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MCL: Ibrutinib could become the ‘new standard’
First-line patients fared well on ibrutinib, a Bruton’s tyrosine kinase inhibitor, according to the findings.
“Based on the results so far ... at least for the majority of patients, ibrutinib early will become the new standard,” said study lead author Martin Dreyling, MD, associate professor of medicine at Ludwig Maximilian University (LMU) Munich. Dr. Dreyling spoke in a news briefing and at a separate presentation at the annual meeting of the American Society of Hematology. “It might well be that specific subsets of patients may benefit from autologous transplant.”
MCL is a rare form of non-Hodgkin’s lymphoma that strikes cells in the mantle zone of lymph nodes. It is usually diagnosed in older men and often presents at an advanced stage. Multiple available treatments include rituximab/bendamustine, CAR-T cell therapy, stem cell transplants, and Bruton’s tyrosine kinase inhibitors. Ibrutinib is approved by the Food and Drug Administration only for refractory/relapsed cases, however.
Dr. Dreyling was a pioneer in confirming benefit from stem-cell transplants for MCL. “However,” he said, “no one likes autologous transplant because it also has side effects.”
For the new open-label study, Dr. Dreyling and colleagues in the European MCL Network in 2016 began recruiting patients with newly diagnosed, advanced stage II-IV MCL. The patients were younger than 65.
The subjects were randomly assigned to three trial arms: Standard treatment (high-dose cytarabine followed by autologous stem cell transplant and rituximab maintenance, n = 288), the standard treatment plus ibrutinib (n = 292), and ibrutinib without stem cell transplant (n = 290). The median age was 57, and 76% of patients were male.
The primary endpoint was failure-free survival at 31 months. Standard therapy was not superior to the ibrutinib without transplant group (72% vs. 86%, respectively, P = .9979). However, standard therapy with ibrutinib was superior to the standard therapy group (88% vs. 72%, respectively, P = .0008). The researchers haven’t finished their analysis of standard therapy with ibrutinib vs. ibrutinib without transplant.
Subjects in the standard therapy plus ibrutinib arm had more grade 3-5 adverse events than did the standard therapy and ibrutinib without transplant groups: Neutropenia, 44%, 17%, and 23%, respectively; leukopenia, 4%, 2%, and 2%; febrile neutropenia, 6%, 3%, and 3%; infections and infestations, 25%, 13%, and 19%; and cardiac disorders, 3%, 1%, 4%. P values were not provided.
In an interview, Ohio State University hematologist Narendranath Epperla, MD, MS, who was not involved in the study, said that this research reflects efforts to understand how novel agents such as ibrutinib and cellular therapies fit into MCL treatment. “We are trying to incorporate them in the frontline setting with either chemo backbone or with other targeted agents to improve outcomes and minimize toxicity. We are also trying to understand in whom auto-HCT can be precluded.”
The results of the new study appear promising, Dr. Epperla said, but he questioned the primary endpoint (failure-free survival instead of progress-free survival) and the short duration of the trial.
“I would like to see how the patients with high-risk features such as TP53 mutation, complex cytogenetics, and blastoid/pleomorphic variants did on the three arms,” Dr. Epperla said. “And I would like to see longer follow-up data before adapting this – [addition] of ibrutinib to the chemotherapy backbone without auto-HCT – into clinical practice.”
What’s next? Dr. Dreyling said that upcoming data will provide further insight into ibrutinib vs. stem-cell transplantation. And “within the next half year or so,” he said, “there will be a next generation of studies challenging chemotherapy overall in mantle cell lymphoma and substituting targeted treatment, hopefully achieving much better tolerability.”
Funding information was not provided. Dr. Dreyling disclosed ties with Lilly/Loxo, AstraZeneca, Novartis, Amgen, Roche, Janssen, Gilead/Kite, BMS/Celgene, Bayer, Abbvie, and Beigene. The other study authors reported various disclosures. Dr. Epperla disclosed a relationship with Pharmacyclics.
First-line patients fared well on ibrutinib, a Bruton’s tyrosine kinase inhibitor, according to the findings.
“Based on the results so far ... at least for the majority of patients, ibrutinib early will become the new standard,” said study lead author Martin Dreyling, MD, associate professor of medicine at Ludwig Maximilian University (LMU) Munich. Dr. Dreyling spoke in a news briefing and at a separate presentation at the annual meeting of the American Society of Hematology. “It might well be that specific subsets of patients may benefit from autologous transplant.”
MCL is a rare form of non-Hodgkin’s lymphoma that strikes cells in the mantle zone of lymph nodes. It is usually diagnosed in older men and often presents at an advanced stage. Multiple available treatments include rituximab/bendamustine, CAR-T cell therapy, stem cell transplants, and Bruton’s tyrosine kinase inhibitors. Ibrutinib is approved by the Food and Drug Administration only for refractory/relapsed cases, however.
Dr. Dreyling was a pioneer in confirming benefit from stem-cell transplants for MCL. “However,” he said, “no one likes autologous transplant because it also has side effects.”
For the new open-label study, Dr. Dreyling and colleagues in the European MCL Network in 2016 began recruiting patients with newly diagnosed, advanced stage II-IV MCL. The patients were younger than 65.
The subjects were randomly assigned to three trial arms: Standard treatment (high-dose cytarabine followed by autologous stem cell transplant and rituximab maintenance, n = 288), the standard treatment plus ibrutinib (n = 292), and ibrutinib without stem cell transplant (n = 290). The median age was 57, and 76% of patients were male.
The primary endpoint was failure-free survival at 31 months. Standard therapy was not superior to the ibrutinib without transplant group (72% vs. 86%, respectively, P = .9979). However, standard therapy with ibrutinib was superior to the standard therapy group (88% vs. 72%, respectively, P = .0008). The researchers haven’t finished their analysis of standard therapy with ibrutinib vs. ibrutinib without transplant.
Subjects in the standard therapy plus ibrutinib arm had more grade 3-5 adverse events than did the standard therapy and ibrutinib without transplant groups: Neutropenia, 44%, 17%, and 23%, respectively; leukopenia, 4%, 2%, and 2%; febrile neutropenia, 6%, 3%, and 3%; infections and infestations, 25%, 13%, and 19%; and cardiac disorders, 3%, 1%, 4%. P values were not provided.
In an interview, Ohio State University hematologist Narendranath Epperla, MD, MS, who was not involved in the study, said that this research reflects efforts to understand how novel agents such as ibrutinib and cellular therapies fit into MCL treatment. “We are trying to incorporate them in the frontline setting with either chemo backbone or with other targeted agents to improve outcomes and minimize toxicity. We are also trying to understand in whom auto-HCT can be precluded.”
The results of the new study appear promising, Dr. Epperla said, but he questioned the primary endpoint (failure-free survival instead of progress-free survival) and the short duration of the trial.
“I would like to see how the patients with high-risk features such as TP53 mutation, complex cytogenetics, and blastoid/pleomorphic variants did on the three arms,” Dr. Epperla said. “And I would like to see longer follow-up data before adapting this – [addition] of ibrutinib to the chemotherapy backbone without auto-HCT – into clinical practice.”
What’s next? Dr. Dreyling said that upcoming data will provide further insight into ibrutinib vs. stem-cell transplantation. And “within the next half year or so,” he said, “there will be a next generation of studies challenging chemotherapy overall in mantle cell lymphoma and substituting targeted treatment, hopefully achieving much better tolerability.”
Funding information was not provided. Dr. Dreyling disclosed ties with Lilly/Loxo, AstraZeneca, Novartis, Amgen, Roche, Janssen, Gilead/Kite, BMS/Celgene, Bayer, Abbvie, and Beigene. The other study authors reported various disclosures. Dr. Epperla disclosed a relationship with Pharmacyclics.
First-line patients fared well on ibrutinib, a Bruton’s tyrosine kinase inhibitor, according to the findings.
“Based on the results so far ... at least for the majority of patients, ibrutinib early will become the new standard,” said study lead author Martin Dreyling, MD, associate professor of medicine at Ludwig Maximilian University (LMU) Munich. Dr. Dreyling spoke in a news briefing and at a separate presentation at the annual meeting of the American Society of Hematology. “It might well be that specific subsets of patients may benefit from autologous transplant.”
MCL is a rare form of non-Hodgkin’s lymphoma that strikes cells in the mantle zone of lymph nodes. It is usually diagnosed in older men and often presents at an advanced stage. Multiple available treatments include rituximab/bendamustine, CAR-T cell therapy, stem cell transplants, and Bruton’s tyrosine kinase inhibitors. Ibrutinib is approved by the Food and Drug Administration only for refractory/relapsed cases, however.
Dr. Dreyling was a pioneer in confirming benefit from stem-cell transplants for MCL. “However,” he said, “no one likes autologous transplant because it also has side effects.”
For the new open-label study, Dr. Dreyling and colleagues in the European MCL Network in 2016 began recruiting patients with newly diagnosed, advanced stage II-IV MCL. The patients were younger than 65.
The subjects were randomly assigned to three trial arms: Standard treatment (high-dose cytarabine followed by autologous stem cell transplant and rituximab maintenance, n = 288), the standard treatment plus ibrutinib (n = 292), and ibrutinib without stem cell transplant (n = 290). The median age was 57, and 76% of patients were male.
The primary endpoint was failure-free survival at 31 months. Standard therapy was not superior to the ibrutinib without transplant group (72% vs. 86%, respectively, P = .9979). However, standard therapy with ibrutinib was superior to the standard therapy group (88% vs. 72%, respectively, P = .0008). The researchers haven’t finished their analysis of standard therapy with ibrutinib vs. ibrutinib without transplant.
Subjects in the standard therapy plus ibrutinib arm had more grade 3-5 adverse events than did the standard therapy and ibrutinib without transplant groups: Neutropenia, 44%, 17%, and 23%, respectively; leukopenia, 4%, 2%, and 2%; febrile neutropenia, 6%, 3%, and 3%; infections and infestations, 25%, 13%, and 19%; and cardiac disorders, 3%, 1%, 4%. P values were not provided.
In an interview, Ohio State University hematologist Narendranath Epperla, MD, MS, who was not involved in the study, said that this research reflects efforts to understand how novel agents such as ibrutinib and cellular therapies fit into MCL treatment. “We are trying to incorporate them in the frontline setting with either chemo backbone or with other targeted agents to improve outcomes and minimize toxicity. We are also trying to understand in whom auto-HCT can be precluded.”
The results of the new study appear promising, Dr. Epperla said, but he questioned the primary endpoint (failure-free survival instead of progress-free survival) and the short duration of the trial.
“I would like to see how the patients with high-risk features such as TP53 mutation, complex cytogenetics, and blastoid/pleomorphic variants did on the three arms,” Dr. Epperla said. “And I would like to see longer follow-up data before adapting this – [addition] of ibrutinib to the chemotherapy backbone without auto-HCT – into clinical practice.”
What’s next? Dr. Dreyling said that upcoming data will provide further insight into ibrutinib vs. stem-cell transplantation. And “within the next half year or so,” he said, “there will be a next generation of studies challenging chemotherapy overall in mantle cell lymphoma and substituting targeted treatment, hopefully achieving much better tolerability.”
Funding information was not provided. Dr. Dreyling disclosed ties with Lilly/Loxo, AstraZeneca, Novartis, Amgen, Roche, Janssen, Gilead/Kite, BMS/Celgene, Bayer, Abbvie, and Beigene. The other study authors reported various disclosures. Dr. Epperla disclosed a relationship with Pharmacyclics.
AT ASH 2022
SSRI tied to improved cognition in comorbid depression, dementia
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
FROM CTAD 2022
Melanoma mortality rates fell in 2010s as new therapies took hold
, a new study finds, although the dip appeared to stabilize over the next 2 years.
“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”
The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”
New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.
The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.
Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.
“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”
But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”
In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”
Which treatments are making the biggest difference? “It is difficult to say, but it’s likely immunotherapy because some patients on these medications have durable responses for many years,” Dr. Adamson said. “Studies are ongoing to figure out just how much more life some patients may expect after treatment.”
He added that “while this study did not evaluate mortality trends by race or ethnicity, it is important to note that the sharp decline in melanoma mortality rates is exclusively among non-Hispanic White Americans.”
Dermatologist David Polsky, MD, PhD, professor of dermatologic oncology at New York (N.Y.) University, said in an interview that the findings reflect extraordinary progress in melanoma treatment. “Historically, only 10% of metastatic melanoma patients would live 5 years. And now 30% to 50% of metastatic patients are living 5 years. That’s amazing to me,” said Dr. Polsky, who coauthored the 2020 report cited by Dr. Adamson.
A few years ago, Dr. Polsky added, he talked to an oncologist about how life at her clinic had changed as a result of new melanoma treatments. “She said, ‘My clinic has gotten really crowded. It used to be that patients died in a span of about a year and a half, and I would turn over my patient population. Now all those patients are still alive, and I’m getting new patients.’”
The study was funded by the University of Toledo College of Medicine and Life Sciences. One author reported receiving honoraria from Boston Healthcare Associates and research funding from Bayer, ImmunoVaccine, and the Ludwig Institute for Cancer Research. Dr. Polsky disclosed relationships with Merck (advisory board) and Novartis and Bristol Myers Squibb (consulting). Dr. Adamson disclosed he is web editor and associate editor at JAMA Dermatology.
, a new study finds, although the dip appeared to stabilize over the next 2 years.
“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”
The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”
New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.
The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.
Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.
“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”
But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”
In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”
Which treatments are making the biggest difference? “It is difficult to say, but it’s likely immunotherapy because some patients on these medications have durable responses for many years,” Dr. Adamson said. “Studies are ongoing to figure out just how much more life some patients may expect after treatment.”
He added that “while this study did not evaluate mortality trends by race or ethnicity, it is important to note that the sharp decline in melanoma mortality rates is exclusively among non-Hispanic White Americans.”
Dermatologist David Polsky, MD, PhD, professor of dermatologic oncology at New York (N.Y.) University, said in an interview that the findings reflect extraordinary progress in melanoma treatment. “Historically, only 10% of metastatic melanoma patients would live 5 years. And now 30% to 50% of metastatic patients are living 5 years. That’s amazing to me,” said Dr. Polsky, who coauthored the 2020 report cited by Dr. Adamson.
A few years ago, Dr. Polsky added, he talked to an oncologist about how life at her clinic had changed as a result of new melanoma treatments. “She said, ‘My clinic has gotten really crowded. It used to be that patients died in a span of about a year and a half, and I would turn over my patient population. Now all those patients are still alive, and I’m getting new patients.’”
The study was funded by the University of Toledo College of Medicine and Life Sciences. One author reported receiving honoraria from Boston Healthcare Associates and research funding from Bayer, ImmunoVaccine, and the Ludwig Institute for Cancer Research. Dr. Polsky disclosed relationships with Merck (advisory board) and Novartis and Bristol Myers Squibb (consulting). Dr. Adamson disclosed he is web editor and associate editor at JAMA Dermatology.
, a new study finds, although the dip appeared to stabilize over the next 2 years.
“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”
The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”
New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.
The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.
Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.
“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”
But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”
In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”
Which treatments are making the biggest difference? “It is difficult to say, but it’s likely immunotherapy because some patients on these medications have durable responses for many years,” Dr. Adamson said. “Studies are ongoing to figure out just how much more life some patients may expect after treatment.”
He added that “while this study did not evaluate mortality trends by race or ethnicity, it is important to note that the sharp decline in melanoma mortality rates is exclusively among non-Hispanic White Americans.”
Dermatologist David Polsky, MD, PhD, professor of dermatologic oncology at New York (N.Y.) University, said in an interview that the findings reflect extraordinary progress in melanoma treatment. “Historically, only 10% of metastatic melanoma patients would live 5 years. And now 30% to 50% of metastatic patients are living 5 years. That’s amazing to me,” said Dr. Polsky, who coauthored the 2020 report cited by Dr. Adamson.
A few years ago, Dr. Polsky added, he talked to an oncologist about how life at her clinic had changed as a result of new melanoma treatments. “She said, ‘My clinic has gotten really crowded. It used to be that patients died in a span of about a year and a half, and I would turn over my patient population. Now all those patients are still alive, and I’m getting new patients.’”
The study was funded by the University of Toledo College of Medicine and Life Sciences. One author reported receiving honoraria from Boston Healthcare Associates and research funding from Bayer, ImmunoVaccine, and the Ludwig Institute for Cancer Research. Dr. Polsky disclosed relationships with Merck (advisory board) and Novartis and Bristol Myers Squibb (consulting). Dr. Adamson disclosed he is web editor and associate editor at JAMA Dermatology.
FROM JAMA NETWORK OPEN
Post-transplant diet: Gruel no longer rules
NEW ORLEANS – A new Italian study yields more evidence that stem-cell transplant patients need not lose their appetites along with their immune systems. Low-bacterial, gruel-like diets, once the mainstay of immunity-lowering surgeries, don’t actually provide any protection against infections, researchers reported.
University of Miami hematologist Mikkael A. Sekeres, MD, MS, expressed delight to hear these findings.
“Around the world, we should eliminate these silly neutropenic diets, let people eat what they want, and give them a much better quality of life while they’re in the hospital,” said Dr. Sekeres, moderator of the news briefing where these research results were discussed at the annual meeting of the American Society of Hematology.
In recent decades, physicians and nutritionists have questioned the value of low-bacterial/neutropenic menus, designed to protect people with compromised immune systems from germs in food. These diets can be quite strict, outlawing food such as deli, processed, and cured meats; yogurt; hummus; strawberries and raspberries; lettuce; raw nuts; certain kinds of seafood; and herbs and spices such as pepper, unless they were cooked. Patients may be urged to avoid salad bars, buffets, and potlucks.
MD Anderson Cancer Center pediatrician Karen Moody, MD, MS, who has studied the diet, said in an interview that the diet has been around since the 1970s, despite a lack of evidence supporting it. “Cancer patients often suffer from treatment-related side effects that affect taste, appetite, and tolerance of food,” she said. “Further restricting food options in this population can be burdensome and reduce diet-related satisfaction.”
For the new multi-center, phase 3 study, researchers led by hematology resident Federico Stella, MD, of the University of Milan, randomly assigned consecutive adult patients undergoing hematopoietic stem cells transplantation or high-dose induction chemotherapy to either a low-bacterial diet (n = 224) or a non-restrictive diet (n = 224).
The low-bacterial diet emphasized food cooked to at least 176 degrees Fahrenheit and thick-skinned fruit. Raw fruits/vegetables, yogurt, honey, cold cuts and sausages, and raw fish and meat were forbidden.
The two groups were similar in age (median = 56 years), gender (about 57% male), and reason for admission (97% stem-cell transplants and 3% high-dose chemotherapy). The plan was to follow the patients for 100 days (stem-cell transplant recipients) or 30 days (high-dose chemotherapy patients).
No statistically significant differences between the group were found in the rates of infections of higher than Grade 2 (per CTCAE 4.0): These infections occurred in 38 (34%) of those on the low-bacterial diet and 44 (39%) of those on the non-restrictive diet (P = 0.5).
There were also no statistically significant differences in rates of fever of unknown origin (P = 0.2), sepsis (P = 0.5), and gastrointestinal infection (P = 0.7).
The findings show that the “use of a restrictive diet is an unnecessary burden for our patients’ quality of life,” said study lead author Dr. Stella at the news briefing.
Dr. Sekeres, the news briefing moderator, noted that the findings reflect his own suspicions about the worthlessness of the low-bacterial diet. “I’ve never seen a patient die of an infection that was foodborne. So years ago, when I was still in Cleveland, I eliminated the neutropenic diet on the leukemia floor. That did face a lot of resistance, as you can imagine. There were decades of people saying we should do this.”
Now, Dr. Sekeres said, he feels validated. “I love this study because it formalizes what I thought was true,” he said.
Dr. Moody said it’s difficult to evaluate the study since it’s in abstract form, and details are limited. “However,” she said, “the sample size, study design, and outcomes appear very appropriate, and I think most likely the full-length study will provide additional evidence to support abandonment of the low-microbial diet in transplant patients.”
Also, Dr. Moody said, the study “replicates the same findings of other prospective randomized trials of this diet that say it confers no protection from infection and has no identified health benefit whatsoever. Bottom line? This diet has burden without benefit.”
Moving forward, she said, “we need a lot more research on diet in general for cancer patients. Recently, there is a lot more interest in this topic. I think we are going to learn a lot in the next few decades about the relationship between diet, epigenetics, the microbiome, and various cancer-related health issues.”
No study funding was reported. Dr. Stella reports no disclosures, and other authors report various relationships with industry. Dr. Moody reports no disclosures, and disclosures for Dr. Sekeres were not available.
NEW ORLEANS – A new Italian study yields more evidence that stem-cell transplant patients need not lose their appetites along with their immune systems. Low-bacterial, gruel-like diets, once the mainstay of immunity-lowering surgeries, don’t actually provide any protection against infections, researchers reported.
University of Miami hematologist Mikkael A. Sekeres, MD, MS, expressed delight to hear these findings.
“Around the world, we should eliminate these silly neutropenic diets, let people eat what they want, and give them a much better quality of life while they’re in the hospital,” said Dr. Sekeres, moderator of the news briefing where these research results were discussed at the annual meeting of the American Society of Hematology.
In recent decades, physicians and nutritionists have questioned the value of low-bacterial/neutropenic menus, designed to protect people with compromised immune systems from germs in food. These diets can be quite strict, outlawing food such as deli, processed, and cured meats; yogurt; hummus; strawberries and raspberries; lettuce; raw nuts; certain kinds of seafood; and herbs and spices such as pepper, unless they were cooked. Patients may be urged to avoid salad bars, buffets, and potlucks.
MD Anderson Cancer Center pediatrician Karen Moody, MD, MS, who has studied the diet, said in an interview that the diet has been around since the 1970s, despite a lack of evidence supporting it. “Cancer patients often suffer from treatment-related side effects that affect taste, appetite, and tolerance of food,” she said. “Further restricting food options in this population can be burdensome and reduce diet-related satisfaction.”
For the new multi-center, phase 3 study, researchers led by hematology resident Federico Stella, MD, of the University of Milan, randomly assigned consecutive adult patients undergoing hematopoietic stem cells transplantation or high-dose induction chemotherapy to either a low-bacterial diet (n = 224) or a non-restrictive diet (n = 224).
The low-bacterial diet emphasized food cooked to at least 176 degrees Fahrenheit and thick-skinned fruit. Raw fruits/vegetables, yogurt, honey, cold cuts and sausages, and raw fish and meat were forbidden.
The two groups were similar in age (median = 56 years), gender (about 57% male), and reason for admission (97% stem-cell transplants and 3% high-dose chemotherapy). The plan was to follow the patients for 100 days (stem-cell transplant recipients) or 30 days (high-dose chemotherapy patients).
No statistically significant differences between the group were found in the rates of infections of higher than Grade 2 (per CTCAE 4.0): These infections occurred in 38 (34%) of those on the low-bacterial diet and 44 (39%) of those on the non-restrictive diet (P = 0.5).
There were also no statistically significant differences in rates of fever of unknown origin (P = 0.2), sepsis (P = 0.5), and gastrointestinal infection (P = 0.7).
The findings show that the “use of a restrictive diet is an unnecessary burden for our patients’ quality of life,” said study lead author Dr. Stella at the news briefing.
Dr. Sekeres, the news briefing moderator, noted that the findings reflect his own suspicions about the worthlessness of the low-bacterial diet. “I’ve never seen a patient die of an infection that was foodborne. So years ago, when I was still in Cleveland, I eliminated the neutropenic diet on the leukemia floor. That did face a lot of resistance, as you can imagine. There were decades of people saying we should do this.”
Now, Dr. Sekeres said, he feels validated. “I love this study because it formalizes what I thought was true,” he said.
Dr. Moody said it’s difficult to evaluate the study since it’s in abstract form, and details are limited. “However,” she said, “the sample size, study design, and outcomes appear very appropriate, and I think most likely the full-length study will provide additional evidence to support abandonment of the low-microbial diet in transplant patients.”
Also, Dr. Moody said, the study “replicates the same findings of other prospective randomized trials of this diet that say it confers no protection from infection and has no identified health benefit whatsoever. Bottom line? This diet has burden without benefit.”
Moving forward, she said, “we need a lot more research on diet in general for cancer patients. Recently, there is a lot more interest in this topic. I think we are going to learn a lot in the next few decades about the relationship between diet, epigenetics, the microbiome, and various cancer-related health issues.”
No study funding was reported. Dr. Stella reports no disclosures, and other authors report various relationships with industry. Dr. Moody reports no disclosures, and disclosures for Dr. Sekeres were not available.
NEW ORLEANS – A new Italian study yields more evidence that stem-cell transplant patients need not lose their appetites along with their immune systems. Low-bacterial, gruel-like diets, once the mainstay of immunity-lowering surgeries, don’t actually provide any protection against infections, researchers reported.
University of Miami hematologist Mikkael A. Sekeres, MD, MS, expressed delight to hear these findings.
“Around the world, we should eliminate these silly neutropenic diets, let people eat what they want, and give them a much better quality of life while they’re in the hospital,” said Dr. Sekeres, moderator of the news briefing where these research results were discussed at the annual meeting of the American Society of Hematology.
In recent decades, physicians and nutritionists have questioned the value of low-bacterial/neutropenic menus, designed to protect people with compromised immune systems from germs in food. These diets can be quite strict, outlawing food such as deli, processed, and cured meats; yogurt; hummus; strawberries and raspberries; lettuce; raw nuts; certain kinds of seafood; and herbs and spices such as pepper, unless they were cooked. Patients may be urged to avoid salad bars, buffets, and potlucks.
MD Anderson Cancer Center pediatrician Karen Moody, MD, MS, who has studied the diet, said in an interview that the diet has been around since the 1970s, despite a lack of evidence supporting it. “Cancer patients often suffer from treatment-related side effects that affect taste, appetite, and tolerance of food,” she said. “Further restricting food options in this population can be burdensome and reduce diet-related satisfaction.”
For the new multi-center, phase 3 study, researchers led by hematology resident Federico Stella, MD, of the University of Milan, randomly assigned consecutive adult patients undergoing hematopoietic stem cells transplantation or high-dose induction chemotherapy to either a low-bacterial diet (n = 224) or a non-restrictive diet (n = 224).
The low-bacterial diet emphasized food cooked to at least 176 degrees Fahrenheit and thick-skinned fruit. Raw fruits/vegetables, yogurt, honey, cold cuts and sausages, and raw fish and meat were forbidden.
The two groups were similar in age (median = 56 years), gender (about 57% male), and reason for admission (97% stem-cell transplants and 3% high-dose chemotherapy). The plan was to follow the patients for 100 days (stem-cell transplant recipients) or 30 days (high-dose chemotherapy patients).
No statistically significant differences between the group were found in the rates of infections of higher than Grade 2 (per CTCAE 4.0): These infections occurred in 38 (34%) of those on the low-bacterial diet and 44 (39%) of those on the non-restrictive diet (P = 0.5).
There were also no statistically significant differences in rates of fever of unknown origin (P = 0.2), sepsis (P = 0.5), and gastrointestinal infection (P = 0.7).
The findings show that the “use of a restrictive diet is an unnecessary burden for our patients’ quality of life,” said study lead author Dr. Stella at the news briefing.
Dr. Sekeres, the news briefing moderator, noted that the findings reflect his own suspicions about the worthlessness of the low-bacterial diet. “I’ve never seen a patient die of an infection that was foodborne. So years ago, when I was still in Cleveland, I eliminated the neutropenic diet on the leukemia floor. That did face a lot of resistance, as you can imagine. There were decades of people saying we should do this.”
Now, Dr. Sekeres said, he feels validated. “I love this study because it formalizes what I thought was true,” he said.
Dr. Moody said it’s difficult to evaluate the study since it’s in abstract form, and details are limited. “However,” she said, “the sample size, study design, and outcomes appear very appropriate, and I think most likely the full-length study will provide additional evidence to support abandonment of the low-microbial diet in transplant patients.”
Also, Dr. Moody said, the study “replicates the same findings of other prospective randomized trials of this diet that say it confers no protection from infection and has no identified health benefit whatsoever. Bottom line? This diet has burden without benefit.”
Moving forward, she said, “we need a lot more research on diet in general for cancer patients. Recently, there is a lot more interest in this topic. I think we are going to learn a lot in the next few decades about the relationship between diet, epigenetics, the microbiome, and various cancer-related health issues.”
No study funding was reported. Dr. Stella reports no disclosures, and other authors report various relationships with industry. Dr. Moody reports no disclosures, and disclosures for Dr. Sekeres were not available.
AT ASH 2022
For minorities with PE: Less advanced treatment, more mortality
NEW ORLEANS –
According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).
“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.
As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.
The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.
Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.
With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.
These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.
As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.
In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).
Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.
The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).
As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”
Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”
In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”
In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”
For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said.
Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”
Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.
NEW ORLEANS –
According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).
“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.
As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.
The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.
Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.
With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.
These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.
As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.
In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).
Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.
The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).
As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”
Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”
In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”
In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”
For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said.
Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”
Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.
NEW ORLEANS –
According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).
“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.
As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.
The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.
Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.
With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.
These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.
As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.
In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).
Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.
The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).
As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”
Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”
In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”
In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”
For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said.
Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”
Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.
AT ASH 2022
High cost and demand for old cancer drug sparks crisis
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
‘Modest’ benefit for lecanemab in Alzheimer’s disease, but adverse events are common
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
AT CTAD 2022
Atezolizumab fails to improve outcomes in postsurgery kidney cancer
Adjuvant immunotherapy with atezolizumab for patients with renal cell carcinoma who have had a nephrectomy with or without a metastasectomy, failed to improve clinical outcomes in a group of patients who are at high risk of recurrence, finds a new international study conducted across 28 countries.
The study, called IMmotion010 and published in The Lancet, was a randomized, double-blind, multicenter, phase 3 trial of 778 adult patients with renal cell carcinoma (RCC) with a clear cell or sarcomatoid component. The study failed to meet its primary endpoint which was defined as a statistically significant improvement in disease-free survival as compared with placebo.
“Our results add to an emerging body of literature around the role of adjuvant immunotherapy for renal cell carcinoma. With the longest duration of follow-up to date to our knowledge. We observed no evidence of clinical benefit in disease-free survival or overall survival with adjuvant atezolizumab in patients with high-risk localized or fully resected renal cell carcinoma,” wrote the authors who were led by Sumanta Kumar Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif. “Given a growing list of trials that have not shown benefit with adjuvant immunotherapy, the results call for greater attention to patient selection with this approach.”
Dr. Pal and associates conducted the study to gain more insight into the potential role of adjuvant immunotherapy in patients with renal cell carcinoma who have undergone the standard treatment of nephrectomy with or without metastasectomy. Previous studies of anti-VEGF treatments have produced mixed results, including the large phase 3 ASSURE trial, the authors wrote. “Given these mixed results, use of adjuvant targeted therapy in renal cell carcinoma remains infrequent,” Dr. Pal and associates wrote.
However, pembrolizumab (Keytruda, Merck) a programmed death receptor-1–blocking antibody, is an immunotherapy which, in combination with axitinib, is approved as a first-line treatment for patients with advanced RCC.
Atezolizumab (Tecentriq, Genentech) is approved for treatment in urothelial carcinoma, non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), and melanoma. There are currently a number of ongoing studies that are exploring the use of atezolizumab as a treatment for renal cell carcinoma.
The study details
This new study was conducted between 2017 and 2019. It included 778 patients from 215 clinics in 28 countries who were assigned to the treatment arm (1,200 mg of IV atezolizumab (n = 390, 50%) once every 3 weeks for 16 cycles or 1 year, which ever came first – or, they were assigned to the placebo group (n = 388, 50%). The two groups were similar: average age 60-61, 72%-74% male, 78%-83% white, and 36%-37% based in North America. Most patients, (92%-93%) had clear cell cancer, and 64%-65% were at pathological disease stage T2 or T3a.
The 3-year disease-free survival rate at 36 months was 65.0% (95% confidence interval, 59.9-70.2) in the treatment group and 62.7% (95% CI, 57.5-67.9) in the placebo group. At follow-up at 44.7 months, there was no statistically significant difference in median disease-free survival between atezolizumab (57.2 months; 95% CI, 44.6 to not evaluable) and placebo (49.5 months; 95% CI, 47.4 to not evaluable).
While there were no deaths attributable to treatment, 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo experienced a serious adverse event.
“. Future work will include exploration of clinical-based or biomarker-based subsets that might derive benefit from this approach,” the authors wrote.
The researchers acknowledge their findings contrast with those of the KEYNOTE-564 trial of adjuvant immunotherapy with pembrolizumab after nephrectomy in renal cell carcinoma. KEYNOTE-564 reported a disease-free survival benefit of over 24 months and in an analysis done at 30 months. But in KEYNOTE-564, the study comprised only 6% of patients with M1 no evidence of disease. And, it included only patients with synchronous metastases or metastases resected within 1 year of nephrectomy. In the new study, 14% of patients had M1 no evidence of disease, and it included both synchronous and metachronous disease with recurrence within 1year of surgery.
Adjuvant immunotherapy with pembrolizumab is considered optional for patients with intermediate-risk or high-risk operable clear cell renal cell carcinoma per European Society for Medical Oncology and European Association of Urology guidelines because of the lack of confirmed overall survival benefit and toxicity-related considerations associated with immunotherapy.
“These factors must be considered in the adjuvant setting as, following nephrectomy, patients are cancer free and might be cured by surgery alone. As such, additional trials are needed to clarify the role of adjuvant immunotherapy in this disease space,” the authors wrote.
What’s next? “Biomarker work is underway to determine whether tumor genomic characteristics or circulating biomarkers can identify patient populations who derive benefit from adjuvant atezolizumab,” Dr. Pal and associates wrote. “There is precedent for tissue-based adjuvant therapy selection in other diseases, such as HER2-based and endocrine receptor–based approaches in breast cancer and EGFR mutation–directed therapy in lung cancer.”
The study was funded by F Hoffmann-La Roche and Genentech. The academic authors of the study collaborated with F Hoffmann-La Roche and Genentech on all facets of the trial.
Adjuvant immunotherapy with atezolizumab for patients with renal cell carcinoma who have had a nephrectomy with or without a metastasectomy, failed to improve clinical outcomes in a group of patients who are at high risk of recurrence, finds a new international study conducted across 28 countries.
The study, called IMmotion010 and published in The Lancet, was a randomized, double-blind, multicenter, phase 3 trial of 778 adult patients with renal cell carcinoma (RCC) with a clear cell or sarcomatoid component. The study failed to meet its primary endpoint which was defined as a statistically significant improvement in disease-free survival as compared with placebo.
“Our results add to an emerging body of literature around the role of adjuvant immunotherapy for renal cell carcinoma. With the longest duration of follow-up to date to our knowledge. We observed no evidence of clinical benefit in disease-free survival or overall survival with adjuvant atezolizumab in patients with high-risk localized or fully resected renal cell carcinoma,” wrote the authors who were led by Sumanta Kumar Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif. “Given a growing list of trials that have not shown benefit with adjuvant immunotherapy, the results call for greater attention to patient selection with this approach.”
Dr. Pal and associates conducted the study to gain more insight into the potential role of adjuvant immunotherapy in patients with renal cell carcinoma who have undergone the standard treatment of nephrectomy with or without metastasectomy. Previous studies of anti-VEGF treatments have produced mixed results, including the large phase 3 ASSURE trial, the authors wrote. “Given these mixed results, use of adjuvant targeted therapy in renal cell carcinoma remains infrequent,” Dr. Pal and associates wrote.
However, pembrolizumab (Keytruda, Merck) a programmed death receptor-1–blocking antibody, is an immunotherapy which, in combination with axitinib, is approved as a first-line treatment for patients with advanced RCC.
Atezolizumab (Tecentriq, Genentech) is approved for treatment in urothelial carcinoma, non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), and melanoma. There are currently a number of ongoing studies that are exploring the use of atezolizumab as a treatment for renal cell carcinoma.
The study details
This new study was conducted between 2017 and 2019. It included 778 patients from 215 clinics in 28 countries who were assigned to the treatment arm (1,200 mg of IV atezolizumab (n = 390, 50%) once every 3 weeks for 16 cycles or 1 year, which ever came first – or, they were assigned to the placebo group (n = 388, 50%). The two groups were similar: average age 60-61, 72%-74% male, 78%-83% white, and 36%-37% based in North America. Most patients, (92%-93%) had clear cell cancer, and 64%-65% were at pathological disease stage T2 or T3a.
The 3-year disease-free survival rate at 36 months was 65.0% (95% confidence interval, 59.9-70.2) in the treatment group and 62.7% (95% CI, 57.5-67.9) in the placebo group. At follow-up at 44.7 months, there was no statistically significant difference in median disease-free survival between atezolizumab (57.2 months; 95% CI, 44.6 to not evaluable) and placebo (49.5 months; 95% CI, 47.4 to not evaluable).
While there were no deaths attributable to treatment, 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo experienced a serious adverse event.
“. Future work will include exploration of clinical-based or biomarker-based subsets that might derive benefit from this approach,” the authors wrote.
The researchers acknowledge their findings contrast with those of the KEYNOTE-564 trial of adjuvant immunotherapy with pembrolizumab after nephrectomy in renal cell carcinoma. KEYNOTE-564 reported a disease-free survival benefit of over 24 months and in an analysis done at 30 months. But in KEYNOTE-564, the study comprised only 6% of patients with M1 no evidence of disease. And, it included only patients with synchronous metastases or metastases resected within 1 year of nephrectomy. In the new study, 14% of patients had M1 no evidence of disease, and it included both synchronous and metachronous disease with recurrence within 1year of surgery.
Adjuvant immunotherapy with pembrolizumab is considered optional for patients with intermediate-risk or high-risk operable clear cell renal cell carcinoma per European Society for Medical Oncology and European Association of Urology guidelines because of the lack of confirmed overall survival benefit and toxicity-related considerations associated with immunotherapy.
“These factors must be considered in the adjuvant setting as, following nephrectomy, patients are cancer free and might be cured by surgery alone. As such, additional trials are needed to clarify the role of adjuvant immunotherapy in this disease space,” the authors wrote.
What’s next? “Biomarker work is underway to determine whether tumor genomic characteristics or circulating biomarkers can identify patient populations who derive benefit from adjuvant atezolizumab,” Dr. Pal and associates wrote. “There is precedent for tissue-based adjuvant therapy selection in other diseases, such as HER2-based and endocrine receptor–based approaches in breast cancer and EGFR mutation–directed therapy in lung cancer.”
The study was funded by F Hoffmann-La Roche and Genentech. The academic authors of the study collaborated with F Hoffmann-La Roche and Genentech on all facets of the trial.
Adjuvant immunotherapy with atezolizumab for patients with renal cell carcinoma who have had a nephrectomy with or without a metastasectomy, failed to improve clinical outcomes in a group of patients who are at high risk of recurrence, finds a new international study conducted across 28 countries.
The study, called IMmotion010 and published in The Lancet, was a randomized, double-blind, multicenter, phase 3 trial of 778 adult patients with renal cell carcinoma (RCC) with a clear cell or sarcomatoid component. The study failed to meet its primary endpoint which was defined as a statistically significant improvement in disease-free survival as compared with placebo.
“Our results add to an emerging body of literature around the role of adjuvant immunotherapy for renal cell carcinoma. With the longest duration of follow-up to date to our knowledge. We observed no evidence of clinical benefit in disease-free survival or overall survival with adjuvant atezolizumab in patients with high-risk localized or fully resected renal cell carcinoma,” wrote the authors who were led by Sumanta Kumar Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif. “Given a growing list of trials that have not shown benefit with adjuvant immunotherapy, the results call for greater attention to patient selection with this approach.”
Dr. Pal and associates conducted the study to gain more insight into the potential role of adjuvant immunotherapy in patients with renal cell carcinoma who have undergone the standard treatment of nephrectomy with or without metastasectomy. Previous studies of anti-VEGF treatments have produced mixed results, including the large phase 3 ASSURE trial, the authors wrote. “Given these mixed results, use of adjuvant targeted therapy in renal cell carcinoma remains infrequent,” Dr. Pal and associates wrote.
However, pembrolizumab (Keytruda, Merck) a programmed death receptor-1–blocking antibody, is an immunotherapy which, in combination with axitinib, is approved as a first-line treatment for patients with advanced RCC.
Atezolizumab (Tecentriq, Genentech) is approved for treatment in urothelial carcinoma, non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), and melanoma. There are currently a number of ongoing studies that are exploring the use of atezolizumab as a treatment for renal cell carcinoma.
The study details
This new study was conducted between 2017 and 2019. It included 778 patients from 215 clinics in 28 countries who were assigned to the treatment arm (1,200 mg of IV atezolizumab (n = 390, 50%) once every 3 weeks for 16 cycles or 1 year, which ever came first – or, they were assigned to the placebo group (n = 388, 50%). The two groups were similar: average age 60-61, 72%-74% male, 78%-83% white, and 36%-37% based in North America. Most patients, (92%-93%) had clear cell cancer, and 64%-65% were at pathological disease stage T2 or T3a.
The 3-year disease-free survival rate at 36 months was 65.0% (95% confidence interval, 59.9-70.2) in the treatment group and 62.7% (95% CI, 57.5-67.9) in the placebo group. At follow-up at 44.7 months, there was no statistically significant difference in median disease-free survival between atezolizumab (57.2 months; 95% CI, 44.6 to not evaluable) and placebo (49.5 months; 95% CI, 47.4 to not evaluable).
While there were no deaths attributable to treatment, 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo experienced a serious adverse event.
“. Future work will include exploration of clinical-based or biomarker-based subsets that might derive benefit from this approach,” the authors wrote.
The researchers acknowledge their findings contrast with those of the KEYNOTE-564 trial of adjuvant immunotherapy with pembrolizumab after nephrectomy in renal cell carcinoma. KEYNOTE-564 reported a disease-free survival benefit of over 24 months and in an analysis done at 30 months. But in KEYNOTE-564, the study comprised only 6% of patients with M1 no evidence of disease. And, it included only patients with synchronous metastases or metastases resected within 1 year of nephrectomy. In the new study, 14% of patients had M1 no evidence of disease, and it included both synchronous and metachronous disease with recurrence within 1year of surgery.
Adjuvant immunotherapy with pembrolizumab is considered optional for patients with intermediate-risk or high-risk operable clear cell renal cell carcinoma per European Society for Medical Oncology and European Association of Urology guidelines because of the lack of confirmed overall survival benefit and toxicity-related considerations associated with immunotherapy.
“These factors must be considered in the adjuvant setting as, following nephrectomy, patients are cancer free and might be cured by surgery alone. As such, additional trials are needed to clarify the role of adjuvant immunotherapy in this disease space,” the authors wrote.
What’s next? “Biomarker work is underway to determine whether tumor genomic characteristics or circulating biomarkers can identify patient populations who derive benefit from adjuvant atezolizumab,” Dr. Pal and associates wrote. “There is precedent for tissue-based adjuvant therapy selection in other diseases, such as HER2-based and endocrine receptor–based approaches in breast cancer and EGFR mutation–directed therapy in lung cancer.”
The study was funded by F Hoffmann-La Roche and Genentech. The academic authors of the study collaborated with F Hoffmann-La Roche and Genentech on all facets of the trial.
FROM THE LANCET
Chronic hepatitis B infections associated with a range of liver malignancies
, shows a new study conducted in South Korea.
In this study, which was published in the Journal of Clinical Oncology, researchers found that long-term treatment with nucleos(t)ide analogues (NAs) for patients with chronic hepatitis B lowered their risk of developing extrahepatic cancer types.
In addition to lowering the risk of liver cancers, treatment with nucleos(t)ide analogues, including tenofovir disoproxil fumarate, entecavir, lamivudine, telbivudine, adefovir, and clevudine, lowered the risk of developing cancer of the pancreas and prostate, but increased the risk of breast cancer.
By controlling chronic hepatitis B infections (CHB), NAs have been known to reduce the risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. About half of the 700,000 people who die each year from chronic hepatitis B infections also have an intrahepatic malignancy.
But extrahepatic cholangiocarcinoma, in which tumors grow outside of the liver in the bile ducts, is exceedingly rare, affecting only 8,000 people each year in the United States.
The study was led by Jeong-Hoon Lee, MD, PhD, Seoul National University, South Korea.
The study details
Researchers sought to understand whether CHB treatment with NA drugs could reduce the risk of extrahepatic cancer. The study is based on an analysis of South Korean medical insurance claims data that included 90,944 patients (6,539 treated with NAs) with a newly diagnosed chronic hepatitis B infection, and 685,436 controls. The median age of the groups ranged from 47 to 51, and the percentage of men ranged from 51.3% to 62.5%.
Over the median 47.4-month study period, 3.9% (30,413) of subjects developed cancer outside the liver. Patients with CHB who weren’t treated with NAs had a higher overall risk vs. the NA-treatment group (adjusted subdistribution hazard ratio = 1.28; 95% confidence interval, 1.12-1.45; P < .001) and vs. controls (aSHR = 1.22; 95% CI, 1.18-1.26; P < .001).
The researchers write that “the direction of the original result was maintained” even after adjustment for cancer risk factors such as smoking and alcohol consumption. “Randomized controlled trials might be warranted to explore whether NA treatment will reduce the risk of extrahepatic malignancy in patients with CHB outside the current treatment indication,” they wrote.
In an accompanying commentary, Lewis R. Roberts, MBChB, PhD, of Mayo Clinic, Rochester, Minn., said that what is perhaps “the most controversial result ... one that is not the direct subject of their study, the observation that NA treatment was not associated with a decrease in risk of primary intrahepatic malignancy – hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma. The observed decrease in risk of intrahepatic malignancy was 12%, with an adjusted subdistribution hazard ratio of 0.88 (95% CI, 0.77-1.01; P = .08).”
As Dr. Roberts wrote, the authors suggested this could be related to the low prevalence of cirrhosis in the study group. “This explanation is plausible, as it has previously been shown that the major impact of NA treatment in reducing HCC incidence is in those with CHB-induced cirrhosis,” he wrote.
Dr. Roberts added that randomized trials of NA in CHB would be difficult because the drugs are so effective. “The most important implication of this study may be the observation that CHB is associated with a higher risk of a range of extrahepatic malignancies, and the opportunity to advise patients with CHB to adhere to current recommendations for screening for the major cancer types.”
The study was publicly funded, but several study authors report numerous disclosures including relationships with Yuhan Corporation, Bayer, Gilead Sciences, Bristol Myers Squibb, and others. Dr. Roberts reports numerous personal and institutional disclosures including relationships with Bayer, Gilead Sciences, Medscape, Roche, and others plus a patent and royalties.
, shows a new study conducted in South Korea.
In this study, which was published in the Journal of Clinical Oncology, researchers found that long-term treatment with nucleos(t)ide analogues (NAs) for patients with chronic hepatitis B lowered their risk of developing extrahepatic cancer types.
In addition to lowering the risk of liver cancers, treatment with nucleos(t)ide analogues, including tenofovir disoproxil fumarate, entecavir, lamivudine, telbivudine, adefovir, and clevudine, lowered the risk of developing cancer of the pancreas and prostate, but increased the risk of breast cancer.
By controlling chronic hepatitis B infections (CHB), NAs have been known to reduce the risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. About half of the 700,000 people who die each year from chronic hepatitis B infections also have an intrahepatic malignancy.
But extrahepatic cholangiocarcinoma, in which tumors grow outside of the liver in the bile ducts, is exceedingly rare, affecting only 8,000 people each year in the United States.
The study was led by Jeong-Hoon Lee, MD, PhD, Seoul National University, South Korea.
The study details
Researchers sought to understand whether CHB treatment with NA drugs could reduce the risk of extrahepatic cancer. The study is based on an analysis of South Korean medical insurance claims data that included 90,944 patients (6,539 treated with NAs) with a newly diagnosed chronic hepatitis B infection, and 685,436 controls. The median age of the groups ranged from 47 to 51, and the percentage of men ranged from 51.3% to 62.5%.
Over the median 47.4-month study period, 3.9% (30,413) of subjects developed cancer outside the liver. Patients with CHB who weren’t treated with NAs had a higher overall risk vs. the NA-treatment group (adjusted subdistribution hazard ratio = 1.28; 95% confidence interval, 1.12-1.45; P < .001) and vs. controls (aSHR = 1.22; 95% CI, 1.18-1.26; P < .001).
The researchers write that “the direction of the original result was maintained” even after adjustment for cancer risk factors such as smoking and alcohol consumption. “Randomized controlled trials might be warranted to explore whether NA treatment will reduce the risk of extrahepatic malignancy in patients with CHB outside the current treatment indication,” they wrote.
In an accompanying commentary, Lewis R. Roberts, MBChB, PhD, of Mayo Clinic, Rochester, Minn., said that what is perhaps “the most controversial result ... one that is not the direct subject of their study, the observation that NA treatment was not associated with a decrease in risk of primary intrahepatic malignancy – hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma. The observed decrease in risk of intrahepatic malignancy was 12%, with an adjusted subdistribution hazard ratio of 0.88 (95% CI, 0.77-1.01; P = .08).”
As Dr. Roberts wrote, the authors suggested this could be related to the low prevalence of cirrhosis in the study group. “This explanation is plausible, as it has previously been shown that the major impact of NA treatment in reducing HCC incidence is in those with CHB-induced cirrhosis,” he wrote.
Dr. Roberts added that randomized trials of NA in CHB would be difficult because the drugs are so effective. “The most important implication of this study may be the observation that CHB is associated with a higher risk of a range of extrahepatic malignancies, and the opportunity to advise patients with CHB to adhere to current recommendations for screening for the major cancer types.”
The study was publicly funded, but several study authors report numerous disclosures including relationships with Yuhan Corporation, Bayer, Gilead Sciences, Bristol Myers Squibb, and others. Dr. Roberts reports numerous personal and institutional disclosures including relationships with Bayer, Gilead Sciences, Medscape, Roche, and others plus a patent and royalties.
, shows a new study conducted in South Korea.
In this study, which was published in the Journal of Clinical Oncology, researchers found that long-term treatment with nucleos(t)ide analogues (NAs) for patients with chronic hepatitis B lowered their risk of developing extrahepatic cancer types.
In addition to lowering the risk of liver cancers, treatment with nucleos(t)ide analogues, including tenofovir disoproxil fumarate, entecavir, lamivudine, telbivudine, adefovir, and clevudine, lowered the risk of developing cancer of the pancreas and prostate, but increased the risk of breast cancer.
By controlling chronic hepatitis B infections (CHB), NAs have been known to reduce the risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. About half of the 700,000 people who die each year from chronic hepatitis B infections also have an intrahepatic malignancy.
But extrahepatic cholangiocarcinoma, in which tumors grow outside of the liver in the bile ducts, is exceedingly rare, affecting only 8,000 people each year in the United States.
The study was led by Jeong-Hoon Lee, MD, PhD, Seoul National University, South Korea.
The study details
Researchers sought to understand whether CHB treatment with NA drugs could reduce the risk of extrahepatic cancer. The study is based on an analysis of South Korean medical insurance claims data that included 90,944 patients (6,539 treated with NAs) with a newly diagnosed chronic hepatitis B infection, and 685,436 controls. The median age of the groups ranged from 47 to 51, and the percentage of men ranged from 51.3% to 62.5%.
Over the median 47.4-month study period, 3.9% (30,413) of subjects developed cancer outside the liver. Patients with CHB who weren’t treated with NAs had a higher overall risk vs. the NA-treatment group (adjusted subdistribution hazard ratio = 1.28; 95% confidence interval, 1.12-1.45; P < .001) and vs. controls (aSHR = 1.22; 95% CI, 1.18-1.26; P < .001).
The researchers write that “the direction of the original result was maintained” even after adjustment for cancer risk factors such as smoking and alcohol consumption. “Randomized controlled trials might be warranted to explore whether NA treatment will reduce the risk of extrahepatic malignancy in patients with CHB outside the current treatment indication,” they wrote.
In an accompanying commentary, Lewis R. Roberts, MBChB, PhD, of Mayo Clinic, Rochester, Minn., said that what is perhaps “the most controversial result ... one that is not the direct subject of their study, the observation that NA treatment was not associated with a decrease in risk of primary intrahepatic malignancy – hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma. The observed decrease in risk of intrahepatic malignancy was 12%, with an adjusted subdistribution hazard ratio of 0.88 (95% CI, 0.77-1.01; P = .08).”
As Dr. Roberts wrote, the authors suggested this could be related to the low prevalence of cirrhosis in the study group. “This explanation is plausible, as it has previously been shown that the major impact of NA treatment in reducing HCC incidence is in those with CHB-induced cirrhosis,” he wrote.
Dr. Roberts added that randomized trials of NA in CHB would be difficult because the drugs are so effective. “The most important implication of this study may be the observation that CHB is associated with a higher risk of a range of extrahepatic malignancies, and the opportunity to advise patients with CHB to adhere to current recommendations for screening for the major cancer types.”
The study was publicly funded, but several study authors report numerous disclosures including relationships with Yuhan Corporation, Bayer, Gilead Sciences, Bristol Myers Squibb, and others. Dr. Roberts reports numerous personal and institutional disclosures including relationships with Bayer, Gilead Sciences, Medscape, Roche, and others plus a patent and royalties.
FROM JOURNAL OF CLINICAL ONCOLOGY
Previous breast cancer doesn’t increase poor outcomes in pregnancy, study finds
A new retrospective study provides more evidence that previous breast cancer diagnoses don’t disrupt the health of mothers and newborns in pregnancy: Women who became pregnant at least 12 months after breast cancer diagnosis weren’t more likely than a control group to have preterm births or suffer maternal/neonatal morbidity – even though they were more likely to undergo cesarean section.
“For patients who are more than 1 year out from the diagnosis of breast cancer, it may be safe and reasonable to consider pregnancy without significantly increased odds of maternal or neonatal complications,” said study lead author Kirsten Jorgensen, MD, a gynecologic oncology fellow at the University of Texas Houston School of Public Health, in an interview. “This study does not suggest there is no risk, but it does place the risk that exists in context with the risk that is associated with any pregnancy.”
The study appears in Obstetrics & Gynecology.
The researchers launched the analysis because “there is relatively little data to help guide patients, their oncologists, and their obstetricians as they navigate the potential for pregnancy after a cancer diagnosis,” Dr. Jorgensen said. “There have been prior studies looking at birth outcomes, but they often include people who become pregnant very shortly after diagnosis, which may skew results.”
Researchers used databases to track 30,021 women in California aged 18-45 who were diagnosed with breast cancer from 2000 to 2012. Of those, only 553 met the study criteria and conceived at least 1 year after a stage I-III breast cancer diagnosis (median age at delivery = 36; 50.6% non-Hispanic White, 23.9% Hispanic, 6.0% Black; 83.2% private insurance).
Study authors compared these women to a matched control group of 1,659 women without breast cancer.
After adjustment for various factors, there was no significant difference between the groups in terms of maternal outcomes – preterm birth at less than 37 weeks of gestation (12.5% in the breast cancer group vs. 10.0% in the control group; odds ratio = 1.29; 95% confidence interval, 0.95-1.74) or preterm birth at less than 32 weeks of gestation (1.3% vs. 1.6%, respectively, OR = 0.77; 95% CI, 0.34-1.79).
Researchers didn’t find a significant difference in neonatal outcomes either – small for gestational age (less than the 5th percentile, 3.1% vs. 5.0%, respectively; OR = 0.60, 95% CI, 0.35-1.03; less than the 10th percentile: 9.4% vs. 10%, respectively; OR = 0.94; 95% CI, 0.68-1.30), or neonatal morbidity (8.7% vs. 7.7%, respectively; OR = 1.15; 95% CI, 0.81-1.62).
“It is possible that breast cancer may have little impact because some breast cancer is treated only with surgery or radiation to the chest,” Dr. Jorgensen said. “These treatments likely do not impact fertility and may not impact a developing pregnancy.”
There were neonatal deaths: one in the breast cancer group and four in the control group. The researchers said the small number of deaths limited their ability to interpret the data.
Researchers found no evidence that treatment with chemotherapy affected outcomes. They did turn up a difference between the groups: those who’d had breast cancer were more likely to undergo cesarean delivery (45.6% in the breast cancer group, and 40.1% in the control group; OR = 1.25; 95% CI 1.03-1.53), However, offspring of women in the cesarean group weren’t more likely to have neonatal morbidity (OR = 1.15; 95% CI 0.81-1.62).
It’s hard to explain the higher rate of cesarean deliveries in the breast cancer group, Dr. Jorgensen said. “Overall, among our study population and the matched controls there was a high rate of cesarean section. It is possible there was bias on the provider side. Perhaps they intervened with cesarean section earlier among those with a history of breast cancer – a type of bias due to knowing the history of the patient. We attempted to match for other comorbidities that impact obstetric outcomes, but it is possible that we did not account for all of them.”
In an interview, Patricia A. Ganz, MD, director of cancer prevention and control research at University of California, Los Angeles, praised the new research.
It’s “a well-conducted study with state-of-the-art analysis and interpretation,” she said. “Based on my experience with patients I have cared for with breast cancer, there were no surprises here. Most have had uncomplicated pregnancies. This should be reassuring for women who wish to have children after treatment for breast cancer and clinicians should support this decision.”
As for the higher rate of cesarean delivery in breast-cancer survivors, she said “there may be a tendency to think of these as ‘high risk’ pregnancies, and C-sections may be selected at a more frequent rate as a result.”
The study was funded by the National Institutes of Health, including grants from the National Cancer Institute and the National Center for Advancing Translational Sciences. Dr. Jorgensen has no disclosures. Other authors disclosed advisory board service (Delfina Care) and payments from the NIH, Guidepoint, the Schlesinger Group, and Johnson & Johnson. Dr. Ganz has no disclosures.
A new retrospective study provides more evidence that previous breast cancer diagnoses don’t disrupt the health of mothers and newborns in pregnancy: Women who became pregnant at least 12 months after breast cancer diagnosis weren’t more likely than a control group to have preterm births or suffer maternal/neonatal morbidity – even though they were more likely to undergo cesarean section.
“For patients who are more than 1 year out from the diagnosis of breast cancer, it may be safe and reasonable to consider pregnancy without significantly increased odds of maternal or neonatal complications,” said study lead author Kirsten Jorgensen, MD, a gynecologic oncology fellow at the University of Texas Houston School of Public Health, in an interview. “This study does not suggest there is no risk, but it does place the risk that exists in context with the risk that is associated with any pregnancy.”
The study appears in Obstetrics & Gynecology.
The researchers launched the analysis because “there is relatively little data to help guide patients, their oncologists, and their obstetricians as they navigate the potential for pregnancy after a cancer diagnosis,” Dr. Jorgensen said. “There have been prior studies looking at birth outcomes, but they often include people who become pregnant very shortly after diagnosis, which may skew results.”
Researchers used databases to track 30,021 women in California aged 18-45 who were diagnosed with breast cancer from 2000 to 2012. Of those, only 553 met the study criteria and conceived at least 1 year after a stage I-III breast cancer diagnosis (median age at delivery = 36; 50.6% non-Hispanic White, 23.9% Hispanic, 6.0% Black; 83.2% private insurance).
Study authors compared these women to a matched control group of 1,659 women without breast cancer.
After adjustment for various factors, there was no significant difference between the groups in terms of maternal outcomes – preterm birth at less than 37 weeks of gestation (12.5% in the breast cancer group vs. 10.0% in the control group; odds ratio = 1.29; 95% confidence interval, 0.95-1.74) or preterm birth at less than 32 weeks of gestation (1.3% vs. 1.6%, respectively, OR = 0.77; 95% CI, 0.34-1.79).
Researchers didn’t find a significant difference in neonatal outcomes either – small for gestational age (less than the 5th percentile, 3.1% vs. 5.0%, respectively; OR = 0.60, 95% CI, 0.35-1.03; less than the 10th percentile: 9.4% vs. 10%, respectively; OR = 0.94; 95% CI, 0.68-1.30), or neonatal morbidity (8.7% vs. 7.7%, respectively; OR = 1.15; 95% CI, 0.81-1.62).
“It is possible that breast cancer may have little impact because some breast cancer is treated only with surgery or radiation to the chest,” Dr. Jorgensen said. “These treatments likely do not impact fertility and may not impact a developing pregnancy.”
There were neonatal deaths: one in the breast cancer group and four in the control group. The researchers said the small number of deaths limited their ability to interpret the data.
Researchers found no evidence that treatment with chemotherapy affected outcomes. They did turn up a difference between the groups: those who’d had breast cancer were more likely to undergo cesarean delivery (45.6% in the breast cancer group, and 40.1% in the control group; OR = 1.25; 95% CI 1.03-1.53), However, offspring of women in the cesarean group weren’t more likely to have neonatal morbidity (OR = 1.15; 95% CI 0.81-1.62).
It’s hard to explain the higher rate of cesarean deliveries in the breast cancer group, Dr. Jorgensen said. “Overall, among our study population and the matched controls there was a high rate of cesarean section. It is possible there was bias on the provider side. Perhaps they intervened with cesarean section earlier among those with a history of breast cancer – a type of bias due to knowing the history of the patient. We attempted to match for other comorbidities that impact obstetric outcomes, but it is possible that we did not account for all of them.”
In an interview, Patricia A. Ganz, MD, director of cancer prevention and control research at University of California, Los Angeles, praised the new research.
It’s “a well-conducted study with state-of-the-art analysis and interpretation,” she said. “Based on my experience with patients I have cared for with breast cancer, there were no surprises here. Most have had uncomplicated pregnancies. This should be reassuring for women who wish to have children after treatment for breast cancer and clinicians should support this decision.”
As for the higher rate of cesarean delivery in breast-cancer survivors, she said “there may be a tendency to think of these as ‘high risk’ pregnancies, and C-sections may be selected at a more frequent rate as a result.”
The study was funded by the National Institutes of Health, including grants from the National Cancer Institute and the National Center for Advancing Translational Sciences. Dr. Jorgensen has no disclosures. Other authors disclosed advisory board service (Delfina Care) and payments from the NIH, Guidepoint, the Schlesinger Group, and Johnson & Johnson. Dr. Ganz has no disclosures.
A new retrospective study provides more evidence that previous breast cancer diagnoses don’t disrupt the health of mothers and newborns in pregnancy: Women who became pregnant at least 12 months after breast cancer diagnosis weren’t more likely than a control group to have preterm births or suffer maternal/neonatal morbidity – even though they were more likely to undergo cesarean section.
“For patients who are more than 1 year out from the diagnosis of breast cancer, it may be safe and reasonable to consider pregnancy without significantly increased odds of maternal or neonatal complications,” said study lead author Kirsten Jorgensen, MD, a gynecologic oncology fellow at the University of Texas Houston School of Public Health, in an interview. “This study does not suggest there is no risk, but it does place the risk that exists in context with the risk that is associated with any pregnancy.”
The study appears in Obstetrics & Gynecology.
The researchers launched the analysis because “there is relatively little data to help guide patients, their oncologists, and their obstetricians as they navigate the potential for pregnancy after a cancer diagnosis,” Dr. Jorgensen said. “There have been prior studies looking at birth outcomes, but they often include people who become pregnant very shortly after diagnosis, which may skew results.”
Researchers used databases to track 30,021 women in California aged 18-45 who were diagnosed with breast cancer from 2000 to 2012. Of those, only 553 met the study criteria and conceived at least 1 year after a stage I-III breast cancer diagnosis (median age at delivery = 36; 50.6% non-Hispanic White, 23.9% Hispanic, 6.0% Black; 83.2% private insurance).
Study authors compared these women to a matched control group of 1,659 women without breast cancer.
After adjustment for various factors, there was no significant difference between the groups in terms of maternal outcomes – preterm birth at less than 37 weeks of gestation (12.5% in the breast cancer group vs. 10.0% in the control group; odds ratio = 1.29; 95% confidence interval, 0.95-1.74) or preterm birth at less than 32 weeks of gestation (1.3% vs. 1.6%, respectively, OR = 0.77; 95% CI, 0.34-1.79).
Researchers didn’t find a significant difference in neonatal outcomes either – small for gestational age (less than the 5th percentile, 3.1% vs. 5.0%, respectively; OR = 0.60, 95% CI, 0.35-1.03; less than the 10th percentile: 9.4% vs. 10%, respectively; OR = 0.94; 95% CI, 0.68-1.30), or neonatal morbidity (8.7% vs. 7.7%, respectively; OR = 1.15; 95% CI, 0.81-1.62).
“It is possible that breast cancer may have little impact because some breast cancer is treated only with surgery or radiation to the chest,” Dr. Jorgensen said. “These treatments likely do not impact fertility and may not impact a developing pregnancy.”
There were neonatal deaths: one in the breast cancer group and four in the control group. The researchers said the small number of deaths limited their ability to interpret the data.
Researchers found no evidence that treatment with chemotherapy affected outcomes. They did turn up a difference between the groups: those who’d had breast cancer were more likely to undergo cesarean delivery (45.6% in the breast cancer group, and 40.1% in the control group; OR = 1.25; 95% CI 1.03-1.53), However, offspring of women in the cesarean group weren’t more likely to have neonatal morbidity (OR = 1.15; 95% CI 0.81-1.62).
It’s hard to explain the higher rate of cesarean deliveries in the breast cancer group, Dr. Jorgensen said. “Overall, among our study population and the matched controls there was a high rate of cesarean section. It is possible there was bias on the provider side. Perhaps they intervened with cesarean section earlier among those with a history of breast cancer – a type of bias due to knowing the history of the patient. We attempted to match for other comorbidities that impact obstetric outcomes, but it is possible that we did not account for all of them.”
In an interview, Patricia A. Ganz, MD, director of cancer prevention and control research at University of California, Los Angeles, praised the new research.
It’s “a well-conducted study with state-of-the-art analysis and interpretation,” she said. “Based on my experience with patients I have cared for with breast cancer, there were no surprises here. Most have had uncomplicated pregnancies. This should be reassuring for women who wish to have children after treatment for breast cancer and clinicians should support this decision.”
As for the higher rate of cesarean delivery in breast-cancer survivors, she said “there may be a tendency to think of these as ‘high risk’ pregnancies, and C-sections may be selected at a more frequent rate as a result.”
The study was funded by the National Institutes of Health, including grants from the National Cancer Institute and the National Center for Advancing Translational Sciences. Dr. Jorgensen has no disclosures. Other authors disclosed advisory board service (Delfina Care) and payments from the NIH, Guidepoint, the Schlesinger Group, and Johnson & Johnson. Dr. Ganz has no disclosures.
FROM OBSTETRICS & GYNECOLOGY