing.

These management organizations, which include American Oncology Network, Integrated Oncology Network, OneOncology, and Verdi Oncology, are, however, backed by private equity. According to a 2022 report, private equity–backed management organizations have ramped up arrangements with community oncology practices over the past few years — a trend that has concerned some experts.

The authors of a recent analysis in JAMA Internal Medicine explained that, although private equity involvement in physician practices may enable operational efficiencies, “critics point to potential conflicts of interest” and highlight concerns that patients “may face additional barriers to both accessibility and affordability of care.”

The difference, according to some oncologists, is their practices are not owned by the management services organization; instead, the practices enter contracts that outline the boundaries of the relationship and stipulate fees to the management organizations.

In 2020, Dr. Chasky’s practice, Alliance Cancer Specialists, joined The US Oncology Network, a management services organization wholly owned by McKesson. The organization provides the practice with capital and other resources, as well as access to the Sarah Cannon Research Institute, so patients can participate in clinical trials.

“We totally function as an independent practice,” said Dr. Chasky. “We make our own management decisions,” he said. For instance, if Alliance wants to hire a new clinician, US Oncology helps with the recruitment. “But at the end of the day, it’s our practice,” he said.

Davey Daniel, MD — whose community practice joined the management services organization OneOncology — has seen the benefits of being part of a larger network. For instance, bispecific therapies for leukemias, lymphomas, and multiple myeloma are typically administered at academic centers because of the risk for cytokine release syndrome.

However, physician leaders in the OneOncology network “came up with a playbook on how to do it safely” in the community setting, said Dr. Daniel. “It meant that we were adopting FDA newly approved therapies in a very short course.”

Being able to draw from a wider pool of expertise has had other advantages. Dr. Daniel can lean on pathologists and research scientists in the network for advice on targeted therapy use. “We’re actually bringing precision medicine expertise to the community,” Dr. Daniel said.

Dr. Chasky and Dr. Eagle, whose practice is also part of OneOncology, said that continuing to work in the community setting has allowed them greater flexibility.

Dr. Eagle explained that New York Cancer & Blood Specialists tries to offer patients an appointment within 2 days of a referral, and it allows walk-in visits.

Dr. Chasky leans into the flexibility by having staff stay late, when needed, to ensure that all patients are seen. “We’re there for our patients at all hours,” Dr. Chasky said, adding that often “you don’t have that flexibility when you work for a big hospital system.”

The bottom line is community oncology can still thrive, said Nick Ferreyros, managing director of COA, “as long as we have a healthy competitive ecosystem where [we] are valued and seen as an important part of our cancer care system.”

A version of this article first appeared on Medscape.com.

When he completed his fellowship at Fox Chase Cancer Center in Philadelphia, Moshe Chasky, MD, joined a small five-person practice that rented space from the city’s Jefferson Hospital in Philadelphia. The arrangement seemed to work well for the hospital and the small practice, which remained independent.

Within 10 years, the hospital sought to buy the practice, Alliance Cancer Specialists.

But the oncologists at Alliance did not want to join Jefferson.

The hospital eventually entered into an exclusive agreement with its own medical group to provide inpatient oncology/hematology services at three Jefferson Health–Northeast hospitals and stripped Dr. Chasky and his colleagues of their privileges at those facilities, Medscape Medical News reported last year.

The Alliance story is a familiar one for independent community oncology practices, said Jeff Patton, MD, CEO of OneOncology, a management services organization.

A 2020 report from the Community Oncology Alliance (COA), for instance, tracked mergers, acquisitions, and closures in the community oncology setting and found the number of practices acquired by hospitals, known as vertical integration, nearly tripled from 2010 to 2020.

“Some hospitals are pretty predatory in their approach,” Dr. Patton said. If hospitals have their own oncology program, “they’ll employ the referring doctors and then discourage them or prevent them from referring patients to our independent practices that are not owned by the hospital.”

Still, in the face of growing pressure to join hospitals, some community oncology practices are finding ways to survive and maintain their independence.
 

A Growing Trend

The latest data continue to show a clear trend: Consolidation in oncology is on the rise.

A 2024 study revealed that the pace of consolidation seems to be increasing.

The analysis found that, between 2015 and 2022, the number of medical oncologists increased by 14% and the number of medical oncologists per practice increased by 40%, while the number of practices decreased by 18%.

While about 44% of practices remain independent, the percentage of medical oncologists working in practices with more than 25 clinicians has increased from 34% in 2015 to 44% in 2022. By 2022, the largest 102 practices in the United States employed more than 40% of all medical oncologists.

“The rate of consolidation seems to be rapid,” study coauthor Parsa Erfani, MD, an internal medicine resident at Brigham & Women’s Hospital, Boston, explained.

Consolidation appears to breed more consolidation. The researchers found, for instance, that markets with greater hospital consolidation and more hospital beds per capita were more likely to undergo consolidation in oncology.

Consolidation may be higher in these markets “because hospitals or health systems are buying up oncology practices or conversely because oncology practices are merging to compete more effectively with larger hospitals in the area,” Dr. Erfani told this news organization.

Mergers among independent practices, known as horizontal integration, have also been on the rise, according to the 2020 COA report. These mergers can help counter pressures from hospitals seeking to acquire community practices as well as prevent practices and their clinics from closing.

Although Dr. Erfani’s research wasn’t designed to determine the factors behind consolidation, he and his colleagues point to the Affordable Care Act (ACA) and the federal 340B Drug Pricing Program as potential drivers of this trend.

The ACA encouraged consolidation as a way to improve efficiency and created the need for ever-larger information systems to collect and report quality data. But these data collection and reporting requirements have become increasingly difficult for smaller practices to take on.

The 340B Program, however, may be a bigger contributing factor to consolidation. Created in 1992, the 340B Program allows qualifying hospitals and clinics that treat low-income and uninsured patients to buy outpatient prescription drugs at a 25%-50% discount.

Hospitals seeking to capitalize on the margins possible under the 340B Program will “buy all the referring physicians in a market so that the medical oncology group is left with little choice but to sell to the hospital,” said Dr. Patton.

“Those 340B dollars are worth a lot to hospitals,” said David A. Eagle, MD, a hematologist/oncologist with New York Cancer & Blood Specialists and past president of COA. The program “creates an appetite for nonprofit hospitals to want to grow their medical oncology programs,” he told this news organization.

Declining Medicare reimbursement has also hit independent practices hard.

Over the past 15 years, compared with inflation, physicians have gotten “a pay rate decrease from Medicare,” said Dr. Patton. Payers have followed that lead and tried to cut pay for clinicians, especially those who do not have market share, he said. Paying them less is “disingenuous knowing that our costs of providing care are going up,” he said.
 

Less Access, Higher Costs, Worse Care?

Many studies have demonstrated that, when hospitals become behemoths in a given market, healthcare costs go up.

“There are robust data showing that consolidation increases healthcare costs by reducing competition, including in oncology,” wrote Dr. Erfani and colleagues.

Oncology practices that are owned by hospitals bill facility fees for outpatient chemotherapy treatment, adding another layer of cost, the researchers explained, citing a 2019 Health Economics study.

Another analysis, published in 2020, found that hospital prices for the top 37 infused cancer drugs averaged 86% more per unit than the price charged by physician offices. Hospital outpatient departments charged even more, on average, for drugs — 128% more for nivolumab and 428% more for fluorouracil, for instance.

In their 2024 analysis, Dr. Erfani and colleagues also found that increased hospital market concentration was associated with worse quality of care, across all assessed patient satisfaction measures, and may result in worse access to care as well.

Overall, these consolidation “trends have important implications for cancer care cost, quality, and access,” the authors concluded.
 

Navigating the Consolidation Trend

In the face of mounting pressure to join hospitals, community oncology practices have typically relied on horizontal mergers to maintain their independence. An increasing number of practices, however, are now turning to another strategy: Management services organizations.

According to some oncologists, a core benefit of joining a management services organization is their community practices can maintain autonomy, hold on to referrals, and benefit from access to a wider network of peers and recently approved treatments such as chimeric antigen receptor T-cell therapies.

In these arrangements, the management company also provides business assistance to practices, including help with billing and collection, payer negotiations, supply chain issues, and credentialing, as well as recruiting, hiring, and marketing.

These management organizations, which include American Oncology Network, Integrated Oncology Network, OneOncology, and Verdi Oncology, are, however, backed by private equity. According to a 2022 report, private equity–backed management organizations have ramped up arrangements with community oncology practices over the past few years — a trend that has concerned some experts.

The authors of a recent analysis in JAMA Internal Medicine explained that, although private equity involvement in physician practices may enable operational efficiencies, “critics point to potential conflicts of interest” and highlight concerns that patients “may face additional barriers to both accessibility and affordability of care.”

The difference, according to some oncologists, is their practices are not owned by the management services organization; instead, the practices enter contracts that outline the boundaries of the relationship and stipulate fees to the management organizations.

In 2020, Dr. Chasky’s practice, Alliance Cancer Specialists, joined The US Oncology Network, a management services organization wholly owned by McKesson. The organization provides the practice with capital and other resources, as well as access to the Sarah Cannon Research Institute, so patients can participate in clinical trials.

“We totally function as an independent practice,” said Dr. Chasky. “We make our own management decisions,” he said. For instance, if Alliance wants to hire a new clinician, US Oncology helps with the recruitment. “But at the end of the day, it’s our practice,” he said.

Davey Daniel, MD — whose community practice joined the management services organization OneOncology — has seen the benefits of being part of a larger network. For instance, bispecific therapies for leukemias, lymphomas, and multiple myeloma are typically administered at academic centers because of the risk for cytokine release syndrome.

However, physician leaders in the OneOncology network “came up with a playbook on how to do it safely” in the community setting, said Dr. Daniel. “It meant that we were adopting FDA newly approved therapies in a very short course.”

Being able to draw from a wider pool of expertise has had other advantages. Dr. Daniel can lean on pathologists and research scientists in the network for advice on targeted therapy use. “We’re actually bringing precision medicine expertise to the community,” Dr. Daniel said.

Dr. Chasky and Dr. Eagle, whose practice is also part of OneOncology, said that continuing to work in the community setting has allowed them greater flexibility.

Dr. Eagle explained that New York Cancer & Blood Specialists tries to offer patients an appointment within 2 days of a referral, and it allows walk-in visits.

Dr. Chasky leans into the flexibility by having staff stay late, when needed, to ensure that all patients are seen. “We’re there for our patients at all hours,” Dr. Chasky said, adding that often “you don’t have that flexibility when you work for a big hospital system.”

The bottom line is community oncology can still thrive, said Nick Ferreyros, managing director of COA, “as long as we have a healthy competitive ecosystem where [we] are valued and seen as an important part of our cancer care system.”

A version of this article first appeared on Medscape.com.

When he completed his fellowship at Fox Chase Cancer Center in Philadelphia, Moshe Chasky, MD, joined a small five-person practice that rented space from the city’s Jefferson Hospital in Philadelphia. The arrangement seemed to work well for the hospital and the small practice, which remained independent.

Within 10 years, the hospital sought to buy the practice, Alliance Cancer Specialists.

But the oncologists at Alliance did not want to join Jefferson.

The hospital eventually entered into an exclusive agreement with its own medical group to provide inpatient oncology/hematology services at three Jefferson Health–Northeast hospitals and stripped Dr. Chasky and his colleagues of their privileges at those facilities, Medscape Medical News reported last year.

The Alliance story is a familiar one for independent community oncology practices, said Jeff Patton, MD, CEO of OneOncology, a management services organization.

A 2020 report from the Community Oncology Alliance (COA), for instance, tracked mergers, acquisitions, and closures in the community oncology setting and found the number of practices acquired by hospitals, known as vertical integration, nearly tripled from 2010 to 2020.

“Some hospitals are pretty predatory in their approach,” Dr. Patton said. If hospitals have their own oncology program, “they’ll employ the referring doctors and then discourage them or prevent them from referring patients to our independent practices that are not owned by the hospital.”

Still, in the face of growing pressure to join hospitals, some community oncology practices are finding ways to survive and maintain their independence.
 

A Growing Trend

The latest data continue to show a clear trend: Consolidation in oncology is on the rise.

A 2024 study revealed that the pace of consolidation seems to be increasing.

The analysis found that, between 2015 and 2022, the number of medical oncologists increased by 14% and the number of medical oncologists per practice increased by 40%, while the number of practices decreased by 18%.

While about 44% of practices remain independent, the percentage of medical oncologists working in practices with more than 25 clinicians has increased from 34% in 2015 to 44% in 2022. By 2022, the largest 102 practices in the United States employed more than 40% of all medical oncologists.

“The rate of consolidation seems to be rapid,” study coauthor Parsa Erfani, MD, an internal medicine resident at Brigham & Women’s Hospital, Boston, explained.

Consolidation appears to breed more consolidation. The researchers found, for instance, that markets with greater hospital consolidation and more hospital beds per capita were more likely to undergo consolidation in oncology.

Consolidation may be higher in these markets “because hospitals or health systems are buying up oncology practices or conversely because oncology practices are merging to compete more effectively with larger hospitals in the area,” Dr. Erfani told this news organization.

Mergers among independent practices, known as horizontal integration, have also been on the rise, according to the 2020 COA report. These mergers can help counter pressures from hospitals seeking to acquire community practices as well as prevent practices and their clinics from closing.

Although Dr. Erfani’s research wasn’t designed to determine the factors behind consolidation, he and his colleagues point to the Affordable Care Act (ACA) and the federal 340B Drug Pricing Program as potential drivers of this trend.

The ACA encouraged consolidation as a way to improve efficiency and created the need for ever-larger information systems to collect and report quality data. But these data collection and reporting requirements have become increasingly difficult for smaller practices to take on.

The 340B Program, however, may be a bigger contributing factor to consolidation. Created in 1992, the 340B Program allows qualifying hospitals and clinics that treat low-income and uninsured patients to buy outpatient prescription drugs at a 25%-50% discount.

Hospitals seeking to capitalize on the margins possible under the 340B Program will “buy all the referring physicians in a market so that the medical oncology group is left with little choice but to sell to the hospital,” said Dr. Patton.

“Those 340B dollars are worth a lot to hospitals,” said David A. Eagle, MD, a hematologist/oncologist with New York Cancer & Blood Specialists and past president of COA. The program “creates an appetite for nonprofit hospitals to want to grow their medical oncology programs,” he told this news organization.

Declining Medicare reimbursement has also hit independent practices hard.

Over the past 15 years, compared with inflation, physicians have gotten “a pay rate decrease from Medicare,” said Dr. Patton. Payers have followed that lead and tried to cut pay for clinicians, especially those who do not have market share, he said. Paying them less is “disingenuous knowing that our costs of providing care are going up,” he said.
 

Less Access, Higher Costs, Worse Care?

Many studies have demonstrated that, when hospitals become behemoths in a given market, healthcare costs go up.

“There are robust data showing that consolidation increases healthcare costs by reducing competition, including in oncology,” wrote Dr. Erfani and colleagues.

Oncology practices that are owned by hospitals bill facility fees for outpatient chemotherapy treatment, adding another layer of cost, the researchers explained, citing a 2019 Health Economics study.

Another analysis, published in 2020, found that hospital prices for the top 37 infused cancer drugs averaged 86% more per unit than the price charged by physician offices. Hospital outpatient departments charged even more, on average, for drugs — 128% more for nivolumab and 428% more for fluorouracil, for instance.

In their 2024 analysis, Dr. Erfani and colleagues also found that increased hospital market concentration was associated with worse quality of care, across all assessed patient satisfaction measures, and may result in worse access to care as well.

Overall, these consolidation “trends have important implications for cancer care cost, quality, and access,” the authors concluded.
 

Navigating the Consolidation Trend

In the face of mounting pressure to join hospitals, community oncology practices have typically relied on horizontal mergers to maintain their independence. An increasing number of practices, however, are now turning to another strategy: Management services organizations.

According to some oncologists, a core benefit of joining a management services organization is their community practices can maintain autonomy, hold on to referrals, and benefit from access to a wider network of peers and recently approved treatments such as chimeric antigen receptor T-cell therapies.

In these arrangements, the management company also provides business assistance to practices, including help with billing and collection, payer negotiations, supply chain issues, and credentialing, as well as recruiting, hiring, and marketing.

These management organizations, which include American Oncology Network, Integrated Oncology Network, OneOncology, and Verdi Oncology, are, however, backed by private equity. According to a 2022 report, private equity–backed management organizations have ramped up arrangements with community oncology practices over the past few years — a trend that has concerned some experts.

The authors of a recent analysis in JAMA Internal Medicine explained that, although private equity involvement in physician practices may enable operational efficiencies, “critics point to potential conflicts of interest” and highlight concerns that patients “may face additional barriers to both accessibility and affordability of care.”

The difference, according to some oncologists, is their practices are not owned by the management services organization; instead, the practices enter contracts that outline the boundaries of the relationship and stipulate fees to the management organizations.

In 2020, Dr. Chasky’s practice, Alliance Cancer Specialists, joined The US Oncology Network, a management services organization wholly owned by McKesson. The organization provides the practice with capital and other resources, as well as access to the Sarah Cannon Research Institute, so patients can participate in clinical trials.

“We totally function as an independent practice,” said Dr. Chasky. “We make our own management decisions,” he said. For instance, if Alliance wants to hire a new clinician, US Oncology helps with the recruitment. “But at the end of the day, it’s our practice,” he said.

Davey Daniel, MD — whose community practice joined the management services organization OneOncology — has seen the benefits of being part of a larger network. For instance, bispecific therapies for leukemias, lymphomas, and multiple myeloma are typically administered at academic centers because of the risk for cytokine release syndrome.

However, physician leaders in the OneOncology network “came up with a playbook on how to do it safely” in the community setting, said Dr. Daniel. “It meant that we were adopting FDA newly approved therapies in a very short course.”

Being able to draw from a wider pool of expertise has had other advantages. Dr. Daniel can lean on pathologists and research scientists in the network for advice on targeted therapy use. “We’re actually bringing precision medicine expertise to the community,” Dr. Daniel said.

Dr. Chasky and Dr. Eagle, whose practice is also part of OneOncology, said that continuing to work in the community setting has allowed them greater flexibility.

Dr. Eagle explained that New York Cancer & Blood Specialists tries to offer patients an appointment within 2 days of a referral, and it allows walk-in visits.

Dr. Chasky leans into the flexibility by having staff stay late, when needed, to ensure that all patients are seen. “We’re there for our patients at all hours,” Dr. Chasky said, adding that often “you don’t have that flexibility when you work for a big hospital system.”

The bottom line is community oncology can still thrive, said Nick Ferreyros, managing director of COA, “as long as we have a healthy competitive ecosystem where [we] are valued and seen as an important part of our cancer care system.”

A version of this article first appeared on Medscape.com.

While Medicare Advantage (MA) plans are marketed as providing more generous benefits than traditional Medicare (TM), differences in the financial burden between beneficiaries switching to MA and staying with TM, are minimal, a longitudinal cohort analysis found.

In fact, according to a study by Sungchul Park, PhD, a health economist at Korea University in Seoul, and colleagues, the estimated annual out-of-pocket spending when switching to MA was $168 higher than staying in TM. That amounted to a 10.5% relative increase based on baseline out-of-pocket spending of $1597 annually among switchers, ranging widely, however, from a $133 decrease to a $469 increase. And for some, MA enrollment was associated with a higher likelihood of catastrophic financial burden.

“Our findings contrast with the notion that MA’s apparently more generous health insurance benefits lead to financial savings for enrollees,” Dr. Park and associates wrote in Annals of Internal Medicine.
 

The study

The analysis looked at costs for 7054 TM stayers and 1544 TM-to-MA switchers from the 2014-2020 Medical Expenditure Panel Survey, focusing on a cohort in which 18% of TM-covered individuals in year 1 switched to MA in year 2.

Comparative financial outcome measures included individual healthcare costs (out-of-pocket spending/cost sharing), financial burden (high/catastrophic), and subjective financial hardship (difficulty paying medical bills).

Although the overall out-of-pocket differences for MA were minimal and amounted to less than 1% of total healthcare expenses, MA was associated with a greater financial burden in vulnerable, especially in low-income populations. For every 100 beneficiaries with family incomes below 200% of the federal poverty level, one to six more switchers faced a catastrophic financial burden, with their out-of-pocket costs consuming more than 40% of household income in the year after switching.

The gap between the perception of lower costs and reality may be caused by a substantially heavier cost-sharing burden for certain services in MA plans, Dr. Park and associates pointed out. While MA enrollees generally paid less in some studies than the Part A hospital deductible for TM for inpatient stays of 3 days, they were more likely to face higher cost sharing for stays exceeding 7 days

Furthermore, whereas TM covers home health services without cost sharing, some MA plans have copayments. In addition, out-of-network health services can cost more. MA enrollees paid an average of $9 more for mental health services than for other in-network services and often encountered limited access to in-network providers. According to a 2021 study, only 18.2% of mental health professionals, 34.4% of cardiologists, 50.0% of psychiatrists, and 57.9% of primary care providers were included in MA networks,

An accompanying editorial noted that private MA plans will reap $83 billion in overpayments from U.S. taxpayers this year, according to Congress’s Medicare Payment Advisory Commission.

And as the data from Dr. Park and colleagues reveal, switchers don’t get much financial protection, according to primary care physician and healthcare researcher Steffi J. Woolhandler, MD, MPH, and internist David U. Himmelstein, MD, both of City University of New York at Hunter College in New York City.

“Medicare Advantage looks good when you’re healthy and don’t need much care. But when you need coverage, it often fails, leaving you with big bills and narrow choices for care,” Dr. Woolhandler said in an interview.

So how do these findings square with insurers’ hard-sell claims and enrollees’ perceptions that MA cuts out-of-pocket costs? “The likeliest explanation is that MA insurers have structured their benefits to advantage low-cost (that is, profitable) enrollees and disadvantage those requiring expensive care,” the editorial commentators wrote. For beneficiaries on inexpensive medications, MA plans would be a financial win. “But for patients requiring expensive chemotherapies, the 20% coinsurance that most MA plans charge could be financially ruinous.”

Commenting on the study but not involved in it, David A. Lipschutz, JD, LLB, associate director of the Center for Medicare Advocacy in Washington, DC, called the study an important one that provides more evidence that significant overpayments to MA plans don’t translate to better financial protections for plan enrollees, particularly lower-income individuals. “While there has been some recent movement to hold plans more accountable for providing necessary care, much more impactful action by policymakers is required to mitigate the harms of the growing privatization of the Medicare program,” he said. “MA overpayments could be redistributed to traditional Medicare in order to enrich all Medicare beneficiaries instead of just insurance companies.”

This study was supported by the National Research Foundation of Korea. Dr. Park disclosed no competing interests. One study coauthor reported support from government and not-for-profit research-funding bodies. Editorialists Dr. Woolhandler and Dr. Himmelstein had no competing interests to declare. Dr. Lipschutz disclosed Medicare advocacy work.

While Medicare Advantage (MA) plans are marketed as providing more generous benefits than traditional Medicare (TM), differences in the financial burden between beneficiaries switching to MA and staying with TM, are minimal, a longitudinal cohort analysis found.

In fact, according to a study by Sungchul Park, PhD, a health economist at Korea University in Seoul, and colleagues, the estimated annual out-of-pocket spending when switching to MA was $168 higher than staying in TM. That amounted to a 10.5% relative increase based on baseline out-of-pocket spending of $1597 annually among switchers, ranging widely, however, from a $133 decrease to a $469 increase. And for some, MA enrollment was associated with a higher likelihood of catastrophic financial burden.

“Our findings contrast with the notion that MA’s apparently more generous health insurance benefits lead to financial savings for enrollees,” Dr. Park and associates wrote in Annals of Internal Medicine.
 

The study

The analysis looked at costs for 7054 TM stayers and 1544 TM-to-MA switchers from the 2014-2020 Medical Expenditure Panel Survey, focusing on a cohort in which 18% of TM-covered individuals in year 1 switched to MA in year 2.

Comparative financial outcome measures included individual healthcare costs (out-of-pocket spending/cost sharing), financial burden (high/catastrophic), and subjective financial hardship (difficulty paying medical bills).

Although the overall out-of-pocket differences for MA were minimal and amounted to less than 1% of total healthcare expenses, MA was associated with a greater financial burden in vulnerable, especially in low-income populations. For every 100 beneficiaries with family incomes below 200% of the federal poverty level, one to six more switchers faced a catastrophic financial burden, with their out-of-pocket costs consuming more than 40% of household income in the year after switching.

The gap between the perception of lower costs and reality may be caused by a substantially heavier cost-sharing burden for certain services in MA plans, Dr. Park and associates pointed out. While MA enrollees generally paid less in some studies than the Part A hospital deductible for TM for inpatient stays of 3 days, they were more likely to face higher cost sharing for stays exceeding 7 days

Furthermore, whereas TM covers home health services without cost sharing, some MA plans have copayments. In addition, out-of-network health services can cost more. MA enrollees paid an average of $9 more for mental health services than for other in-network services and often encountered limited access to in-network providers. According to a 2021 study, only 18.2% of mental health professionals, 34.4% of cardiologists, 50.0% of psychiatrists, and 57.9% of primary care providers were included in MA networks,

An accompanying editorial noted that private MA plans will reap $83 billion in overpayments from U.S. taxpayers this year, according to Congress’s Medicare Payment Advisory Commission.

And as the data from Dr. Park and colleagues reveal, switchers don’t get much financial protection, according to primary care physician and healthcare researcher Steffi J. Woolhandler, MD, MPH, and internist David U. Himmelstein, MD, both of City University of New York at Hunter College in New York City.

“Medicare Advantage looks good when you’re healthy and don’t need much care. But when you need coverage, it often fails, leaving you with big bills and narrow choices for care,” Dr. Woolhandler said in an interview.

So how do these findings square with insurers’ hard-sell claims and enrollees’ perceptions that MA cuts out-of-pocket costs? “The likeliest explanation is that MA insurers have structured their benefits to advantage low-cost (that is, profitable) enrollees and disadvantage those requiring expensive care,” the editorial commentators wrote. For beneficiaries on inexpensive medications, MA plans would be a financial win. “But for patients requiring expensive chemotherapies, the 20% coinsurance that most MA plans charge could be financially ruinous.”

Commenting on the study but not involved in it, David A. Lipschutz, JD, LLB, associate director of the Center for Medicare Advocacy in Washington, DC, called the study an important one that provides more evidence that significant overpayments to MA plans don’t translate to better financial protections for plan enrollees, particularly lower-income individuals. “While there has been some recent movement to hold plans more accountable for providing necessary care, much more impactful action by policymakers is required to mitigate the harms of the growing privatization of the Medicare program,” he said. “MA overpayments could be redistributed to traditional Medicare in order to enrich all Medicare beneficiaries instead of just insurance companies.”

This study was supported by the National Research Foundation of Korea. Dr. Park disclosed no competing interests. One study coauthor reported support from government and not-for-profit research-funding bodies. Editorialists Dr. Woolhandler and Dr. Himmelstein had no competing interests to declare. Dr. Lipschutz disclosed Medicare advocacy work.

While Medicare Advantage (MA) plans are marketed as providing more generous benefits than traditional Medicare (TM), differences in the financial burden between beneficiaries switching to MA and staying with TM, are minimal, a longitudinal cohort analysis found.

In fact, according to a study by Sungchul Park, PhD, a health economist at Korea University in Seoul, and colleagues, the estimated annual out-of-pocket spending when switching to MA was $168 higher than staying in TM. That amounted to a 10.5% relative increase based on baseline out-of-pocket spending of $1597 annually among switchers, ranging widely, however, from a $133 decrease to a $469 increase. And for some, MA enrollment was associated with a higher likelihood of catastrophic financial burden.

“Our findings contrast with the notion that MA’s apparently more generous health insurance benefits lead to financial savings for enrollees,” Dr. Park and associates wrote in Annals of Internal Medicine.
 

The study

The analysis looked at costs for 7054 TM stayers and 1544 TM-to-MA switchers from the 2014-2020 Medical Expenditure Panel Survey, focusing on a cohort in which 18% of TM-covered individuals in year 1 switched to MA in year 2.

Comparative financial outcome measures included individual healthcare costs (out-of-pocket spending/cost sharing), financial burden (high/catastrophic), and subjective financial hardship (difficulty paying medical bills).

Although the overall out-of-pocket differences for MA were minimal and amounted to less than 1% of total healthcare expenses, MA was associated with a greater financial burden in vulnerable, especially in low-income populations. For every 100 beneficiaries with family incomes below 200% of the federal poverty level, one to six more switchers faced a catastrophic financial burden, with their out-of-pocket costs consuming more than 40% of household income in the year after switching.

The gap between the perception of lower costs and reality may be caused by a substantially heavier cost-sharing burden for certain services in MA plans, Dr. Park and associates pointed out. While MA enrollees generally paid less in some studies than the Part A hospital deductible for TM for inpatient stays of 3 days, they were more likely to face higher cost sharing for stays exceeding 7 days

Furthermore, whereas TM covers home health services without cost sharing, some MA plans have copayments. In addition, out-of-network health services can cost more. MA enrollees paid an average of $9 more for mental health services than for other in-network services and often encountered limited access to in-network providers. According to a 2021 study, only 18.2% of mental health professionals, 34.4% of cardiologists, 50.0% of psychiatrists, and 57.9% of primary care providers were included in MA networks,

An accompanying editorial noted that private MA plans will reap $83 billion in overpayments from U.S. taxpayers this year, according to Congress’s Medicare Payment Advisory Commission.

And as the data from Dr. Park and colleagues reveal, switchers don’t get much financial protection, according to primary care physician and healthcare researcher Steffi J. Woolhandler, MD, MPH, and internist David U. Himmelstein, MD, both of City University of New York at Hunter College in New York City.

“Medicare Advantage looks good when you’re healthy and don’t need much care. But when you need coverage, it often fails, leaving you with big bills and narrow choices for care,” Dr. Woolhandler said in an interview.

So how do these findings square with insurers’ hard-sell claims and enrollees’ perceptions that MA cuts out-of-pocket costs? “The likeliest explanation is that MA insurers have structured their benefits to advantage low-cost (that is, profitable) enrollees and disadvantage those requiring expensive care,” the editorial commentators wrote. For beneficiaries on inexpensive medications, MA plans would be a financial win. “But for patients requiring expensive chemotherapies, the 20% coinsurance that most MA plans charge could be financially ruinous.”

Commenting on the study but not involved in it, David A. Lipschutz, JD, LLB, associate director of the Center for Medicare Advocacy in Washington, DC, called the study an important one that provides more evidence that significant overpayments to MA plans don’t translate to better financial protections for plan enrollees, particularly lower-income individuals. “While there has been some recent movement to hold plans more accountable for providing necessary care, much more impactful action by policymakers is required to mitigate the harms of the growing privatization of the Medicare program,” he said. “MA overpayments could be redistributed to traditional Medicare in order to enrich all Medicare beneficiaries instead of just insurance companies.”

This study was supported by the National Research Foundation of Korea. Dr. Park disclosed no competing interests. One study coauthor reported support from government and not-for-profit research-funding bodies. Editorialists Dr. Woolhandler and Dr. Himmelstein had no competing interests to declare. Dr. Lipschutz disclosed Medicare advocacy work.

In the wake of a debilitating cyberattack against one of the nation’s largest health care systems, Marvin Ruckle, a nurse at an Ascension hospital in Wichita, Kansas, said he had a frightening experience: He nearly gave a baby “the wrong dose of narcotic” because of confusing paperwork.

Ruckle, who has worked in the neonatal intensive care unit at Ascension Via Christi St. Joseph for two decades, said it was “hard to decipher which was the correct dose” on the medication record. He’d “never seen that happen,” he said, “when we were on the computer system” before the cyberattack.

A May 8 ransomware attack against Ascension, a Catholic health system with 140 hospitals in at least 10 states, locked providers out of systems that track and coordinate nearly every aspect of patient care. They include its systems for electronic health records, some phones, and ones “utilized to order certain tests, procedures and medications,” the company said in a May 9 statement.

More than a dozen doctors and nurses who work for the sprawling health system told Michigan Public and KFF Health News that patient care at its hospitals across the nation was compromised in the fallout of the cyberattack over the past several weeks. Clinicians working for hospitals in three states described harrowing lapses, including delayed or lost lab results, medication errors, and an absence of routine safety checks via technology to prevent potentially fatal mistakes.

Despite a precipitous rise in cyberattacks against the health sector in recent years, a weeks-long disruption of this magnitude is beyond what most health systems are prepared for, said John S. Clark, an associate chief pharmacy officer at the University of Michigan health system.

“I don’t believe that anyone is fully prepared,” he said. Most emergency management plans “are designed around long-term downtimes that are into one, two, or three days.”

Ascension in a public statement May 9 said its care teams were “trained for these kinds of disruptions,” but did not respond to questions in early June about whether it had prepared for longer periods of downtime. Ascension said June 14 it had restored access to electronic health records across its network, but that patient “medical records and other information collected between May 8” and when the service was restored “may be temporarily inaccessible as we work to update the portal with information collected during the system downtime.”

Ruckle said he “had no training” for the cyberattack.
 

Back to Paper

Lisa Watson, an intensive care unit nurse at Ascension Via Christi St. Francis hospital in Wichita, described her own close call. She said she nearly administered the wrong medication to a critically ill patient because she couldn’t scan it as she normally would. “My patient probably would have passed away had I not caught it,” she said.

Watson is no stranger to using paper for patients’ medical charts, saying she did so “for probably half of my career,” before electronic health records became ubiquitous in hospitals. What happened after the cyberattack was “by no means the same.”

“When we paper-charted, we had systems in place to get those orders to other departments in a timely manner,” she said, “and those have all gone away.”

Melissa LaRue, an ICU nurse at Ascension Saint Agnes Hospital in Baltimore, described a close call with “administering the wrong dosage” of a patient’s blood pressure medication. “Luckily,” she said, it was “triple-checked and remedied before that could happen. But I think the potential for harm is there when you have so much information and paperwork that you have to go through.”

Clinicians say their hospitals have relied on slapdash workarounds, using handwritten notes, faxes, sticky notes, and basic computer spreadsheets — many devised on the fly by doctors and nurses — to care for patients.

More than a dozen other nurses and doctors, some of them without union protections, at Ascension hospitals in Michigan recounted situations in which they say patient care was compromised. Those clinicians spoke on the condition that they not be named for fear of retaliation by their employer.

An Ascension hospital emergency room doctor in Detroit said a man on the city’s east side was given a dangerous narcotic intended for another patient because of a paperwork mix-up. As a result, the patient’s breathing slowed to the point that he had to be put on a ventilator. “We intubated him and we sent him to the ICU because he got the wrong medication.”

A nurse in a Michigan Ascension hospital ER said a woman with low blood sugar and “altered mental status” went into cardiac arrest and died after staff said they waited four hours for lab results they needed to determine how to treat her, but never received. “If I started having crushing chest pain in the middle of work and thought I was having a big one, I would grab someone to drive me down the street to another hospital,” the same ER nurse said.

Similar concerns reportedly led a travel nurse at an Ascension hospital in Indiana to quit. “I just want to warn those patients that are coming to any of the Ascension facilities that there will be delays in care. There is potential for error and for harm,” Justin Neisser told CBS4 in Indianapolis in May.

Several nurses and doctors at Ascension hospitals said they feared the errors they’ve witnessed since the cyberattack began could threaten their professional licenses. “This is how a RaDonda Vaught happens,” one nurse said, referring to the Tennessee nurse who was convicted of criminally negligent homicide in 2022 for a fatal drug error.

Reporters were not able to review records to verify clinicians’ claims because of privacy laws surrounding patients’ medical information that apply to health care professionals.

Ascension declined to answer questions about claims that care has been affected by the ransomware attack. “As we have made clear throughout this cyber attack which has impacted our system and our dedicated clinical providers, caring for our patients is our highest priority,” Sean Fitzpatrick, Ascension’s vice president of external communications, said via email on June 3. “We are confident that our care providers in our hospitals and facilities continue to provide quality medical care.”

The federal government requires hospitals to protect patients’ sensitive health data, according to cybersecurity experts. However, there are no federal requirements for hospitals to prevent or prepare for cyberattacks that could compromise their electronic systems.
 

Hospitals: ‘The No.1 Target of Ransomware’

“We’ve started to think about these as public health issues and disasters on the scale of earthquakes or hurricanes,” said Jeff Tully, a co-director of the Center for Healthcare Cybersecurity at the University of California-San Diego. “These types of cybersecurity incidents should be thought of as a matter of when, and not if.”

Josh Corman, a cybersecurity expert and advocate, said ransom crews regard hospitals as the perfect prey: “They have terrible security and they’ll pay. So almost immediately, hospitals went to the No. 1 target of ransomware.”

In 2023, the health sector experienced the largest share of ransomware attacks of 16 infrastructure sectors considered vital to national security or safety, according to an FBI report on internet crimes. In March, the federal Department of Health and Human Services said reported large breaches involving ransomware had jumped by 264% over the past five years.

A cyberattack this year on Change Healthcare, a unit of UnitedHealth Group’s Optum division that processes billions of health care transactions every year, crippled the business of providers, pharmacies, and hospitals.

In May, UnitedHealth Group CEO Andrew Witty told lawmakers the company paid a $22 million ransom as a result of the Change Healthcare attack — which occurred after hackers accessed a company portal that didn’t have multifactor authentication, a basic cybersecurity tool.

The Biden administration in recent months has pushed to bolster health care cybersecurity standards, but it’s not clear which new measures will be required.

In January, HHS nudged companies to improve email security, add multifactor authentication, and institute cybersecurity training and testing, among other voluntary measures. The Centers for Medicare & Medicaid Services is expected to release new requirements for hospitals, but the scope and timing are unclear. The same is true of an update HHS is expected to make to patient privacy regulations.

HHS said the voluntary measures “will inform the creation of new enforceable cybersecurity standards,” department spokesperson Jeff Nesbit said in a statement.

“The recent cyberattack at Ascension only underscores the need for everyone in the health care ecosystem to do their part to secure their systems and protect patients,” Nesbit said.

Meanwhile, lobbyists for the hospital industry contend cybersecurity mandates or penalties are misplaced and would curtail hospitals’ resources to fend off attacks.

“Hospitals and health systems are not the primary source of cyber risk exposure facing the health care sector,” the American Hospital Association, the largest lobbying group for U.S. hospitals, said in an April statement prepared for U.S. House lawmakers. Most large data breaches that hit hospitals in 2023 originated with third-party “business associates” or other health entities, including CMS itself, the AHA statement said.

Hospitals consolidating into large multistate health systems face increased risk of data breaches and ransomware attacks, according to one study. Ascension in 2022 was the third-largest hospital chain in the U.S. by number of beds, according to the most recent data from the federal Agency for Healthcare Research and Quality.

And while cybersecurity regulations can quickly become outdated, they can at least make it clear that if health systems fail to implement basic protections there “should be consequences for that,” Jim Bagian, a former director of the National Center for Patient Safety at the Veterans Health Administration, told Michigan Public’s Stateside.

Patients can pay the price when lapses occur. Those in hospital care face a greater likelihood of death during a cyberattack, according to researchers at the University of Minnesota School of Public Health.

Workers concerned about patient safety at Ascension hospitals in Michigan have called for the company to make changes.

“We implore Ascension to recognize the internal problems that continue to plague its hospitals, both publicly and transparently,” said Dina Carlisle, a nurse and the president of the OPEIU Local 40 union, which represents nurses at Ascension Providence Rochester. At least 125 staff members at that Ascension hospital have signed a petition asking administrators to temporarily reduce elective surgeries and nonemergency patient admissions, like under the protocols many hospitals adopted early in the covid-19 pandemic.

Watson, the Kansas ICU nurse, said in late May that nurses had urged management to bring in more nurses to help manage the workflow. “Everything that we say has fallen on deaf ears,” she said.

“It is very hard to be a nurse at Ascension right now,” Watson said in late May. “It is very hard to be a patient at Ascension right now.”

If you’re a patient or worker at an Ascension hospital and would like to tell KFF Health News about your experiences, click here to share your story with us.
 

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

In the wake of a debilitating cyberattack against one of the nation’s largest health care systems, Marvin Ruckle, a nurse at an Ascension hospital in Wichita, Kansas, said he had a frightening experience: He nearly gave a baby “the wrong dose of narcotic” because of confusing paperwork.

Ruckle, who has worked in the neonatal intensive care unit at Ascension Via Christi St. Joseph for two decades, said it was “hard to decipher which was the correct dose” on the medication record. He’d “never seen that happen,” he said, “when we were on the computer system” before the cyberattack.

A May 8 ransomware attack against Ascension, a Catholic health system with 140 hospitals in at least 10 states, locked providers out of systems that track and coordinate nearly every aspect of patient care. They include its systems for electronic health records, some phones, and ones “utilized to order certain tests, procedures and medications,” the company said in a May 9 statement.

More than a dozen doctors and nurses who work for the sprawling health system told Michigan Public and KFF Health News that patient care at its hospitals across the nation was compromised in the fallout of the cyberattack over the past several weeks. Clinicians working for hospitals in three states described harrowing lapses, including delayed or lost lab results, medication errors, and an absence of routine safety checks via technology to prevent potentially fatal mistakes.

Despite a precipitous rise in cyberattacks against the health sector in recent years, a weeks-long disruption of this magnitude is beyond what most health systems are prepared for, said John S. Clark, an associate chief pharmacy officer at the University of Michigan health system.

“I don’t believe that anyone is fully prepared,” he said. Most emergency management plans “are designed around long-term downtimes that are into one, two, or three days.”

Ascension in a public statement May 9 said its care teams were “trained for these kinds of disruptions,” but did not respond to questions in early June about whether it had prepared for longer periods of downtime. Ascension said June 14 it had restored access to electronic health records across its network, but that patient “medical records and other information collected between May 8” and when the service was restored “may be temporarily inaccessible as we work to update the portal with information collected during the system downtime.”

Ruckle said he “had no training” for the cyberattack.
 

Back to Paper

Lisa Watson, an intensive care unit nurse at Ascension Via Christi St. Francis hospital in Wichita, described her own close call. She said she nearly administered the wrong medication to a critically ill patient because she couldn’t scan it as she normally would. “My patient probably would have passed away had I not caught it,” she said.

Watson is no stranger to using paper for patients’ medical charts, saying she did so “for probably half of my career,” before electronic health records became ubiquitous in hospitals. What happened after the cyberattack was “by no means the same.”

“When we paper-charted, we had systems in place to get those orders to other departments in a timely manner,” she said, “and those have all gone away.”

Melissa LaRue, an ICU nurse at Ascension Saint Agnes Hospital in Baltimore, described a close call with “administering the wrong dosage” of a patient’s blood pressure medication. “Luckily,” she said, it was “triple-checked and remedied before that could happen. But I think the potential for harm is there when you have so much information and paperwork that you have to go through.”

Clinicians say their hospitals have relied on slapdash workarounds, using handwritten notes, faxes, sticky notes, and basic computer spreadsheets — many devised on the fly by doctors and nurses — to care for patients.

More than a dozen other nurses and doctors, some of them without union protections, at Ascension hospitals in Michigan recounted situations in which they say patient care was compromised. Those clinicians spoke on the condition that they not be named for fear of retaliation by their employer.

An Ascension hospital emergency room doctor in Detroit said a man on the city’s east side was given a dangerous narcotic intended for another patient because of a paperwork mix-up. As a result, the patient’s breathing slowed to the point that he had to be put on a ventilator. “We intubated him and we sent him to the ICU because he got the wrong medication.”

A nurse in a Michigan Ascension hospital ER said a woman with low blood sugar and “altered mental status” went into cardiac arrest and died after staff said they waited four hours for lab results they needed to determine how to treat her, but never received. “If I started having crushing chest pain in the middle of work and thought I was having a big one, I would grab someone to drive me down the street to another hospital,” the same ER nurse said.

Similar concerns reportedly led a travel nurse at an Ascension hospital in Indiana to quit. “I just want to warn those patients that are coming to any of the Ascension facilities that there will be delays in care. There is potential for error and for harm,” Justin Neisser told CBS4 in Indianapolis in May.

Several nurses and doctors at Ascension hospitals said they feared the errors they’ve witnessed since the cyberattack began could threaten their professional licenses. “This is how a RaDonda Vaught happens,” one nurse said, referring to the Tennessee nurse who was convicted of criminally negligent homicide in 2022 for a fatal drug error.

Reporters were not able to review records to verify clinicians’ claims because of privacy laws surrounding patients’ medical information that apply to health care professionals.

Ascension declined to answer questions about claims that care has been affected by the ransomware attack. “As we have made clear throughout this cyber attack which has impacted our system and our dedicated clinical providers, caring for our patients is our highest priority,” Sean Fitzpatrick, Ascension’s vice president of external communications, said via email on June 3. “We are confident that our care providers in our hospitals and facilities continue to provide quality medical care.”

The federal government requires hospitals to protect patients’ sensitive health data, according to cybersecurity experts. However, there are no federal requirements for hospitals to prevent or prepare for cyberattacks that could compromise their electronic systems.
 

Hospitals: ‘The No.1 Target of Ransomware’

“We’ve started to think about these as public health issues and disasters on the scale of earthquakes or hurricanes,” said Jeff Tully, a co-director of the Center for Healthcare Cybersecurity at the University of California-San Diego. “These types of cybersecurity incidents should be thought of as a matter of when, and not if.”

Josh Corman, a cybersecurity expert and advocate, said ransom crews regard hospitals as the perfect prey: “They have terrible security and they’ll pay. So almost immediately, hospitals went to the No. 1 target of ransomware.”

In 2023, the health sector experienced the largest share of ransomware attacks of 16 infrastructure sectors considered vital to national security or safety, according to an FBI report on internet crimes. In March, the federal Department of Health and Human Services said reported large breaches involving ransomware had jumped by 264% over the past five years.

A cyberattack this year on Change Healthcare, a unit of UnitedHealth Group’s Optum division that processes billions of health care transactions every year, crippled the business of providers, pharmacies, and hospitals.

In May, UnitedHealth Group CEO Andrew Witty told lawmakers the company paid a $22 million ransom as a result of the Change Healthcare attack — which occurred after hackers accessed a company portal that didn’t have multifactor authentication, a basic cybersecurity tool.

The Biden administration in recent months has pushed to bolster health care cybersecurity standards, but it’s not clear which new measures will be required.

In January, HHS nudged companies to improve email security, add multifactor authentication, and institute cybersecurity training and testing, among other voluntary measures. The Centers for Medicare & Medicaid Services is expected to release new requirements for hospitals, but the scope and timing are unclear. The same is true of an update HHS is expected to make to patient privacy regulations.

HHS said the voluntary measures “will inform the creation of new enforceable cybersecurity standards,” department spokesperson Jeff Nesbit said in a statement.

“The recent cyberattack at Ascension only underscores the need for everyone in the health care ecosystem to do their part to secure their systems and protect patients,” Nesbit said.

Meanwhile, lobbyists for the hospital industry contend cybersecurity mandates or penalties are misplaced and would curtail hospitals’ resources to fend off attacks.

“Hospitals and health systems are not the primary source of cyber risk exposure facing the health care sector,” the American Hospital Association, the largest lobbying group for U.S. hospitals, said in an April statement prepared for U.S. House lawmakers. Most large data breaches that hit hospitals in 2023 originated with third-party “business associates” or other health entities, including CMS itself, the AHA statement said.

Hospitals consolidating into large multistate health systems face increased risk of data breaches and ransomware attacks, according to one study. Ascension in 2022 was the third-largest hospital chain in the U.S. by number of beds, according to the most recent data from the federal Agency for Healthcare Research and Quality.

And while cybersecurity regulations can quickly become outdated, they can at least make it clear that if health systems fail to implement basic protections there “should be consequences for that,” Jim Bagian, a former director of the National Center for Patient Safety at the Veterans Health Administration, told Michigan Public’s Stateside.

Patients can pay the price when lapses occur. Those in hospital care face a greater likelihood of death during a cyberattack, according to researchers at the University of Minnesota School of Public Health.

Workers concerned about patient safety at Ascension hospitals in Michigan have called for the company to make changes.

“We implore Ascension to recognize the internal problems that continue to plague its hospitals, both publicly and transparently,” said Dina Carlisle, a nurse and the president of the OPEIU Local 40 union, which represents nurses at Ascension Providence Rochester. At least 125 staff members at that Ascension hospital have signed a petition asking administrators to temporarily reduce elective surgeries and nonemergency patient admissions, like under the protocols many hospitals adopted early in the covid-19 pandemic.

Watson, the Kansas ICU nurse, said in late May that nurses had urged management to bring in more nurses to help manage the workflow. “Everything that we say has fallen on deaf ears,” she said.

“It is very hard to be a nurse at Ascension right now,” Watson said in late May. “It is very hard to be a patient at Ascension right now.”

If you’re a patient or worker at an Ascension hospital and would like to tell KFF Health News about your experiences, click here to share your story with us.
 

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

In the wake of a debilitating cyberattack against one of the nation’s largest health care systems, Marvin Ruckle, a nurse at an Ascension hospital in Wichita, Kansas, said he had a frightening experience: He nearly gave a baby “the wrong dose of narcotic” because of confusing paperwork.

Ruckle, who has worked in the neonatal intensive care unit at Ascension Via Christi St. Joseph for two decades, said it was “hard to decipher which was the correct dose” on the medication record. He’d “never seen that happen,” he said, “when we were on the computer system” before the cyberattack.

A May 8 ransomware attack against Ascension, a Catholic health system with 140 hospitals in at least 10 states, locked providers out of systems that track and coordinate nearly every aspect of patient care. They include its systems for electronic health records, some phones, and ones “utilized to order certain tests, procedures and medications,” the company said in a May 9 statement.

More than a dozen doctors and nurses who work for the sprawling health system told Michigan Public and KFF Health News that patient care at its hospitals across the nation was compromised in the fallout of the cyberattack over the past several weeks. Clinicians working for hospitals in three states described harrowing lapses, including delayed or lost lab results, medication errors, and an absence of routine safety checks via technology to prevent potentially fatal mistakes.

Despite a precipitous rise in cyberattacks against the health sector in recent years, a weeks-long disruption of this magnitude is beyond what most health systems are prepared for, said John S. Clark, an associate chief pharmacy officer at the University of Michigan health system.

“I don’t believe that anyone is fully prepared,” he said. Most emergency management plans “are designed around long-term downtimes that are into one, two, or three days.”

Ascension in a public statement May 9 said its care teams were “trained for these kinds of disruptions,” but did not respond to questions in early June about whether it had prepared for longer periods of downtime. Ascension said June 14 it had restored access to electronic health records across its network, but that patient “medical records and other information collected between May 8” and when the service was restored “may be temporarily inaccessible as we work to update the portal with information collected during the system downtime.”

Ruckle said he “had no training” for the cyberattack.
 

Back to Paper

Lisa Watson, an intensive care unit nurse at Ascension Via Christi St. Francis hospital in Wichita, described her own close call. She said she nearly administered the wrong medication to a critically ill patient because she couldn’t scan it as she normally would. “My patient probably would have passed away had I not caught it,” she said.

Watson is no stranger to using paper for patients’ medical charts, saying she did so “for probably half of my career,” before electronic health records became ubiquitous in hospitals. What happened after the cyberattack was “by no means the same.”

“When we paper-charted, we had systems in place to get those orders to other departments in a timely manner,” she said, “and those have all gone away.”

Melissa LaRue, an ICU nurse at Ascension Saint Agnes Hospital in Baltimore, described a close call with “administering the wrong dosage” of a patient’s blood pressure medication. “Luckily,” she said, it was “triple-checked and remedied before that could happen. But I think the potential for harm is there when you have so much information and paperwork that you have to go through.”

Clinicians say their hospitals have relied on slapdash workarounds, using handwritten notes, faxes, sticky notes, and basic computer spreadsheets — many devised on the fly by doctors and nurses — to care for patients.

More than a dozen other nurses and doctors, some of them without union protections, at Ascension hospitals in Michigan recounted situations in which they say patient care was compromised. Those clinicians spoke on the condition that they not be named for fear of retaliation by their employer.

An Ascension hospital emergency room doctor in Detroit said a man on the city’s east side was given a dangerous narcotic intended for another patient because of a paperwork mix-up. As a result, the patient’s breathing slowed to the point that he had to be put on a ventilator. “We intubated him and we sent him to the ICU because he got the wrong medication.”

A nurse in a Michigan Ascension hospital ER said a woman with low blood sugar and “altered mental status” went into cardiac arrest and died after staff said they waited four hours for lab results they needed to determine how to treat her, but never received. “If I started having crushing chest pain in the middle of work and thought I was having a big one, I would grab someone to drive me down the street to another hospital,” the same ER nurse said.

Similar concerns reportedly led a travel nurse at an Ascension hospital in Indiana to quit. “I just want to warn those patients that are coming to any of the Ascension facilities that there will be delays in care. There is potential for error and for harm,” Justin Neisser told CBS4 in Indianapolis in May.

Several nurses and doctors at Ascension hospitals said they feared the errors they’ve witnessed since the cyberattack began could threaten their professional licenses. “This is how a RaDonda Vaught happens,” one nurse said, referring to the Tennessee nurse who was convicted of criminally negligent homicide in 2022 for a fatal drug error.

Reporters were not able to review records to verify clinicians’ claims because of privacy laws surrounding patients’ medical information that apply to health care professionals.

Ascension declined to answer questions about claims that care has been affected by the ransomware attack. “As we have made clear throughout this cyber attack which has impacted our system and our dedicated clinical providers, caring for our patients is our highest priority,” Sean Fitzpatrick, Ascension’s vice president of external communications, said via email on June 3. “We are confident that our care providers in our hospitals and facilities continue to provide quality medical care.”

The federal government requires hospitals to protect patients’ sensitive health data, according to cybersecurity experts. However, there are no federal requirements for hospitals to prevent or prepare for cyberattacks that could compromise their electronic systems.
 

Hospitals: ‘The No.1 Target of Ransomware’

“We’ve started to think about these as public health issues and disasters on the scale of earthquakes or hurricanes,” said Jeff Tully, a co-director of the Center for Healthcare Cybersecurity at the University of California-San Diego. “These types of cybersecurity incidents should be thought of as a matter of when, and not if.”

Josh Corman, a cybersecurity expert and advocate, said ransom crews regard hospitals as the perfect prey: “They have terrible security and they’ll pay. So almost immediately, hospitals went to the No. 1 target of ransomware.”

In 2023, the health sector experienced the largest share of ransomware attacks of 16 infrastructure sectors considered vital to national security or safety, according to an FBI report on internet crimes. In March, the federal Department of Health and Human Services said reported large breaches involving ransomware had jumped by 264% over the past five years.

A cyberattack this year on Change Healthcare, a unit of UnitedHealth Group’s Optum division that processes billions of health care transactions every year, crippled the business of providers, pharmacies, and hospitals.

In May, UnitedHealth Group CEO Andrew Witty told lawmakers the company paid a $22 million ransom as a result of the Change Healthcare attack — which occurred after hackers accessed a company portal that didn’t have multifactor authentication, a basic cybersecurity tool.

The Biden administration in recent months has pushed to bolster health care cybersecurity standards, but it’s not clear which new measures will be required.

In January, HHS nudged companies to improve email security, add multifactor authentication, and institute cybersecurity training and testing, among other voluntary measures. The Centers for Medicare & Medicaid Services is expected to release new requirements for hospitals, but the scope and timing are unclear. The same is true of an update HHS is expected to make to patient privacy regulations.

HHS said the voluntary measures “will inform the creation of new enforceable cybersecurity standards,” department spokesperson Jeff Nesbit said in a statement.

“The recent cyberattack at Ascension only underscores the need for everyone in the health care ecosystem to do their part to secure their systems and protect patients,” Nesbit said.

Meanwhile, lobbyists for the hospital industry contend cybersecurity mandates or penalties are misplaced and would curtail hospitals’ resources to fend off attacks.

“Hospitals and health systems are not the primary source of cyber risk exposure facing the health care sector,” the American Hospital Association, the largest lobbying group for U.S. hospitals, said in an April statement prepared for U.S. House lawmakers. Most large data breaches that hit hospitals in 2023 originated with third-party “business associates” or other health entities, including CMS itself, the AHA statement said.

Hospitals consolidating into large multistate health systems face increased risk of data breaches and ransomware attacks, according to one study. Ascension in 2022 was the third-largest hospital chain in the U.S. by number of beds, according to the most recent data from the federal Agency for Healthcare Research and Quality.

And while cybersecurity regulations can quickly become outdated, they can at least make it clear that if health systems fail to implement basic protections there “should be consequences for that,” Jim Bagian, a former director of the National Center for Patient Safety at the Veterans Health Administration, told Michigan Public’s Stateside.

Patients can pay the price when lapses occur. Those in hospital care face a greater likelihood of death during a cyberattack, according to researchers at the University of Minnesota School of Public Health.

Workers concerned about patient safety at Ascension hospitals in Michigan have called for the company to make changes.

“We implore Ascension to recognize the internal problems that continue to plague its hospitals, both publicly and transparently,” said Dina Carlisle, a nurse and the president of the OPEIU Local 40 union, which represents nurses at Ascension Providence Rochester. At least 125 staff members at that Ascension hospital have signed a petition asking administrators to temporarily reduce elective surgeries and nonemergency patient admissions, like under the protocols many hospitals adopted early in the covid-19 pandemic.

Watson, the Kansas ICU nurse, said in late May that nurses had urged management to bring in more nurses to help manage the workflow. “Everything that we say has fallen on deaf ears,” she said.

“It is very hard to be a nurse at Ascension right now,” Watson said in late May. “It is very hard to be a patient at Ascension right now.”

If you’re a patient or worker at an Ascension hospital and would like to tell KFF Health News about your experiences, click here to share your story with us.
 

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Glofitamab, a fixed-duration CD20xCD3 bispecific antibody, combined with a chemotherapy regimen of gemcitabine and oxaliplatin (GemOx), shows significant survival benefits in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), compared with the standard-of-care regimen.

“Glofitamab is the first CD20xCD3 bispecific antibody to demonstrate an overall survival benefit in DLBCL in a randomized phase 3 trial,” said first author Jeremy Abramson, MD, of the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, in a press briefing at the annual meeting of the European Hematology Association (EHA) in Madrid.

“These results support the use of glofitamab GemOx as new, off-the-shelf treatment for relapsed/refractory DLBCL in patients who are transplant ineligible in the second-line or later setting,” he said.

The findings are from the phase 3 STARGLO study involving 274 patients with R/R DLBCL who had previously been treated either with at least two prior lines of therapy, or—if only one prior line of therapy—were determined to be ineligible for autologous stem cell transplant (ASCT).

At a median follow-up of 21 months, those treated with glofitamab combined with GemOx had a significantly higher median overall survival of 25.5 months, compared with those treated with the standard of care of rituximab and GemOx (12.9 months; hazard ratio [HR], 0.62; P = .006).

“The results show a 38% lower risk of death with the glofitamab plus GemOx, compared with [the rituximab regimen],” Dr. Abramson said.

Secondary endpoints showed consistent benefits with the glofitamab regimen, with significant improvements in progression-free survival and complete remission.
 

Unmet Need for Accessible Therapies

Relapsed/refractory DLBCL, the most common form of non-Hodgkin lymphoma (NHL) in the United States, is an aggressive blood cancer. The standard second-line therapy is high-dose chemotherapy followed by ASCT. However, factors including older age or coexisting medical conditions can compromise response, and those who relapse or are refractory to subsequent therapies have poor outcomes.

“Relapsed DLBCL in the second-line setting or later continues to represent an area of medical need,” Dr. Abramson said.

While several CD20xCD3 bispecific antibody drugs are under development to address the need, glofitamab was the first off-the-shelf, fixed-duration bispecific antibody to receive accelerated approval from the US Food and Drug Administration (FDA) for the treatment of R/R DLBCL, specifically as monotherapy after two or more lines of systemic therapy.

That approval was based on results from a pivotal phase 1/2 study, which showed high rates of deep and durable complete remission with the monotherapy.

To further evaluate glofitamab in combination with GemOx, the authors conducted the multicenter, open-label STARGLO trial, which extended enrollment to patients with just one prior therapy if they were determined to be stem cell transplant ineligible. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Patients were randomized 2:1 either to treatment with glofitamab combined with GemOx, involving 8 cycles, in addition to 4 cycles of glofitamab monotherapy (n = 183), or to the rituximab plus GemOx regimen in 8 cycles (n = 91).

Overall, 153 (55.8%) of patients had primary refractory disease and 166 (60.6%) were refractory to their last therapy. The median age was 68, and 37% had two or more lines of therapy, including some who had received chimeric antigen receptor T-cell (CAR T) therapy (8.8% in the glofitamab group and 7.1% in the rituximab group).

In addition to the significant overall survival benefit, the glofitamab regimen also showed significantly improved progression-free survival at a median follow-up of 16.1 months, as observed by IRC-assessed PFS, with a median progression-free survival rate of 13.8 months vs 3.6 months (HR, 0.40; P < .0001).

The complete remission rate was doubled with glofitamab-GemOx, with a rate of 58.5% vs 25.3%, respectively; P < .0001.

Similar results were observed in subgroups, including relapsed vs refractory patients and those treated as a second or third line of care.

The median number of cycles received was higher among those receiving glofitamab (11 vs four cycles).

Adverse event (AE) rates were higher with glofitamab vs rituximab, including grade 3-4 AEs (69.4 vs 36.4%), grade 5 AEs (8.3 vs 4.5%; primarily driven by an imbalance of COVID-19 AEs), and serious AEs (54.4 vs 17.0%; primarily cytokine release syndrome [CRS]).

CRS was the most frequently reported AE in the glofitamab group (grade 1: 31.4%; grade 2: 10.5%; and grade 3: 2.3%), and events consistent with immune effector cell–associated neurotoxicity syndrome were reported in four patients (2.3%), all of which were concurrent with CRS.

Other AEs were consistent with the known risks associated with the therapy regimens.

“We found that with glofitamab GemOx, the toxicities were manageable, and the most common toxicity of CRS was predominantly low-grade and occurred with step-up dosing in cycle one and was completely reversible,” Dr. Abramson said.

He noted that the higher rate of grade 5 AEs with glofitamab GemOx “was far outweighed by the survival benefit for disease control.”

Overall, “these findings represent the best outcomes observed in a phase 3 trial for relapsed/refractory diffuse large B-cell lymphoma patients who are considered transplant ineligible,” Dr. Abramson said in an interview.
 

Improved Accessibility Vs CAR-T Therapy

Among key developments in the treatment of R/R DLBCL has been the advent and approval of potentially highly effective CAR T-cell therapy, with the anti-CD19 CAR T cell isiocabtagene maraleucel also FDA approved in the non–transplant eligible DLBCL second-line setting.

Asked in the press briefing about the role of glofitamab GemOx in relation to CAR T cell’s significant benefits, Dr. Abramson underscored the important limitations in CAR T-cell accessibility.

“What I would say is a rising tide lifts all boats,” he responded. “It’s great to have multiple effective immunotherapy strategies.”

However, “CAR T cells of course are not available to most people in the US or worldwide,” he explained.

“They are more difficult to access, they require lymphodepleting chemotherapy, and so ultimately, the majority of patients who could potentially benefit from a CAR T cell probably don’t have access to them in the first place.”

He noted that “the appeal of a regimen like [glofitamab] is that it is an off-the-shelf, targeted immunotherapy combined with a well-tolerated chemotherapy backbone and should be more broadly accessible outside of just tertiary care centers in major cities.”
 

Long-Term Durability?

Looking ahead, Dr. Abramson noted that a key issue of focus is how long the encouraging results actually last.

“The major ongoing question with this trial is the long-term durability of remissions,” he said.

“Thus far, with a median of 21 months of follow-up for overall survival, the results are encouraging but longer follow-up is needed,” he added.

“Further trials are needed in a broader large B-cell lymphoma population as this trial was limited to DLBCL not otherwise specified, so did not include patients with transformed lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, etc.” 
 

Is Chemo Necessary?

Commenting on the findings, Jonathan W. Friedberg, MD, director of the Wilmot Cancer Institute, University of Rochester School of Medicine, in Rochester, New York, underscored that, “given the overall survival benefit, these findings are clearly clinically significant.”

Noting that “these results add to evidence of high activity of bispecific antibodies in this disease,” Dr. Friedberg speculated on the role of chemotherapy with the therapy.

“Indeed, an important question in this study is whether the addition of chemotherapy to glofitamab is necessary, as high response rates with durable responses in patients who achieve complete remission have been demonstrated with single agent bispecific antibody therapy,” he said. 

With the durability of CAR T therapy shown in long-term follow-up of trials to exceed 5 years, Dr. Friedberg added that “it is not known how bispecific antibody therapy, with or without chemotherapy, compares to CAR T-cell therapy and how to sequence CAR T and bispecific antibody therapy.”

Dr. Friedberg agreed that longer-term results are needed get a clearer, fuller picture of the therapy’s effects.

“I have no doubt that the overall survival benefit will endure, but in DLBCL our goal should be cure, and whether glofitamab cures as many patients as CAR T-cell therapy is not currently known and will require further follow-up of this and other trials.”

The study was sponsored by F. Hoffman-La Roche Ltd. Dr. Abramson reported ties with AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Cellectar, Caribou Biosciences, Celgene, Genentech, Gilead, Incyte, Interius, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd, Seagen, and Takeda. Dr. Friedberg had no disclosures.

Glofitamab, a fixed-duration CD20xCD3 bispecific antibody, combined with a chemotherapy regimen of gemcitabine and oxaliplatin (GemOx), shows significant survival benefits in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), compared with the standard-of-care regimen.

“Glofitamab is the first CD20xCD3 bispecific antibody to demonstrate an overall survival benefit in DLBCL in a randomized phase 3 trial,” said first author Jeremy Abramson, MD, of the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, in a press briefing at the annual meeting of the European Hematology Association (EHA) in Madrid.

“These results support the use of glofitamab GemOx as new, off-the-shelf treatment for relapsed/refractory DLBCL in patients who are transplant ineligible in the second-line or later setting,” he said.

The findings are from the phase 3 STARGLO study involving 274 patients with R/R DLBCL who had previously been treated either with at least two prior lines of therapy, or—if only one prior line of therapy—were determined to be ineligible for autologous stem cell transplant (ASCT).

At a median follow-up of 21 months, those treated with glofitamab combined with GemOx had a significantly higher median overall survival of 25.5 months, compared with those treated with the standard of care of rituximab and GemOx (12.9 months; hazard ratio [HR], 0.62; P = .006).

“The results show a 38% lower risk of death with the glofitamab plus GemOx, compared with [the rituximab regimen],” Dr. Abramson said.

Secondary endpoints showed consistent benefits with the glofitamab regimen, with significant improvements in progression-free survival and complete remission.
 

Unmet Need for Accessible Therapies

Relapsed/refractory DLBCL, the most common form of non-Hodgkin lymphoma (NHL) in the United States, is an aggressive blood cancer. The standard second-line therapy is high-dose chemotherapy followed by ASCT. However, factors including older age or coexisting medical conditions can compromise response, and those who relapse or are refractory to subsequent therapies have poor outcomes.

“Relapsed DLBCL in the second-line setting or later continues to represent an area of medical need,” Dr. Abramson said.

While several CD20xCD3 bispecific antibody drugs are under development to address the need, glofitamab was the first off-the-shelf, fixed-duration bispecific antibody to receive accelerated approval from the US Food and Drug Administration (FDA) for the treatment of R/R DLBCL, specifically as monotherapy after two or more lines of systemic therapy.

That approval was based on results from a pivotal phase 1/2 study, which showed high rates of deep and durable complete remission with the monotherapy.

To further evaluate glofitamab in combination with GemOx, the authors conducted the multicenter, open-label STARGLO trial, which extended enrollment to patients with just one prior therapy if they were determined to be stem cell transplant ineligible. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Patients were randomized 2:1 either to treatment with glofitamab combined with GemOx, involving 8 cycles, in addition to 4 cycles of glofitamab monotherapy (n = 183), or to the rituximab plus GemOx regimen in 8 cycles (n = 91).

Overall, 153 (55.8%) of patients had primary refractory disease and 166 (60.6%) were refractory to their last therapy. The median age was 68, and 37% had two or more lines of therapy, including some who had received chimeric antigen receptor T-cell (CAR T) therapy (8.8% in the glofitamab group and 7.1% in the rituximab group).

In addition to the significant overall survival benefit, the glofitamab regimen also showed significantly improved progression-free survival at a median follow-up of 16.1 months, as observed by IRC-assessed PFS, with a median progression-free survival rate of 13.8 months vs 3.6 months (HR, 0.40; P < .0001).

The complete remission rate was doubled with glofitamab-GemOx, with a rate of 58.5% vs 25.3%, respectively; P < .0001.

Similar results were observed in subgroups, including relapsed vs refractory patients and those treated as a second or third line of care.

The median number of cycles received was higher among those receiving glofitamab (11 vs four cycles).

Adverse event (AE) rates were higher with glofitamab vs rituximab, including grade 3-4 AEs (69.4 vs 36.4%), grade 5 AEs (8.3 vs 4.5%; primarily driven by an imbalance of COVID-19 AEs), and serious AEs (54.4 vs 17.0%; primarily cytokine release syndrome [CRS]).

CRS was the most frequently reported AE in the glofitamab group (grade 1: 31.4%; grade 2: 10.5%; and grade 3: 2.3%), and events consistent with immune effector cell–associated neurotoxicity syndrome were reported in four patients (2.3%), all of which were concurrent with CRS.

Other AEs were consistent with the known risks associated with the therapy regimens.

“We found that with glofitamab GemOx, the toxicities were manageable, and the most common toxicity of CRS was predominantly low-grade and occurred with step-up dosing in cycle one and was completely reversible,” Dr. Abramson said.

He noted that the higher rate of grade 5 AEs with glofitamab GemOx “was far outweighed by the survival benefit for disease control.”

Overall, “these findings represent the best outcomes observed in a phase 3 trial for relapsed/refractory diffuse large B-cell lymphoma patients who are considered transplant ineligible,” Dr. Abramson said in an interview.
 

Improved Accessibility Vs CAR-T Therapy

Among key developments in the treatment of R/R DLBCL has been the advent and approval of potentially highly effective CAR T-cell therapy, with the anti-CD19 CAR T cell isiocabtagene maraleucel also FDA approved in the non–transplant eligible DLBCL second-line setting.

Asked in the press briefing about the role of glofitamab GemOx in relation to CAR T cell’s significant benefits, Dr. Abramson underscored the important limitations in CAR T-cell accessibility.

“What I would say is a rising tide lifts all boats,” he responded. “It’s great to have multiple effective immunotherapy strategies.”

However, “CAR T cells of course are not available to most people in the US or worldwide,” he explained.

“They are more difficult to access, they require lymphodepleting chemotherapy, and so ultimately, the majority of patients who could potentially benefit from a CAR T cell probably don’t have access to them in the first place.”

He noted that “the appeal of a regimen like [glofitamab] is that it is an off-the-shelf, targeted immunotherapy combined with a well-tolerated chemotherapy backbone and should be more broadly accessible outside of just tertiary care centers in major cities.”
 

Long-Term Durability?

Looking ahead, Dr. Abramson noted that a key issue of focus is how long the encouraging results actually last.

“The major ongoing question with this trial is the long-term durability of remissions,” he said.

“Thus far, with a median of 21 months of follow-up for overall survival, the results are encouraging but longer follow-up is needed,” he added.

“Further trials are needed in a broader large B-cell lymphoma population as this trial was limited to DLBCL not otherwise specified, so did not include patients with transformed lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, etc.” 
 

Is Chemo Necessary?

Commenting on the findings, Jonathan W. Friedberg, MD, director of the Wilmot Cancer Institute, University of Rochester School of Medicine, in Rochester, New York, underscored that, “given the overall survival benefit, these findings are clearly clinically significant.”

Noting that “these results add to evidence of high activity of bispecific antibodies in this disease,” Dr. Friedberg speculated on the role of chemotherapy with the therapy.

“Indeed, an important question in this study is whether the addition of chemotherapy to glofitamab is necessary, as high response rates with durable responses in patients who achieve complete remission have been demonstrated with single agent bispecific antibody therapy,” he said. 

With the durability of CAR T therapy shown in long-term follow-up of trials to exceed 5 years, Dr. Friedberg added that “it is not known how bispecific antibody therapy, with or without chemotherapy, compares to CAR T-cell therapy and how to sequence CAR T and bispecific antibody therapy.”

Dr. Friedberg agreed that longer-term results are needed get a clearer, fuller picture of the therapy’s effects.

“I have no doubt that the overall survival benefit will endure, but in DLBCL our goal should be cure, and whether glofitamab cures as many patients as CAR T-cell therapy is not currently known and will require further follow-up of this and other trials.”

The study was sponsored by F. Hoffman-La Roche Ltd. Dr. Abramson reported ties with AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Cellectar, Caribou Biosciences, Celgene, Genentech, Gilead, Incyte, Interius, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd, Seagen, and Takeda. Dr. Friedberg had no disclosures.

Glofitamab, a fixed-duration CD20xCD3 bispecific antibody, combined with a chemotherapy regimen of gemcitabine and oxaliplatin (GemOx), shows significant survival benefits in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), compared with the standard-of-care regimen.

“Glofitamab is the first CD20xCD3 bispecific antibody to demonstrate an overall survival benefit in DLBCL in a randomized phase 3 trial,” said first author Jeremy Abramson, MD, of the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, in a press briefing at the annual meeting of the European Hematology Association (EHA) in Madrid.

“These results support the use of glofitamab GemOx as new, off-the-shelf treatment for relapsed/refractory DLBCL in patients who are transplant ineligible in the second-line or later setting,” he said.

The findings are from the phase 3 STARGLO study involving 274 patients with R/R DLBCL who had previously been treated either with at least two prior lines of therapy, or—if only one prior line of therapy—were determined to be ineligible for autologous stem cell transplant (ASCT).

At a median follow-up of 21 months, those treated with glofitamab combined with GemOx had a significantly higher median overall survival of 25.5 months, compared with those treated with the standard of care of rituximab and GemOx (12.9 months; hazard ratio [HR], 0.62; P = .006).

“The results show a 38% lower risk of death with the glofitamab plus GemOx, compared with [the rituximab regimen],” Dr. Abramson said.

Secondary endpoints showed consistent benefits with the glofitamab regimen, with significant improvements in progression-free survival and complete remission.
 

Unmet Need for Accessible Therapies

Relapsed/refractory DLBCL, the most common form of non-Hodgkin lymphoma (NHL) in the United States, is an aggressive blood cancer. The standard second-line therapy is high-dose chemotherapy followed by ASCT. However, factors including older age or coexisting medical conditions can compromise response, and those who relapse or are refractory to subsequent therapies have poor outcomes.

“Relapsed DLBCL in the second-line setting or later continues to represent an area of medical need,” Dr. Abramson said.

While several CD20xCD3 bispecific antibody drugs are under development to address the need, glofitamab was the first off-the-shelf, fixed-duration bispecific antibody to receive accelerated approval from the US Food and Drug Administration (FDA) for the treatment of R/R DLBCL, specifically as monotherapy after two or more lines of systemic therapy.

That approval was based on results from a pivotal phase 1/2 study, which showed high rates of deep and durable complete remission with the monotherapy.

To further evaluate glofitamab in combination with GemOx, the authors conducted the multicenter, open-label STARGLO trial, which extended enrollment to patients with just one prior therapy if they were determined to be stem cell transplant ineligible. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Patients were randomized 2:1 either to treatment with glofitamab combined with GemOx, involving 8 cycles, in addition to 4 cycles of glofitamab monotherapy (n = 183), or to the rituximab plus GemOx regimen in 8 cycles (n = 91).

Overall, 153 (55.8%) of patients had primary refractory disease and 166 (60.6%) were refractory to their last therapy. The median age was 68, and 37% had two or more lines of therapy, including some who had received chimeric antigen receptor T-cell (CAR T) therapy (8.8% in the glofitamab group and 7.1% in the rituximab group).

In addition to the significant overall survival benefit, the glofitamab regimen also showed significantly improved progression-free survival at a median follow-up of 16.1 months, as observed by IRC-assessed PFS, with a median progression-free survival rate of 13.8 months vs 3.6 months (HR, 0.40; P < .0001).

The complete remission rate was doubled with glofitamab-GemOx, with a rate of 58.5% vs 25.3%, respectively; P < .0001.

Similar results were observed in subgroups, including relapsed vs refractory patients and those treated as a second or third line of care.

The median number of cycles received was higher among those receiving glofitamab (11 vs four cycles).

Adverse event (AE) rates were higher with glofitamab vs rituximab, including grade 3-4 AEs (69.4 vs 36.4%), grade 5 AEs (8.3 vs 4.5%; primarily driven by an imbalance of COVID-19 AEs), and serious AEs (54.4 vs 17.0%; primarily cytokine release syndrome [CRS]).

CRS was the most frequently reported AE in the glofitamab group (grade 1: 31.4%; grade 2: 10.5%; and grade 3: 2.3%), and events consistent with immune effector cell–associated neurotoxicity syndrome were reported in four patients (2.3%), all of which were concurrent with CRS.

Other AEs were consistent with the known risks associated with the therapy regimens.

“We found that with glofitamab GemOx, the toxicities were manageable, and the most common toxicity of CRS was predominantly low-grade and occurred with step-up dosing in cycle one and was completely reversible,” Dr. Abramson said.

He noted that the higher rate of grade 5 AEs with glofitamab GemOx “was far outweighed by the survival benefit for disease control.”

Overall, “these findings represent the best outcomes observed in a phase 3 trial for relapsed/refractory diffuse large B-cell lymphoma patients who are considered transplant ineligible,” Dr. Abramson said in an interview.
 

Improved Accessibility Vs CAR-T Therapy

Among key developments in the treatment of R/R DLBCL has been the advent and approval of potentially highly effective CAR T-cell therapy, with the anti-CD19 CAR T cell isiocabtagene maraleucel also FDA approved in the non–transplant eligible DLBCL second-line setting.

Asked in the press briefing about the role of glofitamab GemOx in relation to CAR T cell’s significant benefits, Dr. Abramson underscored the important limitations in CAR T-cell accessibility.

“What I would say is a rising tide lifts all boats,” he responded. “It’s great to have multiple effective immunotherapy strategies.”

However, “CAR T cells of course are not available to most people in the US or worldwide,” he explained.

“They are more difficult to access, they require lymphodepleting chemotherapy, and so ultimately, the majority of patients who could potentially benefit from a CAR T cell probably don’t have access to them in the first place.”

He noted that “the appeal of a regimen like [glofitamab] is that it is an off-the-shelf, targeted immunotherapy combined with a well-tolerated chemotherapy backbone and should be more broadly accessible outside of just tertiary care centers in major cities.”
 

Long-Term Durability?

Looking ahead, Dr. Abramson noted that a key issue of focus is how long the encouraging results actually last.

“The major ongoing question with this trial is the long-term durability of remissions,” he said.

“Thus far, with a median of 21 months of follow-up for overall survival, the results are encouraging but longer follow-up is needed,” he added.

“Further trials are needed in a broader large B-cell lymphoma population as this trial was limited to DLBCL not otherwise specified, so did not include patients with transformed lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, etc.” 
 

Is Chemo Necessary?

Commenting on the findings, Jonathan W. Friedberg, MD, director of the Wilmot Cancer Institute, University of Rochester School of Medicine, in Rochester, New York, underscored that, “given the overall survival benefit, these findings are clearly clinically significant.”

Noting that “these results add to evidence of high activity of bispecific antibodies in this disease,” Dr. Friedberg speculated on the role of chemotherapy with the therapy.

“Indeed, an important question in this study is whether the addition of chemotherapy to glofitamab is necessary, as high response rates with durable responses in patients who achieve complete remission have been demonstrated with single agent bispecific antibody therapy,” he said. 

With the durability of CAR T therapy shown in long-term follow-up of trials to exceed 5 years, Dr. Friedberg added that “it is not known how bispecific antibody therapy, with or without chemotherapy, compares to CAR T-cell therapy and how to sequence CAR T and bispecific antibody therapy.”

Dr. Friedberg agreed that longer-term results are needed get a clearer, fuller picture of the therapy’s effects.

“I have no doubt that the overall survival benefit will endure, but in DLBCL our goal should be cure, and whether glofitamab cures as many patients as CAR T-cell therapy is not currently known and will require further follow-up of this and other trials.”

The study was sponsored by F. Hoffman-La Roche Ltd. Dr. Abramson reported ties with AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Cellectar, Caribou Biosciences, Celgene, Genentech, Gilead, Incyte, Interius, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd, Seagen, and Takeda. Dr. Friedberg had no disclosures.

The chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) that is standard in treating low-risk acute promyelocytic leukemia (APL) also shows superior benefits in the high-risk APL population, suggesting the regimen should become the standard in those patients as well, new research shows.

“First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior event-free survival, compared to conventional ATRA-chemotherapy in patients with high-risk APL,” said first author Uwe Platzbecker, MD, of the University Hospital Leipzig, department for hematology, cellular therapy, hemostaseology, and infectious diseases, in Leipzig, Germany, at the annual meeting of the European Hematology Association (EHA) in Madrid, Spain.

“We believe that the trial may support the implementation of this regimen as a new standard of care in all patients with high-risk APL,” he said.

In the treatment of low and intermediate risk APL, a subtype of acute myeloid leukemia (AML), the combination of ATRA and ATO has become standard since being shown in a pivotal 2013 study to be superior versus ATRA and chemotherapy. The approach is approved by the Food and Drug Administration in the treatment of adults with newly diagnosed low-risk APL.

Importantly, the improved survival with ATRA/ATO approach may result from “reduced severe hematologic toxicity together with similar antileukemic efficacy,” compared with the regimen that include chemotherapy, the authors of the 2013 study speculated.

However, the treatment regimen has not been evaluated in randomized trials in patients with high-risk APL, defined as having a white blood cell count of more than 10,000 cells per μL.

For those patients, the conventional treatment remains ATRA with a chemotherapy backbone, Dr. Platzbecker explained.

To evaluate if the improvements extend to high-risk APL patients without compromising safety, Dr. Platzbecker and colleagues conducted the open-label, prospective APOLLO trial, involving newly diagnosed high-risk APL who were enrolled between 2016 and 2022 at 143 sites in six European countries.

The patients were randomized into one of two groups: ATRA/ATO, involving treatment consisting of two doses of idarubicin (12 mg/m²) on days 1 and 3 at the time of induction therapy, in addition to ATO 0.15 mg/kg and ATRA 45 mg/m², daily until complete remission, or the ATRA-chemotherapy arm, involving standard ATRA also with idarubicin induction, followed by three cycles of chemotherapy-based consolidation as well as 2 years of maintenance treatment.

While the study was prematurely discontinued in August 2022 because of COVID-19–related recruitment delays and expiration of the study drug, the maintenance and observational periods are ongoing.

Of 131 patients with high-risk APL who were evaluable for the outcome analysis, 68 were in the ATRA/ATO group and 63 in the ATRA-chemotherapy arm.

Overall, participants had a mean age of 46, 50% were female, their median Eastern Cooperative Oncology Group score was 1. Their median white blood cell count was 36 × 10⁹/L, with 39% having a white blood cell count greater than 50 × 10⁹/L.

Molecular resistance occurred in 1.7% in the ATRA/ATO arm vs 5.5% in the ATRA chemotherapy arm, which was not statistically significant (P = .268); however, the incidence of molecular relapse was much lower without chemotherapy, at 1.6% with ATRA/ATO vs 14% with ATRA and chemotherapy.

For the primary endpoint, with a median follow-up of 31 months, the 2-year rate of event-free survival those in the ATRA/ATO arm was 88% vs 70% in the ATRA plus chemotherapy regimen (P = .02). The 5-year event-free survival continued to favor ATRA-ATO (87% vs 55%; P = .0034).

The estimated 5-year overall survival was 93% vs 82% for ATRA/ATO vs ATRA-chemotherapy, respectively, which was not significantly different (P = .17).

There were no significant differences between the arms in complete response (93% with ATRA/ATO vs 91% with ATRA-chemotherapy; P = .65), and rates of early death (within the first 30 days) were also similar across arms, at 7% vs 10%, respectively.

Death while in complete remission occurred in zero patients in the ATRA/ATO arm and three in the ATRA chemotherapy arm.

In terms of toxicities, the ATRA/ATO group had significantly lower rates of hematologic toxicity versus ATRA-chemotherapy, including rates of thrombocytopenia grade 1-4 and neutropenia grade 3-4 (P < .001), while there were no significant differences between the groups in hepatic toxicities (11.8% and 14.3%, respectively; P = .08) or differentiation syndrome (1.5% vs 4.8%; P = .27).

QTc prolongation grade 3-4 occurred in 4.4 patients receiving ATRA/ATO, compared with 0 in the ATRA-chemotherapy group; however, Dr. Platzbecker said the cases had no clinical implications.

Asked to elaborate on the regimens’ toxicities in the press briefing, Dr. Platzbecker noted that “what is very important especially for patients, is [lower rates] of issues such as hair loss and constipation that are much less common with the ATRO/ATO regimen.”

“In addition, we know from the early experiences with this that younger patients are being cured by this regimen,” hence improving pregnancy prospects for women.

A take-home message from the overall results is that the ATRO/ATO regimen for high-risk APL patients should represent “a new treatment paradigm” that will “hopefully soon” be reflected in guideline recommendations, Dr. Platzbecker said in an interview.
 

Concerns Included Relapse, Differentiation Syndrome

Commenting on the research, Mikkael A. Sekeres, MD, explained that, while the “less is more” non-chemotherapy approach was adopted in widespread utilization in low-risk APL because of superior outcomes, a variety of concerns surrounded its use in high-risk patients.

“In high-risk patients, there were concerns that a durable response would be lower and that relapse would be higher for patients receiving ATRA and ATO than those receiving standard chemotherapy,” Dr. Sekeres, who is chief of the division of hematology, department of medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, said in an interview.

“In addition, it was theoretically possible that patients receiving the differentiating agents ATRA and ATO could suffer higher rates of differentiation syndrome, which could contribute to early death,” he explained. “These fears were simply not realized in the trial.”

Caveats of the trial “include the relatively small sample size and that the trial was stopped prematurely due to low enrollment during the COVID pandemic,” he noted.

Another limitation was the median follow-up of about 2.5 years.

However, Dr. Sekeres said he agreed that, “with further follow-up and continued superiority of the idarubicin, ATRA, and ATO combination, this could become a new standard of care for high-risk patients with APL.”

Dr. Platzbecker’s disclosures include ties with Teva, BMS, Curis, Janssen, AbbVie, and Takeda. Dr. Sekeres had no disclosures.

The chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) that is standard in treating low-risk acute promyelocytic leukemia (APL) also shows superior benefits in the high-risk APL population, suggesting the regimen should become the standard in those patients as well, new research shows.

“First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior event-free survival, compared to conventional ATRA-chemotherapy in patients with high-risk APL,” said first author Uwe Platzbecker, MD, of the University Hospital Leipzig, department for hematology, cellular therapy, hemostaseology, and infectious diseases, in Leipzig, Germany, at the annual meeting of the European Hematology Association (EHA) in Madrid, Spain.

“We believe that the trial may support the implementation of this regimen as a new standard of care in all patients with high-risk APL,” he said.

In the treatment of low and intermediate risk APL, a subtype of acute myeloid leukemia (AML), the combination of ATRA and ATO has become standard since being shown in a pivotal 2013 study to be superior versus ATRA and chemotherapy. The approach is approved by the Food and Drug Administration in the treatment of adults with newly diagnosed low-risk APL.

Importantly, the improved survival with ATRA/ATO approach may result from “reduced severe hematologic toxicity together with similar antileukemic efficacy,” compared with the regimen that include chemotherapy, the authors of the 2013 study speculated.

However, the treatment regimen has not been evaluated in randomized trials in patients with high-risk APL, defined as having a white blood cell count of more than 10,000 cells per μL.

For those patients, the conventional treatment remains ATRA with a chemotherapy backbone, Dr. Platzbecker explained.

To evaluate if the improvements extend to high-risk APL patients without compromising safety, Dr. Platzbecker and colleagues conducted the open-label, prospective APOLLO trial, involving newly diagnosed high-risk APL who were enrolled between 2016 and 2022 at 143 sites in six European countries.

The patients were randomized into one of two groups: ATRA/ATO, involving treatment consisting of two doses of idarubicin (12 mg/m²) on days 1 and 3 at the time of induction therapy, in addition to ATO 0.15 mg/kg and ATRA 45 mg/m², daily until complete remission, or the ATRA-chemotherapy arm, involving standard ATRA also with idarubicin induction, followed by three cycles of chemotherapy-based consolidation as well as 2 years of maintenance treatment.

While the study was prematurely discontinued in August 2022 because of COVID-19–related recruitment delays and expiration of the study drug, the maintenance and observational periods are ongoing.

Of 131 patients with high-risk APL who were evaluable for the outcome analysis, 68 were in the ATRA/ATO group and 63 in the ATRA-chemotherapy arm.

Overall, participants had a mean age of 46, 50% were female, their median Eastern Cooperative Oncology Group score was 1. Their median white blood cell count was 36 × 10⁹/L, with 39% having a white blood cell count greater than 50 × 10⁹/L.

Molecular resistance occurred in 1.7% in the ATRA/ATO arm vs 5.5% in the ATRA chemotherapy arm, which was not statistically significant (P = .268); however, the incidence of molecular relapse was much lower without chemotherapy, at 1.6% with ATRA/ATO vs 14% with ATRA and chemotherapy.

For the primary endpoint, with a median follow-up of 31 months, the 2-year rate of event-free survival those in the ATRA/ATO arm was 88% vs 70% in the ATRA plus chemotherapy regimen (P = .02). The 5-year event-free survival continued to favor ATRA-ATO (87% vs 55%; P = .0034).

The estimated 5-year overall survival was 93% vs 82% for ATRA/ATO vs ATRA-chemotherapy, respectively, which was not significantly different (P = .17).

There were no significant differences between the arms in complete response (93% with ATRA/ATO vs 91% with ATRA-chemotherapy; P = .65), and rates of early death (within the first 30 days) were also similar across arms, at 7% vs 10%, respectively.

Death while in complete remission occurred in zero patients in the ATRA/ATO arm and three in the ATRA chemotherapy arm.

In terms of toxicities, the ATRA/ATO group had significantly lower rates of hematologic toxicity versus ATRA-chemotherapy, including rates of thrombocytopenia grade 1-4 and neutropenia grade 3-4 (P < .001), while there were no significant differences between the groups in hepatic toxicities (11.8% and 14.3%, respectively; P = .08) or differentiation syndrome (1.5% vs 4.8%; P = .27).

QTc prolongation grade 3-4 occurred in 4.4 patients receiving ATRA/ATO, compared with 0 in the ATRA-chemotherapy group; however, Dr. Platzbecker said the cases had no clinical implications.

Asked to elaborate on the regimens’ toxicities in the press briefing, Dr. Platzbecker noted that “what is very important especially for patients, is [lower rates] of issues such as hair loss and constipation that are much less common with the ATRO/ATO regimen.”

“In addition, we know from the early experiences with this that younger patients are being cured by this regimen,” hence improving pregnancy prospects for women.

A take-home message from the overall results is that the ATRO/ATO regimen for high-risk APL patients should represent “a new treatment paradigm” that will “hopefully soon” be reflected in guideline recommendations, Dr. Platzbecker said in an interview.
 

Concerns Included Relapse, Differentiation Syndrome

Commenting on the research, Mikkael A. Sekeres, MD, explained that, while the “less is more” non-chemotherapy approach was adopted in widespread utilization in low-risk APL because of superior outcomes, a variety of concerns surrounded its use in high-risk patients.

“In high-risk patients, there were concerns that a durable response would be lower and that relapse would be higher for patients receiving ATRA and ATO than those receiving standard chemotherapy,” Dr. Sekeres, who is chief of the division of hematology, department of medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, said in an interview.

“In addition, it was theoretically possible that patients receiving the differentiating agents ATRA and ATO could suffer higher rates of differentiation syndrome, which could contribute to early death,” he explained. “These fears were simply not realized in the trial.”

Caveats of the trial “include the relatively small sample size and that the trial was stopped prematurely due to low enrollment during the COVID pandemic,” he noted.

Another limitation was the median follow-up of about 2.5 years.

However, Dr. Sekeres said he agreed that, “with further follow-up and continued superiority of the idarubicin, ATRA, and ATO combination, this could become a new standard of care for high-risk patients with APL.”

Dr. Platzbecker’s disclosures include ties with Teva, BMS, Curis, Janssen, AbbVie, and Takeda. Dr. Sekeres had no disclosures.

The chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) that is standard in treating low-risk acute promyelocytic leukemia (APL) also shows superior benefits in the high-risk APL population, suggesting the regimen should become the standard in those patients as well, new research shows.

“First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior event-free survival, compared to conventional ATRA-chemotherapy in patients with high-risk APL,” said first author Uwe Platzbecker, MD, of the University Hospital Leipzig, department for hematology, cellular therapy, hemostaseology, and infectious diseases, in Leipzig, Germany, at the annual meeting of the European Hematology Association (EHA) in Madrid, Spain.

“We believe that the trial may support the implementation of this regimen as a new standard of care in all patients with high-risk APL,” he said.

In the treatment of low and intermediate risk APL, a subtype of acute myeloid leukemia (AML), the combination of ATRA and ATO has become standard since being shown in a pivotal 2013 study to be superior versus ATRA and chemotherapy. The approach is approved by the Food and Drug Administration in the treatment of adults with newly diagnosed low-risk APL.

Importantly, the improved survival with ATRA/ATO approach may result from “reduced severe hematologic toxicity together with similar antileukemic efficacy,” compared with the regimen that include chemotherapy, the authors of the 2013 study speculated.

However, the treatment regimen has not been evaluated in randomized trials in patients with high-risk APL, defined as having a white blood cell count of more than 10,000 cells per μL.

For those patients, the conventional treatment remains ATRA with a chemotherapy backbone, Dr. Platzbecker explained.

To evaluate if the improvements extend to high-risk APL patients without compromising safety, Dr. Platzbecker and colleagues conducted the open-label, prospective APOLLO trial, involving newly diagnosed high-risk APL who were enrolled between 2016 and 2022 at 143 sites in six European countries.

The patients were randomized into one of two groups: ATRA/ATO, involving treatment consisting of two doses of idarubicin (12 mg/m²) on days 1 and 3 at the time of induction therapy, in addition to ATO 0.15 mg/kg and ATRA 45 mg/m², daily until complete remission, or the ATRA-chemotherapy arm, involving standard ATRA also with idarubicin induction, followed by three cycles of chemotherapy-based consolidation as well as 2 years of maintenance treatment.

While the study was prematurely discontinued in August 2022 because of COVID-19–related recruitment delays and expiration of the study drug, the maintenance and observational periods are ongoing.

Of 131 patients with high-risk APL who were evaluable for the outcome analysis, 68 were in the ATRA/ATO group and 63 in the ATRA-chemotherapy arm.

Overall, participants had a mean age of 46, 50% were female, their median Eastern Cooperative Oncology Group score was 1. Their median white blood cell count was 36 × 10⁹/L, with 39% having a white blood cell count greater than 50 × 10⁹/L.

Molecular resistance occurred in 1.7% in the ATRA/ATO arm vs 5.5% in the ATRA chemotherapy arm, which was not statistically significant (P = .268); however, the incidence of molecular relapse was much lower without chemotherapy, at 1.6% with ATRA/ATO vs 14% with ATRA and chemotherapy.

For the primary endpoint, with a median follow-up of 31 months, the 2-year rate of event-free survival those in the ATRA/ATO arm was 88% vs 70% in the ATRA plus chemotherapy regimen (P = .02). The 5-year event-free survival continued to favor ATRA-ATO (87% vs 55%; P = .0034).

The estimated 5-year overall survival was 93% vs 82% for ATRA/ATO vs ATRA-chemotherapy, respectively, which was not significantly different (P = .17).

There were no significant differences between the arms in complete response (93% with ATRA/ATO vs 91% with ATRA-chemotherapy; P = .65), and rates of early death (within the first 30 days) were also similar across arms, at 7% vs 10%, respectively.

Death while in complete remission occurred in zero patients in the ATRA/ATO arm and three in the ATRA chemotherapy arm.

In terms of toxicities, the ATRA/ATO group had significantly lower rates of hematologic toxicity versus ATRA-chemotherapy, including rates of thrombocytopenia grade 1-4 and neutropenia grade 3-4 (P < .001), while there were no significant differences between the groups in hepatic toxicities (11.8% and 14.3%, respectively; P = .08) or differentiation syndrome (1.5% vs 4.8%; P = .27).

QTc prolongation grade 3-4 occurred in 4.4 patients receiving ATRA/ATO, compared with 0 in the ATRA-chemotherapy group; however, Dr. Platzbecker said the cases had no clinical implications.

Asked to elaborate on the regimens’ toxicities in the press briefing, Dr. Platzbecker noted that “what is very important especially for patients, is [lower rates] of issues such as hair loss and constipation that are much less common with the ATRO/ATO regimen.”

“In addition, we know from the early experiences with this that younger patients are being cured by this regimen,” hence improving pregnancy prospects for women.

A take-home message from the overall results is that the ATRO/ATO regimen for high-risk APL patients should represent “a new treatment paradigm” that will “hopefully soon” be reflected in guideline recommendations, Dr. Platzbecker said in an interview.
 

Concerns Included Relapse, Differentiation Syndrome

Commenting on the research, Mikkael A. Sekeres, MD, explained that, while the “less is more” non-chemotherapy approach was adopted in widespread utilization in low-risk APL because of superior outcomes, a variety of concerns surrounded its use in high-risk patients.

“In high-risk patients, there were concerns that a durable response would be lower and that relapse would be higher for patients receiving ATRA and ATO than those receiving standard chemotherapy,” Dr. Sekeres, who is chief of the division of hematology, department of medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, said in an interview.

“In addition, it was theoretically possible that patients receiving the differentiating agents ATRA and ATO could suffer higher rates of differentiation syndrome, which could contribute to early death,” he explained. “These fears were simply not realized in the trial.”

Caveats of the trial “include the relatively small sample size and that the trial was stopped prematurely due to low enrollment during the COVID pandemic,” he noted.

Another limitation was the median follow-up of about 2.5 years.

However, Dr. Sekeres said he agreed that, “with further follow-up and continued superiority of the idarubicin, ATRA, and ATO combination, this could become a new standard of care for high-risk patients with APL.”

Dr. Platzbecker’s disclosures include ties with Teva, BMS, Curis, Janssen, AbbVie, and Takeda. Dr. Sekeres had no disclosures.

Skin manifestations are common in the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and present early in the disease course. Additionally, the most common histologic findings include leukocytoclastic vasculitis, neutrophilic dermatosis, and perivascular dermatitis; different variants in the UBA1 gene are associated with specific skin manifestations.

Those are key findings from a cohort study of 112 patients with VEXAS published online in JAMA Dermatology. The study, conducted by researchers at the National Institutes of Health (NIH) and several other institutions, aimed to define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histologic, and other clinical findings.

vutipragesahuledustukumuroceuuwefracawonauowragoslurajosadrethodrejuwraswocradawrocrapobebithagirespodrowapawrugiuochobaprustoverecewrepabribromebutiphiclislupanacrasuslishumitislojethoclepabajegibacrolo

First described in 2020, VEXAS syndrome is an adult-onset multisystem disease that can pose a diagnostic challenge to clinicians, the study’s corresponding author, Edward W. Cowen, MD, MHSc, of the dermatology branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), said in an interview. The disease is caused by pathogenic variants in the UBA1 gene, located on the X chromosome. Affected individuals exhibit a wide range of manifestations, including cytopenia/myelodysplasia, multiorgan systemic inflammation, and cutaneous involvement.

“Patients may present to a variety of disease specialists depending on their symptoms and providers may not immediately consider a genetic etiology in an older individual,” Dr. Cowen said in an interview. “Although skin involvement occurs in more than 80% of patients, it is pleomorphic and may resemble a variety of other conditions such as vasculitis and Sweet syndrome.”

To better understand the cutaneous manifestations of VEXAS syndrome, the researchers evaluated data from 112 patients with VEXAS-defining genetic variants in the UBA1 gene between 2019 and 2023. Of the 112 patients, 73 underwent medical record review only, and 39 were prospectively evaluated at NIH. All but one of the patients were men, 94% were White individuals, and their mean age was 64 years. Skin involvement occurred in 83% of cases and was the most common presenting feature of VEXAS in 61% of cases.

Of the 64 histopathologic reports available from 60 patients, the main skin histopathologic findings were leukocytoclastic vasculitis in 23 patients (36%), neutrophilic dermatosis in 22 patients (34%), and perivascular dermatitis in 19 patients (30%). According to Dr. Cowen, one key histologic finding was a distinct pattern of “histiocytoid” dermal neutrophilic inflammation, which was present in 13 of 15 specimens (86%) that underwent central re-review. “This pattern can occasionally also be seen in patients with Sweet syndrome, unrelated to VEXAS, but was a hallmark feature found in the majority of skin biopsies of patients with VEXAS,” he said.

chetrabibrocrinutipishoprouodawubochushetibreshororuvustuphatrodadrofrepesheneclimothosilispucewriclamabisanibisiberiwowru

“Together with another pathologic finding, leukocytoclasia, these features can be useful clues to alert the pathologist to a potential diagnosis of VEXAS. This myeloid predominant pattern of skin inflammation was also most strongly associated with the leucine pathogenic variant of the UBA1 gene.” In contrast, cutaneous vasculitis was most strongly associated with the valine pathogenic variant of UBA1. “This is important because the valine variant has been previously independently linked to decreased survival,” he said.

In findings related to pathogenic genetic variants, the researchers observed that the p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates in 14 of 17 patients (82%) with this variant and often resembled histiocytoid Sweet syndrome. In addition, the p.Met41Val variant was associated with vasculitic lesions in 11 of 20 patients (55%) with this variant and with a mixed leukocytic infiltrate in 17 of these 20 patients (85%).
 

Treatment Outcomes

In the realm of therapies, skin manifestations improved in 67 of 73 patients (92%) treated with oral prednisone, while treatment with the interleukin-1 receptor antagonist anakinra improved cutaneous disease in 9 of the 16 (56%) who received it. However, 12 (75%) of those who received anakinra developed severe injection-site reactions, including ulceration in two patients and abscess formation in one patient.

Dr. Cowen noted that VEXAS is associated with high mortality (22% in this cohort), and a high degree of suspicion is required to diagnose patients with VEXAS before significant end organ damage has occurred. “This diagnosis should be considered in all older male patients who present with neutrophilic dermatosis — particularly histiocytoid Sweet syndrome, vasculitis, or leukocytoclasia without vasculitis. Patients who appear to have isolated skin involvement may have cytopenias and acute phase reactants. Therefore, complete blood count with differential and ESR and CRP should be considered to investigate for macrocytosis, cytopenias, and systemic inflammation.”

He acknowledged certain limitations of the study, including the fact that many patients were first evaluated at the NIH after having disease symptoms for many months or years. “It is possible that patients with VEXAS referred to the NIH, either for genetic testing or in person evaluation, represent a population with more aggressive disease.”

[embed:render:related:node:238910]

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was asked to comment on the study, emphasized the importance of the UBA1 mutation in the diagnosis of this complex syndrome. “Dermatologists should be aware of VEXAS syndrome as the majority of patients present with skin lesions, which can range from urticarial to Sweet syndrome–like to palpable purpura,” Dr. Ko said.

“Chondritis and periorbital edema, sometimes unilateral, are also associated. Histopathologic clues include a predominantly histiocytoid infiltrate,” she noted. In addition, “the prominent myxoid stroma around blood vessels and adnexal structures as a clue to VEXAS syndrome surprised me; I had not read that before.”

The study was supported by the Intramural Research Program of NIAMS. One of the study authors reported personal fees from Alexion, Novartis, and Sobi outside of the submitted work. No other disclosures were reported. Dr. Ko reported having no disclosures.

A version of this article appeared on Medscape.com .

Skin manifestations are common in the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and present early in the disease course. Additionally, the most common histologic findings include leukocytoclastic vasculitis, neutrophilic dermatosis, and perivascular dermatitis; different variants in the UBA1 gene are associated with specific skin manifestations.

Those are key findings from a cohort study of 112 patients with VEXAS published online in JAMA Dermatology. The study, conducted by researchers at the National Institutes of Health (NIH) and several other institutions, aimed to define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histologic, and other clinical findings.

vutipragesahuledustukumuroceuuwefracawonauowragoslurajosadrethodrejuwraswocradawrocrapobebithagirespodrowapawrugiuochobaprustoverecewrepabribromebutiphiclislupanacrasuslishumitislojethoclepabajegibacrolo

First described in 2020, VEXAS syndrome is an adult-onset multisystem disease that can pose a diagnostic challenge to clinicians, the study’s corresponding author, Edward W. Cowen, MD, MHSc, of the dermatology branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), said in an interview. The disease is caused by pathogenic variants in the UBA1 gene, located on the X chromosome. Affected individuals exhibit a wide range of manifestations, including cytopenia/myelodysplasia, multiorgan systemic inflammation, and cutaneous involvement.

“Patients may present to a variety of disease specialists depending on their symptoms and providers may not immediately consider a genetic etiology in an older individual,” Dr. Cowen said in an interview. “Although skin involvement occurs in more than 80% of patients, it is pleomorphic and may resemble a variety of other conditions such as vasculitis and Sweet syndrome.”

To better understand the cutaneous manifestations of VEXAS syndrome, the researchers evaluated data from 112 patients with VEXAS-defining genetic variants in the UBA1 gene between 2019 and 2023. Of the 112 patients, 73 underwent medical record review only, and 39 were prospectively evaluated at NIH. All but one of the patients were men, 94% were White individuals, and their mean age was 64 years. Skin involvement occurred in 83% of cases and was the most common presenting feature of VEXAS in 61% of cases.

Of the 64 histopathologic reports available from 60 patients, the main skin histopathologic findings were leukocytoclastic vasculitis in 23 patients (36%), neutrophilic dermatosis in 22 patients (34%), and perivascular dermatitis in 19 patients (30%). According to Dr. Cowen, one key histologic finding was a distinct pattern of “histiocytoid” dermal neutrophilic inflammation, which was present in 13 of 15 specimens (86%) that underwent central re-review. “This pattern can occasionally also be seen in patients with Sweet syndrome, unrelated to VEXAS, but was a hallmark feature found in the majority of skin biopsies of patients with VEXAS,” he said.

chetrabibrocrinutipishoprouodawubochushetibreshororuvustuphatrodadrofrepesheneclimothosilispucewriclamabisanibisiberiwowru

“Together with another pathologic finding, leukocytoclasia, these features can be useful clues to alert the pathologist to a potential diagnosis of VEXAS. This myeloid predominant pattern of skin inflammation was also most strongly associated with the leucine pathogenic variant of the UBA1 gene.” In contrast, cutaneous vasculitis was most strongly associated with the valine pathogenic variant of UBA1. “This is important because the valine variant has been previously independently linked to decreased survival,” he said.

In findings related to pathogenic genetic variants, the researchers observed that the p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates in 14 of 17 patients (82%) with this variant and often resembled histiocytoid Sweet syndrome. In addition, the p.Met41Val variant was associated with vasculitic lesions in 11 of 20 patients (55%) with this variant and with a mixed leukocytic infiltrate in 17 of these 20 patients (85%).
 

Treatment Outcomes

In the realm of therapies, skin manifestations improved in 67 of 73 patients (92%) treated with oral prednisone, while treatment with the interleukin-1 receptor antagonist anakinra improved cutaneous disease in 9 of the 16 (56%) who received it. However, 12 (75%) of those who received anakinra developed severe injection-site reactions, including ulceration in two patients and abscess formation in one patient.

Dr. Cowen noted that VEXAS is associated with high mortality (22% in this cohort), and a high degree of suspicion is required to diagnose patients with VEXAS before significant end organ damage has occurred. “This diagnosis should be considered in all older male patients who present with neutrophilic dermatosis — particularly histiocytoid Sweet syndrome, vasculitis, or leukocytoclasia without vasculitis. Patients who appear to have isolated skin involvement may have cytopenias and acute phase reactants. Therefore, complete blood count with differential and ESR and CRP should be considered to investigate for macrocytosis, cytopenias, and systemic inflammation.”

He acknowledged certain limitations of the study, including the fact that many patients were first evaluated at the NIH after having disease symptoms for many months or years. “It is possible that patients with VEXAS referred to the NIH, either for genetic testing or in person evaluation, represent a population with more aggressive disease.”

[embed:render:related:node:238910]

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was asked to comment on the study, emphasized the importance of the UBA1 mutation in the diagnosis of this complex syndrome. “Dermatologists should be aware of VEXAS syndrome as the majority of patients present with skin lesions, which can range from urticarial to Sweet syndrome–like to palpable purpura,” Dr. Ko said.

“Chondritis and periorbital edema, sometimes unilateral, are also associated. Histopathologic clues include a predominantly histiocytoid infiltrate,” she noted. In addition, “the prominent myxoid stroma around blood vessels and adnexal structures as a clue to VEXAS syndrome surprised me; I had not read that before.”

The study was supported by the Intramural Research Program of NIAMS. One of the study authors reported personal fees from Alexion, Novartis, and Sobi outside of the submitted work. No other disclosures were reported. Dr. Ko reported having no disclosures.

A version of this article appeared on Medscape.com .

Skin manifestations are common in the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and present early in the disease course. Additionally, the most common histologic findings include leukocytoclastic vasculitis, neutrophilic dermatosis, and perivascular dermatitis; different variants in the UBA1 gene are associated with specific skin manifestations.

Those are key findings from a cohort study of 112 patients with VEXAS published online in JAMA Dermatology. The study, conducted by researchers at the National Institutes of Health (NIH) and several other institutions, aimed to define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histologic, and other clinical findings.

vutipragesahuledustukumuroceuuwefracawonauowragoslurajosadrethodrejuwraswocradawrocrapobebithagirespodrowapawrugiuochobaprustoverecewrepabribromebutiphiclislupanacrasuslishumitislojethoclepabajegibacrolo

First described in 2020, VEXAS syndrome is an adult-onset multisystem disease that can pose a diagnostic challenge to clinicians, the study’s corresponding author, Edward W. Cowen, MD, MHSc, of the dermatology branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), said in an interview. The disease is caused by pathogenic variants in the UBA1 gene, located on the X chromosome. Affected individuals exhibit a wide range of manifestations, including cytopenia/myelodysplasia, multiorgan systemic inflammation, and cutaneous involvement.

“Patients may present to a variety of disease specialists depending on their symptoms and providers may not immediately consider a genetic etiology in an older individual,” Dr. Cowen said in an interview. “Although skin involvement occurs in more than 80% of patients, it is pleomorphic and may resemble a variety of other conditions such as vasculitis and Sweet syndrome.”

To better understand the cutaneous manifestations of VEXAS syndrome, the researchers evaluated data from 112 patients with VEXAS-defining genetic variants in the UBA1 gene between 2019 and 2023. Of the 112 patients, 73 underwent medical record review only, and 39 were prospectively evaluated at NIH. All but one of the patients were men, 94% were White individuals, and their mean age was 64 years. Skin involvement occurred in 83% of cases and was the most common presenting feature of VEXAS in 61% of cases.

Of the 64 histopathologic reports available from 60 patients, the main skin histopathologic findings were leukocytoclastic vasculitis in 23 patients (36%), neutrophilic dermatosis in 22 patients (34%), and perivascular dermatitis in 19 patients (30%). According to Dr. Cowen, one key histologic finding was a distinct pattern of “histiocytoid” dermal neutrophilic inflammation, which was present in 13 of 15 specimens (86%) that underwent central re-review. “This pattern can occasionally also be seen in patients with Sweet syndrome, unrelated to VEXAS, but was a hallmark feature found in the majority of skin biopsies of patients with VEXAS,” he said.

chetrabibrocrinutipishoprouodawubochushetibreshororuvustuphatrodadrofrepesheneclimothosilispucewriclamabisanibisiberiwowru

“Together with another pathologic finding, leukocytoclasia, these features can be useful clues to alert the pathologist to a potential diagnosis of VEXAS. This myeloid predominant pattern of skin inflammation was also most strongly associated with the leucine pathogenic variant of the UBA1 gene.” In contrast, cutaneous vasculitis was most strongly associated with the valine pathogenic variant of UBA1. “This is important because the valine variant has been previously independently linked to decreased survival,” he said.

In findings related to pathogenic genetic variants, the researchers observed that the p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates in 14 of 17 patients (82%) with this variant and often resembled histiocytoid Sweet syndrome. In addition, the p.Met41Val variant was associated with vasculitic lesions in 11 of 20 patients (55%) with this variant and with a mixed leukocytic infiltrate in 17 of these 20 patients (85%).
 

Treatment Outcomes

In the realm of therapies, skin manifestations improved in 67 of 73 patients (92%) treated with oral prednisone, while treatment with the interleukin-1 receptor antagonist anakinra improved cutaneous disease in 9 of the 16 (56%) who received it. However, 12 (75%) of those who received anakinra developed severe injection-site reactions, including ulceration in two patients and abscess formation in one patient.

Dr. Cowen noted that VEXAS is associated with high mortality (22% in this cohort), and a high degree of suspicion is required to diagnose patients with VEXAS before significant end organ damage has occurred. “This diagnosis should be considered in all older male patients who present with neutrophilic dermatosis — particularly histiocytoid Sweet syndrome, vasculitis, or leukocytoclasia without vasculitis. Patients who appear to have isolated skin involvement may have cytopenias and acute phase reactants. Therefore, complete blood count with differential and ESR and CRP should be considered to investigate for macrocytosis, cytopenias, and systemic inflammation.”

He acknowledged certain limitations of the study, including the fact that many patients were first evaluated at the NIH after having disease symptoms for many months or years. “It is possible that patients with VEXAS referred to the NIH, either for genetic testing or in person evaluation, represent a population with more aggressive disease.”

[embed:render:related:node:238910]

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was asked to comment on the study, emphasized the importance of the UBA1 mutation in the diagnosis of this complex syndrome. “Dermatologists should be aware of VEXAS syndrome as the majority of patients present with skin lesions, which can range from urticarial to Sweet syndrome–like to palpable purpura,” Dr. Ko said.

“Chondritis and periorbital edema, sometimes unilateral, are also associated. Histopathologic clues include a predominantly histiocytoid infiltrate,” she noted. In addition, “the prominent myxoid stroma around blood vessels and adnexal structures as a clue to VEXAS syndrome surprised me; I had not read that before.”

The study was supported by the Intramural Research Program of NIAMS. One of the study authors reported personal fees from Alexion, Novartis, and Sobi outside of the submitted work. No other disclosures were reported. Dr. Ko reported having no disclosures.

A version of this article appeared on Medscape.com .