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Checkpoint inhibitor rechallenge is possible for select patients
Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.
In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.
As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.
“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.
The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).
The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.
When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).
“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.
“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.
The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.
SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.
Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.
In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.
As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.
“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.
The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).
The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.
When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).
“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.
“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.
The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.
SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.
Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.
In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.
As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.
“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.
The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).
The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.
When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).
“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.
“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.
The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.
SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.
FROM JAMA ONCOLOGY
FDA approves abemaciclib plus aromatase inhibitor as initial therapy
Abemaciclib (Verzenio) in combination with an aromatase inhibitor has been approved as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, the US Food and Drug Administration announced in a press release.
Approval was based on the results of the MONARCH 3 study, a randomized, double-blind, placebo-controlled, multicenter clinical trial in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. A total of 493 patients were randomized to receive either abemaciclib 150 mg or placebo orally twice daily, plus the treating physician’s choice of letrozole or anastrozole. The estimated median progression-free survival (PFS) (RECIST 1.1) was 28.2 months (95% CI: 23.5, not reached) for patients receiving abemaciclib and 14.8 months (95% CI: 11.2, 19.2) for those receiving placebo (HR 0.540; 95% CI: 0.418, 0.698; p<0.0001).
The most common adverse reactions that were seen in at least 20% of patients receiving abemaciclib in MONARCH 3 and were reported at a rate more than 2% higher than the rates seen in the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia.
The recommended starting dose of abemaciclib in combination with an aromatase inhibitor is 150 mg twice daily orally with or without food.
Abemaciclib (Verzenio) is manufactured by Eli Lilly.
Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf.
Abemaciclib (Verzenio) in combination with an aromatase inhibitor has been approved as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, the US Food and Drug Administration announced in a press release.
Approval was based on the results of the MONARCH 3 study, a randomized, double-blind, placebo-controlled, multicenter clinical trial in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. A total of 493 patients were randomized to receive either abemaciclib 150 mg or placebo orally twice daily, plus the treating physician’s choice of letrozole or anastrozole. The estimated median progression-free survival (PFS) (RECIST 1.1) was 28.2 months (95% CI: 23.5, not reached) for patients receiving abemaciclib and 14.8 months (95% CI: 11.2, 19.2) for those receiving placebo (HR 0.540; 95% CI: 0.418, 0.698; p<0.0001).
The most common adverse reactions that were seen in at least 20% of patients receiving abemaciclib in MONARCH 3 and were reported at a rate more than 2% higher than the rates seen in the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia.
The recommended starting dose of abemaciclib in combination with an aromatase inhibitor is 150 mg twice daily orally with or without food.
Abemaciclib (Verzenio) is manufactured by Eli Lilly.
Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf.
Abemaciclib (Verzenio) in combination with an aromatase inhibitor has been approved as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, the US Food and Drug Administration announced in a press release.
Approval was based on the results of the MONARCH 3 study, a randomized, double-blind, placebo-controlled, multicenter clinical trial in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. A total of 493 patients were randomized to receive either abemaciclib 150 mg or placebo orally twice daily, plus the treating physician’s choice of letrozole or anastrozole. The estimated median progression-free survival (PFS) (RECIST 1.1) was 28.2 months (95% CI: 23.5, not reached) for patients receiving abemaciclib and 14.8 months (95% CI: 11.2, 19.2) for those receiving placebo (HR 0.540; 95% CI: 0.418, 0.698; p<0.0001).
The most common adverse reactions that were seen in at least 20% of patients receiving abemaciclib in MONARCH 3 and were reported at a rate more than 2% higher than the rates seen in the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia.
The recommended starting dose of abemaciclib in combination with an aromatase inhibitor is 150 mg twice daily orally with or without food.
Abemaciclib (Verzenio) is manufactured by Eli Lilly.
Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf.
Imfinzi approved for stage III unresectable NSCLC
Durvalumab (Imfinzi) has been approved as the first treatment for patients with stage III unresectable non-small cell lung cancer (NSCLC) that has not progressed after chemotherapy and radiation, the Food and Drug Administration announced on Feb. 16.
Chemoradiation had been the only option for such patients. “Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.
Durvalumab, which targets the PD-1/PD-L1 pathway, was previously granted accelerated approval in 2017 for the treatment of certain patients with locally advanced or metastatic bladder cancer.
The approval for the treatment of stage III, unresectable NSCLC was based on the results of the randomized PACIFIC trial of 713 patients whose cancer had not progressed after completing chemotherapy and radiation. The trial measured progression-free survival with durvalumab or a placebo, and found a median progression-free survival of 16.8 months for patients taking durvalumab and 5.6 months for patients receiving a placebo. The drug's sponsor, AstraZeneca, has agreed to provide data on overall survival in the study.
Common side effects of durvalumab in patients with stage III unresectable NSCLC include cough, fatigue, inflammation in the lungs (pneumonitis/radiation pneumonitis), upper respiratory tract infections, difficulty breathing (dyspnea) and rash.
Serious risks of durvalumab include pneumonitis, hepatitis, colitis, endocrinopathies, and nephritis. Other serious side effects include infection and infusion-related reactions. Durvalumab can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.
Durvalumab (Imfinzi) has been approved as the first treatment for patients with stage III unresectable non-small cell lung cancer (NSCLC) that has not progressed after chemotherapy and radiation, the Food and Drug Administration announced on Feb. 16.
Chemoradiation had been the only option for such patients. “Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.
Durvalumab, which targets the PD-1/PD-L1 pathway, was previously granted accelerated approval in 2017 for the treatment of certain patients with locally advanced or metastatic bladder cancer.
The approval for the treatment of stage III, unresectable NSCLC was based on the results of the randomized PACIFIC trial of 713 patients whose cancer had not progressed after completing chemotherapy and radiation. The trial measured progression-free survival with durvalumab or a placebo, and found a median progression-free survival of 16.8 months for patients taking durvalumab and 5.6 months for patients receiving a placebo. The drug's sponsor, AstraZeneca, has agreed to provide data on overall survival in the study.
Common side effects of durvalumab in patients with stage III unresectable NSCLC include cough, fatigue, inflammation in the lungs (pneumonitis/radiation pneumonitis), upper respiratory tract infections, difficulty breathing (dyspnea) and rash.
Serious risks of durvalumab include pneumonitis, hepatitis, colitis, endocrinopathies, and nephritis. Other serious side effects include infection and infusion-related reactions. Durvalumab can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.
Durvalumab (Imfinzi) has been approved as the first treatment for patients with stage III unresectable non-small cell lung cancer (NSCLC) that has not progressed after chemotherapy and radiation, the Food and Drug Administration announced on Feb. 16.
Chemoradiation had been the only option for such patients. “Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.
Durvalumab, which targets the PD-1/PD-L1 pathway, was previously granted accelerated approval in 2017 for the treatment of certain patients with locally advanced or metastatic bladder cancer.
The approval for the treatment of stage III, unresectable NSCLC was based on the results of the randomized PACIFIC trial of 713 patients whose cancer had not progressed after completing chemotherapy and radiation. The trial measured progression-free survival with durvalumab or a placebo, and found a median progression-free survival of 16.8 months for patients taking durvalumab and 5.6 months for patients receiving a placebo. The drug's sponsor, AstraZeneca, has agreed to provide data on overall survival in the study.
Common side effects of durvalumab in patients with stage III unresectable NSCLC include cough, fatigue, inflammation in the lungs (pneumonitis/radiation pneumonitis), upper respiratory tract infections, difficulty breathing (dyspnea) and rash.
Serious risks of durvalumab include pneumonitis, hepatitis, colitis, endocrinopathies, and nephritis. Other serious side effects include infection and infusion-related reactions. Durvalumab can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.
Only half of appropriate COPD patients get long-acting bronchodilators
Nearly half of Medicare beneficiaries with COPD are not being treated with recommended long-acting bronchodilator (LABD) maintenance therapy, based on study results scheduled to be presented at CHEST 2017.
Bartolome R. Celli, MD, FCCP, of Brigham and Women’s Hospital, Boston, and his colleagues will report results based on Medicare administrative data from 2010 to 2014 on 11,886 patients who had at least two outpatient visits for COPD within 30 days or at least one COPD-related hospitalization and received nebulized arformoterol therapy.
The findings should stimulate further study on why clinicians overrely on short-acting rather than the recommended long-acting bronchodilators for maintenance treatment of appropriate patients, according to the researchers’ abstract. Additionally, studies should examine triggers for initiating arformoterol, and link outcomes to arformoterol monotherapy vs. combination therapy. Such analyses could help advance clinical decision making, particularly for COPD patients with a history of exacerbations and hospitalizations.
Rates of medication initiation and treatment continuation or discontinuation within these classes were determined based on refill patterns following the start of arformoterol therapy. The researchers note that 42% of the patient cohort was 75 years or older, and 37% were dually eligible for Medicaid.
Overall, 46% of the cohort had received no LABD maintenance treatment in the 90 days prior to initiating arformoterol. Instead, they were being treated with a nebulized (50%) or an inhaled (37%) short-acting bronchodilator, a systemic corticosteroid (46%), and antibiotics (37%).
After starting arformoteral, 58% of beneficiaries received dual therapy. More than half of them, 52%, received LABA and inhaled/nebulized corticosteroids, 6% received LAMA/LAMA therapy, and 21% received triple-therapy (LABA/LAMA plus inhaled or nebulized corticosteroids). The other 20% received only arformoterol.
After initiating arformoterol, 41% of the cohort discontinued one or more classes of their pre-arformoteral medications. The largest decrease was a 23% drop in use of corticosteroids.
Dr. Celli is scheduled to present his research on Tuesday, Oct. 31, from 2:45 to 3:00 pm in Convention Center - 602B at the CHEST annual meeting. His presentation will be part of a session entitled “COPD: Lessons for the Real-World Management of Disease,” running from 2:45 to 4:15 pm.
One of the researchers is an employee of Sunovion Pharmaceuticals, and two others are with Advance Health Solutions.
Nearly half of Medicare beneficiaries with COPD are not being treated with recommended long-acting bronchodilator (LABD) maintenance therapy, based on study results scheduled to be presented at CHEST 2017.
Bartolome R. Celli, MD, FCCP, of Brigham and Women’s Hospital, Boston, and his colleagues will report results based on Medicare administrative data from 2010 to 2014 on 11,886 patients who had at least two outpatient visits for COPD within 30 days or at least one COPD-related hospitalization and received nebulized arformoterol therapy.
The findings should stimulate further study on why clinicians overrely on short-acting rather than the recommended long-acting bronchodilators for maintenance treatment of appropriate patients, according to the researchers’ abstract. Additionally, studies should examine triggers for initiating arformoterol, and link outcomes to arformoterol monotherapy vs. combination therapy. Such analyses could help advance clinical decision making, particularly for COPD patients with a history of exacerbations and hospitalizations.
Rates of medication initiation and treatment continuation or discontinuation within these classes were determined based on refill patterns following the start of arformoterol therapy. The researchers note that 42% of the patient cohort was 75 years or older, and 37% were dually eligible for Medicaid.
Overall, 46% of the cohort had received no LABD maintenance treatment in the 90 days prior to initiating arformoterol. Instead, they were being treated with a nebulized (50%) or an inhaled (37%) short-acting bronchodilator, a systemic corticosteroid (46%), and antibiotics (37%).
After starting arformoteral, 58% of beneficiaries received dual therapy. More than half of them, 52%, received LABA and inhaled/nebulized corticosteroids, 6% received LAMA/LAMA therapy, and 21% received triple-therapy (LABA/LAMA plus inhaled or nebulized corticosteroids). The other 20% received only arformoterol.
After initiating arformoterol, 41% of the cohort discontinued one or more classes of their pre-arformoteral medications. The largest decrease was a 23% drop in use of corticosteroids.
Dr. Celli is scheduled to present his research on Tuesday, Oct. 31, from 2:45 to 3:00 pm in Convention Center - 602B at the CHEST annual meeting. His presentation will be part of a session entitled “COPD: Lessons for the Real-World Management of Disease,” running from 2:45 to 4:15 pm.
One of the researchers is an employee of Sunovion Pharmaceuticals, and two others are with Advance Health Solutions.
Nearly half of Medicare beneficiaries with COPD are not being treated with recommended long-acting bronchodilator (LABD) maintenance therapy, based on study results scheduled to be presented at CHEST 2017.
Bartolome R. Celli, MD, FCCP, of Brigham and Women’s Hospital, Boston, and his colleagues will report results based on Medicare administrative data from 2010 to 2014 on 11,886 patients who had at least two outpatient visits for COPD within 30 days or at least one COPD-related hospitalization and received nebulized arformoterol therapy.
The findings should stimulate further study on why clinicians overrely on short-acting rather than the recommended long-acting bronchodilators for maintenance treatment of appropriate patients, according to the researchers’ abstract. Additionally, studies should examine triggers for initiating arformoterol, and link outcomes to arformoterol monotherapy vs. combination therapy. Such analyses could help advance clinical decision making, particularly for COPD patients with a history of exacerbations and hospitalizations.
Rates of medication initiation and treatment continuation or discontinuation within these classes were determined based on refill patterns following the start of arformoterol therapy. The researchers note that 42% of the patient cohort was 75 years or older, and 37% were dually eligible for Medicaid.
Overall, 46% of the cohort had received no LABD maintenance treatment in the 90 days prior to initiating arformoterol. Instead, they were being treated with a nebulized (50%) or an inhaled (37%) short-acting bronchodilator, a systemic corticosteroid (46%), and antibiotics (37%).
After starting arformoteral, 58% of beneficiaries received dual therapy. More than half of them, 52%, received LABA and inhaled/nebulized corticosteroids, 6% received LAMA/LAMA therapy, and 21% received triple-therapy (LABA/LAMA plus inhaled or nebulized corticosteroids). The other 20% received only arformoterol.
After initiating arformoterol, 41% of the cohort discontinued one or more classes of their pre-arformoteral medications. The largest decrease was a 23% drop in use of corticosteroids.
Dr. Celli is scheduled to present his research on Tuesday, Oct. 31, from 2:45 to 3:00 pm in Convention Center - 602B at the CHEST annual meeting. His presentation will be part of a session entitled “COPD: Lessons for the Real-World Management of Disease,” running from 2:45 to 4:15 pm.
One of the researchers is an employee of Sunovion Pharmaceuticals, and two others are with Advance Health Solutions.
FROM CHEST 2017
Key clinical point:
Major finding: Overall, 46% of COPD patients on Medicare had received no long-acting bronchodilator maintenance treatment in the 90 days before they started arformoterol therapy.
Data source: Medicare administrative data from 2010 to 2014 on 11,886 patients who had at least two outpatient visits for COPD within 30 days or at least one COPD-related hospitalization and received nebulized arformoteral therapy.
Disclosures: One of the researchers is an employee of Sunovion Pharmaceuticals, and two others are with Advance Health Solutions.
Lomitapide manufacturer will plead guilty to two misdemeanor charges of misbranding
Juxtapid was misbranded because Aegerion failed to comply with the requirements of the Juxtapid Risk Evaluation and Mitigation Strategy (REMS) program and because the drug’s labeling lacked adequate directions for all of Juxtapid’s intended uses, according to the charges. Aegerion also agreed to a comprehensive compliance program and legal tools for the FDA to ensure that Aegerion complies with the law, subject to judicial oversight.
Rather than following the REMS requirement to distribute Juxtapid only for the narrow indication of homozygous familial hypercholesterolemia, Aegerion portrayed the definition of the rare disorder as vague and indefinite in order to extend its use to lower-risk patients. Further, Aegerion filed a misleading REMS assessment report to the FDA in which the company failed to disclose that it was distributing Juxtapid using this definition, which was inconsistent with Aegerion’s preapproval filings and peer-reviewed clinical standards of diagnosis, according to the FDA release.
Once entered by the court, the plea and consent decree will be part of a global resolution of multiple government investigations into Aegerion’s conduct with respect to the marketing and distribution of Juxtapid. This resolution was the result of a coordinated effort by the U.S. Department of Justice and several government agencies, including the FDA, the press release stated.
Juxtapid was approved in December 2012 as an adjunct therapy to treat homozygous familial hypercholesterolemia. The Juxtapid REMS requires Aegerion to educate prescribers about the risks of hepatotoxicity and the need to monitor patients treated with Juxtapid and to ensure that Juxtapid is prescribed and dispensed only to those patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia.
Juxtapid was misbranded because Aegerion failed to comply with the requirements of the Juxtapid Risk Evaluation and Mitigation Strategy (REMS) program and because the drug’s labeling lacked adequate directions for all of Juxtapid’s intended uses, according to the charges. Aegerion also agreed to a comprehensive compliance program and legal tools for the FDA to ensure that Aegerion complies with the law, subject to judicial oversight.
Rather than following the REMS requirement to distribute Juxtapid only for the narrow indication of homozygous familial hypercholesterolemia, Aegerion portrayed the definition of the rare disorder as vague and indefinite in order to extend its use to lower-risk patients. Further, Aegerion filed a misleading REMS assessment report to the FDA in which the company failed to disclose that it was distributing Juxtapid using this definition, which was inconsistent with Aegerion’s preapproval filings and peer-reviewed clinical standards of diagnosis, according to the FDA release.
Once entered by the court, the plea and consent decree will be part of a global resolution of multiple government investigations into Aegerion’s conduct with respect to the marketing and distribution of Juxtapid. This resolution was the result of a coordinated effort by the U.S. Department of Justice and several government agencies, including the FDA, the press release stated.
Juxtapid was approved in December 2012 as an adjunct therapy to treat homozygous familial hypercholesterolemia. The Juxtapid REMS requires Aegerion to educate prescribers about the risks of hepatotoxicity and the need to monitor patients treated with Juxtapid and to ensure that Juxtapid is prescribed and dispensed only to those patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia.
Juxtapid was misbranded because Aegerion failed to comply with the requirements of the Juxtapid Risk Evaluation and Mitigation Strategy (REMS) program and because the drug’s labeling lacked adequate directions for all of Juxtapid’s intended uses, according to the charges. Aegerion also agreed to a comprehensive compliance program and legal tools for the FDA to ensure that Aegerion complies with the law, subject to judicial oversight.
Rather than following the REMS requirement to distribute Juxtapid only for the narrow indication of homozygous familial hypercholesterolemia, Aegerion portrayed the definition of the rare disorder as vague and indefinite in order to extend its use to lower-risk patients. Further, Aegerion filed a misleading REMS assessment report to the FDA in which the company failed to disclose that it was distributing Juxtapid using this definition, which was inconsistent with Aegerion’s preapproval filings and peer-reviewed clinical standards of diagnosis, according to the FDA release.
Once entered by the court, the plea and consent decree will be part of a global resolution of multiple government investigations into Aegerion’s conduct with respect to the marketing and distribution of Juxtapid. This resolution was the result of a coordinated effort by the U.S. Department of Justice and several government agencies, including the FDA, the press release stated.
Juxtapid was approved in December 2012 as an adjunct therapy to treat homozygous familial hypercholesterolemia. The Juxtapid REMS requires Aegerion to educate prescribers about the risks of hepatotoxicity and the need to monitor patients treated with Juxtapid and to ensure that Juxtapid is prescribed and dispensed only to those patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia.
Polycythemia vera test detects JAK2 V617F/G1849T mutation
The ipsogen JAK2 RGQ PCR Kit has been given marketing authorization by the Food and Drug Administration.
This is the first FDA-authorized test for use in evaluating patients for suspected polycythemia vera, according to an FDA press release. Manufactured by Qiagen, the kit detects the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood.
The presence of JAK2 mutations is one of the major criteria for clinical confirmation of polycythemia vera. The V617F/G1849T mutation is detected in more than 94% of these patients. This test does not detect less common mutations including mutations in exon 12 and is not intended for stand-alone diagnosis, which is based on other clinicopathological factors of polycythemia vera.
Marketing authorization, granted March 27, 2017, was based on data from a clinical study of 216 patients with suspected polycythemia vera. The study compared results from the ipsogen JAK2 RGQ PCR Kit with results obtained with Sanger sequencing. In the study, the ipsogen JAK2 RGQ PCR Kit test detected polycythemia vera with 94.6% sensitivity and 98.1% specificity.
Further information about the JAK2 RGQ PCR Kit is available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/DEN160028.pdf.
mdales@frontlinemedcom.com
On Twitter @maryjodales
The ipsogen JAK2 RGQ PCR Kit has been given marketing authorization by the Food and Drug Administration.
This is the first FDA-authorized test for use in evaluating patients for suspected polycythemia vera, according to an FDA press release. Manufactured by Qiagen, the kit detects the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood.
The presence of JAK2 mutations is one of the major criteria for clinical confirmation of polycythemia vera. The V617F/G1849T mutation is detected in more than 94% of these patients. This test does not detect less common mutations including mutations in exon 12 and is not intended for stand-alone diagnosis, which is based on other clinicopathological factors of polycythemia vera.
Marketing authorization, granted March 27, 2017, was based on data from a clinical study of 216 patients with suspected polycythemia vera. The study compared results from the ipsogen JAK2 RGQ PCR Kit with results obtained with Sanger sequencing. In the study, the ipsogen JAK2 RGQ PCR Kit test detected polycythemia vera with 94.6% sensitivity and 98.1% specificity.
Further information about the JAK2 RGQ PCR Kit is available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/DEN160028.pdf.
mdales@frontlinemedcom.com
On Twitter @maryjodales
The ipsogen JAK2 RGQ PCR Kit has been given marketing authorization by the Food and Drug Administration.
This is the first FDA-authorized test for use in evaluating patients for suspected polycythemia vera, according to an FDA press release. Manufactured by Qiagen, the kit detects the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood.
The presence of JAK2 mutations is one of the major criteria for clinical confirmation of polycythemia vera. The V617F/G1849T mutation is detected in more than 94% of these patients. This test does not detect less common mutations including mutations in exon 12 and is not intended for stand-alone diagnosis, which is based on other clinicopathological factors of polycythemia vera.
Marketing authorization, granted March 27, 2017, was based on data from a clinical study of 216 patients with suspected polycythemia vera. The study compared results from the ipsogen JAK2 RGQ PCR Kit with results obtained with Sanger sequencing. In the study, the ipsogen JAK2 RGQ PCR Kit test detected polycythemia vera with 94.6% sensitivity and 98.1% specificity.
Further information about the JAK2 RGQ PCR Kit is available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/DEN160028.pdf.
mdales@frontlinemedcom.com
On Twitter @maryjodales
VIDEO: CPX-351 may allow more high-risk AML patients to have allogeneic transplants
SAN DIEGO – Induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed more older patients with newly diagnosed secondary AML to bridge successfully to transplant than did standard 7+3 cytarabine and daunorubicin, based on data reported by Jeffrey E. Lancet, MD, at the annual meeting of the American Society of Hematology.
The data come from a subgroup analysis of a phase III study in 60- to 75-year-old patients with secondary AML. Initial survival data from that randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
Dr. Lancet of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., credited the better results to the higher level of complete responses and complete responses with incomplete platelet or neutrophil recovery with the liposomal formulation.
In a video interview, Dr. Lancet discussed how better disease control allowed more patients to be transplanted and next steps for expanded study in this patient population as well as in younger patients with AML.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mdales@frontlinemedcom.com
On Twitter @maryjodales
SAN DIEGO – Induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed more older patients with newly diagnosed secondary AML to bridge successfully to transplant than did standard 7+3 cytarabine and daunorubicin, based on data reported by Jeffrey E. Lancet, MD, at the annual meeting of the American Society of Hematology.
The data come from a subgroup analysis of a phase III study in 60- to 75-year-old patients with secondary AML. Initial survival data from that randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
Dr. Lancet of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., credited the better results to the higher level of complete responses and complete responses with incomplete platelet or neutrophil recovery with the liposomal formulation.
In a video interview, Dr. Lancet discussed how better disease control allowed more patients to be transplanted and next steps for expanded study in this patient population as well as in younger patients with AML.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mdales@frontlinemedcom.com
On Twitter @maryjodales
SAN DIEGO – Induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed more older patients with newly diagnosed secondary AML to bridge successfully to transplant than did standard 7+3 cytarabine and daunorubicin, based on data reported by Jeffrey E. Lancet, MD, at the annual meeting of the American Society of Hematology.
The data come from a subgroup analysis of a phase III study in 60- to 75-year-old patients with secondary AML. Initial survival data from that randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
Dr. Lancet of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., credited the better results to the higher level of complete responses and complete responses with incomplete platelet or neutrophil recovery with the liposomal formulation.
In a video interview, Dr. Lancet discussed how better disease control allowed more patients to be transplanted and next steps for expanded study in this patient population as well as in younger patients with AML.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mdales@frontlinemedcom.com
On Twitter @maryjodales
AT ASH 2016
Factor VIII microcapsules eyed for eluding neutralizing antibodies
Using platelet microcapsules to deliver factor VIII, a process that is expected to increase factor VIII efficacy and avoid the development of neutralizing antibodies, is being examined via in vitro testing, according to an abstract to be featured during a press conference at the annual meeting of the American Society of Hematology.
Caroline E. Hansen of the Georgia Institute of Technology, Atlanta, and her colleagues performed in vitro experiments that show this technology has the potential to increase factor VIII efficacy for hemophilia A patients with inhibitors.
“Current work evaluating localized thrombin generation due to the factor VIII–loaded microcapsules and the effect of platelet contraction force via pharmacologic agents, such as blebbistatin, ROCK, and myosin inhibitors, [is] ongoing,” the researchers wrote in their abstract.
They fabricated polyelectrolyte layers onto calcium carbonate cores and incorporated fibrinogen into the final layer to facilitate binding with platelets. The microcapsule’s inner core contains factor VIII separated from the polyelectrolyte layers by a dextran core.
In the in vitro model, platelets adhered to the microcapsules, which were incorporated into fibrin networks upon platelet activation. During clot contraction, the microcapsules ruptured only in the vicinity of contracting platelets, ensuring drug delivery was targeted at sites of active clot formation.
The researchers perfused recalcified whole blood and platelet poor plasma into in vitro microfluidic models of vascular injury, which consisted of a collagen/tissue factor patch. The efficacy of systemic and microcapsular factor VIII was quantitatively evaluated by comparing fibrin fluorescence intensity on the patch, which was normalized to platelet number.
Fibrin formation was comparable using microcapsules without dextran, fibrinogen, and loaded factor VIII. Compared with standard systemic infusion of 0.05 U/mL factor VIII, however, microcapsules loaded with 0.01 U/mL factor VIII produced four times as much fibrin.
To mimic hemophilia A blood with inhibitors, a factor VIII inhibitory antibody was introduced into healthy blood samples. Again, significantly more fibrin was produced in samples with microcapsules loaded with 0.01 U/mL factor VIII than with systemic factor VIII infusions at clinically relevant high and low dosages of 0.05 and 0.5 U/mL (P less than .05).
This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies, the researchers reported.
Ms. Hansen had no relevant financial disclosures. One of her colleagues, Shannon L. Meeks, MD, disclosed adviser relationships with Biogen, Genentech, Bayer Healthcare, Grifols, CSL Behring, and Shire. Another, Wilbur A Lam, MD, PhD, disclosed equity ownership in Sanguina.
Abstract 81: Leveraging the Contractile Force of Platelets for Targeted Factor VIII Delivery in Hemophilia With Inhibitors.
mdales@frontlinemedcom.com
On Twitter @maryjodales
Using platelet microcapsules to deliver factor VIII, a process that is expected to increase factor VIII efficacy and avoid the development of neutralizing antibodies, is being examined via in vitro testing, according to an abstract to be featured during a press conference at the annual meeting of the American Society of Hematology.
Caroline E. Hansen of the Georgia Institute of Technology, Atlanta, and her colleagues performed in vitro experiments that show this technology has the potential to increase factor VIII efficacy for hemophilia A patients with inhibitors.
“Current work evaluating localized thrombin generation due to the factor VIII–loaded microcapsules and the effect of platelet contraction force via pharmacologic agents, such as blebbistatin, ROCK, and myosin inhibitors, [is] ongoing,” the researchers wrote in their abstract.
They fabricated polyelectrolyte layers onto calcium carbonate cores and incorporated fibrinogen into the final layer to facilitate binding with platelets. The microcapsule’s inner core contains factor VIII separated from the polyelectrolyte layers by a dextran core.
In the in vitro model, platelets adhered to the microcapsules, which were incorporated into fibrin networks upon platelet activation. During clot contraction, the microcapsules ruptured only in the vicinity of contracting platelets, ensuring drug delivery was targeted at sites of active clot formation.
The researchers perfused recalcified whole blood and platelet poor plasma into in vitro microfluidic models of vascular injury, which consisted of a collagen/tissue factor patch. The efficacy of systemic and microcapsular factor VIII was quantitatively evaluated by comparing fibrin fluorescence intensity on the patch, which was normalized to platelet number.
Fibrin formation was comparable using microcapsules without dextran, fibrinogen, and loaded factor VIII. Compared with standard systemic infusion of 0.05 U/mL factor VIII, however, microcapsules loaded with 0.01 U/mL factor VIII produced four times as much fibrin.
To mimic hemophilia A blood with inhibitors, a factor VIII inhibitory antibody was introduced into healthy blood samples. Again, significantly more fibrin was produced in samples with microcapsules loaded with 0.01 U/mL factor VIII than with systemic factor VIII infusions at clinically relevant high and low dosages of 0.05 and 0.5 U/mL (P less than .05).
This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies, the researchers reported.
Ms. Hansen had no relevant financial disclosures. One of her colleagues, Shannon L. Meeks, MD, disclosed adviser relationships with Biogen, Genentech, Bayer Healthcare, Grifols, CSL Behring, and Shire. Another, Wilbur A Lam, MD, PhD, disclosed equity ownership in Sanguina.
Abstract 81: Leveraging the Contractile Force of Platelets for Targeted Factor VIII Delivery in Hemophilia With Inhibitors.
mdales@frontlinemedcom.com
On Twitter @maryjodales
Using platelet microcapsules to deliver factor VIII, a process that is expected to increase factor VIII efficacy and avoid the development of neutralizing antibodies, is being examined via in vitro testing, according to an abstract to be featured during a press conference at the annual meeting of the American Society of Hematology.
Caroline E. Hansen of the Georgia Institute of Technology, Atlanta, and her colleagues performed in vitro experiments that show this technology has the potential to increase factor VIII efficacy for hemophilia A patients with inhibitors.
“Current work evaluating localized thrombin generation due to the factor VIII–loaded microcapsules and the effect of platelet contraction force via pharmacologic agents, such as blebbistatin, ROCK, and myosin inhibitors, [is] ongoing,” the researchers wrote in their abstract.
They fabricated polyelectrolyte layers onto calcium carbonate cores and incorporated fibrinogen into the final layer to facilitate binding with platelets. The microcapsule’s inner core contains factor VIII separated from the polyelectrolyte layers by a dextran core.
In the in vitro model, platelets adhered to the microcapsules, which were incorporated into fibrin networks upon platelet activation. During clot contraction, the microcapsules ruptured only in the vicinity of contracting platelets, ensuring drug delivery was targeted at sites of active clot formation.
The researchers perfused recalcified whole blood and platelet poor plasma into in vitro microfluidic models of vascular injury, which consisted of a collagen/tissue factor patch. The efficacy of systemic and microcapsular factor VIII was quantitatively evaluated by comparing fibrin fluorescence intensity on the patch, which was normalized to platelet number.
Fibrin formation was comparable using microcapsules without dextran, fibrinogen, and loaded factor VIII. Compared with standard systemic infusion of 0.05 U/mL factor VIII, however, microcapsules loaded with 0.01 U/mL factor VIII produced four times as much fibrin.
To mimic hemophilia A blood with inhibitors, a factor VIII inhibitory antibody was introduced into healthy blood samples. Again, significantly more fibrin was produced in samples with microcapsules loaded with 0.01 U/mL factor VIII than with systemic factor VIII infusions at clinically relevant high and low dosages of 0.05 and 0.5 U/mL (P less than .05).
This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies, the researchers reported.
Ms. Hansen had no relevant financial disclosures. One of her colleagues, Shannon L. Meeks, MD, disclosed adviser relationships with Biogen, Genentech, Bayer Healthcare, Grifols, CSL Behring, and Shire. Another, Wilbur A Lam, MD, PhD, disclosed equity ownership in Sanguina.
Abstract 81: Leveraging the Contractile Force of Platelets for Targeted Factor VIII Delivery in Hemophilia With Inhibitors.
mdales@frontlinemedcom.com
On Twitter @maryjodales
ASH 2016 PREVIEW
Investigational AML drugs boosted remission rates
Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.
In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.
The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.
Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.
For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).
For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).
In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.
Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.
Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.
An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.
The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.
The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.
Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.
mdales@frontlinemedcom.com
On Twitter @maryjodales
Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.
In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.
The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.
Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.
For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).
For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).
In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.
Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.
Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.
An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.
The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.
The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.
Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.
mdales@frontlinemedcom.com
On Twitter @maryjodales
Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.
In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.
The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.
Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.
For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).
For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).
In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.
Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.
Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.
An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.
The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.
The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.
Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.
mdales@frontlinemedcom.com
On Twitter @maryjodales
FROM ASH 2016
Oxygen therapy no advantage in stable COPD with moderate desaturation
Longterm supplemental oxygen had no benefit on multiple outcome measures in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation, Robert Wise, MD, and his colleagues in The Long-Term Oxygen Treatment Trial (LOTT) Research Group reported.
Recommendations that supplemental oxygen be administered to patients with severe desaturation – an oxyhemoglobin saturation of less than 89% on pulse oximetry (SpO2) – date to two trials performed in the 1970s. Since that time, subsequent studies have been performed in patients with COPD and mild-to-moderate daytime hypoxemia, but the studies were underpowered to assess mortality and the impact of oxygen therapy on hospitalization, exercise performance, and quality of life were unclear.
Dr. Wise, professor of medicine and director of research, in the division of pulmonary and critical care medicine, Johns Hopkins University, Baltimore, and his fellow LOTT researchers examined whether longterm treatment with supplemental oxygen would extend life and avoid hospitalization among patients who had stable COPD with moderate resting desaturation – defined as an SpO2 of 89% to 93% – and patients who had stable COPD with moderate exercise-induced desaturation during the 6-minute walk test – defined as an SpO2 of at least 80% for at least 5 minutes and less than 90% for 10 seconds or more.
The 738 study participants, about 75% of whom were men, were randomly assigned at one of 42 centers either to receive (368) or not to receive (370) longterm supplemental oxygen. In the supplemental oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep (N Engl J Med. 2016;375:1617-27. DOI: 10.1056/NEJMoa1604344).
The groups were balanced for oxygen-desaturation type: 60 (16%) and 73 (20%) had oxygen desaturation only at rest, 171 (46%) and 148 (40%) had oxygen desaturation only upon exercise, and 139 (38%) and 147 (40%) had oxygen desaturation at rest and upon exercise. Patients were followed for 1 to 6 years.
Supplemental oxygen, regardless of prescription type or adherence, failed to benefit patients overall or any subgroup of patients with stable COPD and moderate desaturation. The results were similar for all groups based on measures of time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = .52), hospitalization for a COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17), non–COPD-related hospitalizations (rate ratio, 1.03; 95% CI, 0.90 to 1.18), the rate of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), and the rate of all COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19). Additionally, patients who did and did not receive oxygen treatment did not differ based on changes on measures of quality of life, depression, anxiety, or functional status.
Oxygen treatment also was not without risk. Among the 51 adverse events attributed to the use of supplemental oxygen were 23 reports of tripping over equipment, including two cases that necessitated hospitalization. There were five patients who reported six cases of fires or burns, including one who had to be hospitalized.
The researchers acknowledged that some patients may not have enrolled in the trial because they were too ill or felt that oxygen was beneficial. “Highly symptomatic patients who declined enrollment might have had a different response to oxygen than what we observed in the enrolled patients,” they noted.
Additionally, uniform devices weren’t used for oxygen delivery, so the amount of oxygen delivered may have varied, and the study did not evaluate the immediate effects of oxygen on symptoms or exercise performance. Nocturnal oxygen saturation was not measured, and “some patients with COPD and severe nocturnal desaturation might benefit from nocturnal oxygen supplementation,” they pointed out. Moreover, “patients’ self-reported adherence may have been an overestimate of their actual oxygen use,” they added, noting, however, that there was good agreement with use “as measured by means of serial meter readings on the concentrator.”
Based on the results, the authors concluded, “the consistency of the null findings strengthens the overall conclusion that long-term supplemental oxygen in patients with stable COPD and resting or exercise-induced moderate desaturation has no benefit with regard to the multiple outcomes measured.”
LOTT was funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services. LOTT researchers reported relationships with a wide variety of drug companies.
mdales@frontlinemedcom.com
On Twitter @maryjodales
This landmark study is the largest to date to provide quality evidence about clinically relevant outcomes of longterm oxygen therapy for COPD patients with moderate hypoxemia, a prescribing decision that is relatively costly and potentially places a burden on patients. For patients with moderate hypoxemia, longterm oxygen therapy consistently did not affect outcomes, and the results were not modified by the type of oxygen prescription, desaturation profile, oxygen use, sex, smoking status, or lung function.
Given the available current data, longterm oxygen therapy should be prescribed to prolong survival among patients with COPD who have more than 3 weeks of severe resting hypoxemia (PaO2 of no more than 55 mm Hg or SaO2 of less than 88%) while they are breathing ambient air. Oxygen therapy might still be appropriate in selected patients with moderate exertional hypoxemia and intractable breathlessness despite appropriate evidence-based treatment.
Ambient air or oxygen can be used to evaluate the potential benefit. Oxygen therapy can be discontinued if the patient perceives no benefit within a day or two. Selected patients who benefit should be prescribed oxygen, and I think that this treatment that should be covered by insurance payers. However, longterm oxygen therapy should not be routinely prescribed in patients with mild or moderate hypoxemia at rest or during exercise.
Magnus Ekström, MD, PhD , is with the Division of Respiratory Medicine and Allergology, Lund (Sweden) University, and the department of medicine, Blekinge Hospital, Karlskrona, Sweden. He had no relevant financial disclosures and made these remarks in an editorial that accompanied the published study ( N Engl J. Med. 2016;375: 1683-4 ).
This landmark study is the largest to date to provide quality evidence about clinically relevant outcomes of longterm oxygen therapy for COPD patients with moderate hypoxemia, a prescribing decision that is relatively costly and potentially places a burden on patients. For patients with moderate hypoxemia, longterm oxygen therapy consistently did not affect outcomes, and the results were not modified by the type of oxygen prescription, desaturation profile, oxygen use, sex, smoking status, or lung function.
Given the available current data, longterm oxygen therapy should be prescribed to prolong survival among patients with COPD who have more than 3 weeks of severe resting hypoxemia (PaO2 of no more than 55 mm Hg or SaO2 of less than 88%) while they are breathing ambient air. Oxygen therapy might still be appropriate in selected patients with moderate exertional hypoxemia and intractable breathlessness despite appropriate evidence-based treatment.
Ambient air or oxygen can be used to evaluate the potential benefit. Oxygen therapy can be discontinued if the patient perceives no benefit within a day or two. Selected patients who benefit should be prescribed oxygen, and I think that this treatment that should be covered by insurance payers. However, longterm oxygen therapy should not be routinely prescribed in patients with mild or moderate hypoxemia at rest or during exercise.
Magnus Ekström, MD, PhD , is with the Division of Respiratory Medicine and Allergology, Lund (Sweden) University, and the department of medicine, Blekinge Hospital, Karlskrona, Sweden. He had no relevant financial disclosures and made these remarks in an editorial that accompanied the published study ( N Engl J. Med. 2016;375: 1683-4 ).
This landmark study is the largest to date to provide quality evidence about clinically relevant outcomes of longterm oxygen therapy for COPD patients with moderate hypoxemia, a prescribing decision that is relatively costly and potentially places a burden on patients. For patients with moderate hypoxemia, longterm oxygen therapy consistently did not affect outcomes, and the results were not modified by the type of oxygen prescription, desaturation profile, oxygen use, sex, smoking status, or lung function.
Given the available current data, longterm oxygen therapy should be prescribed to prolong survival among patients with COPD who have more than 3 weeks of severe resting hypoxemia (PaO2 of no more than 55 mm Hg or SaO2 of less than 88%) while they are breathing ambient air. Oxygen therapy might still be appropriate in selected patients with moderate exertional hypoxemia and intractable breathlessness despite appropriate evidence-based treatment.
Ambient air or oxygen can be used to evaluate the potential benefit. Oxygen therapy can be discontinued if the patient perceives no benefit within a day or two. Selected patients who benefit should be prescribed oxygen, and I think that this treatment that should be covered by insurance payers. However, longterm oxygen therapy should not be routinely prescribed in patients with mild or moderate hypoxemia at rest or during exercise.
Magnus Ekström, MD, PhD , is with the Division of Respiratory Medicine and Allergology, Lund (Sweden) University, and the department of medicine, Blekinge Hospital, Karlskrona, Sweden. He had no relevant financial disclosures and made these remarks in an editorial that accompanied the published study ( N Engl J. Med. 2016;375: 1683-4 ).
Longterm supplemental oxygen had no benefit on multiple outcome measures in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation, Robert Wise, MD, and his colleagues in The Long-Term Oxygen Treatment Trial (LOTT) Research Group reported.
Recommendations that supplemental oxygen be administered to patients with severe desaturation – an oxyhemoglobin saturation of less than 89% on pulse oximetry (SpO2) – date to two trials performed in the 1970s. Since that time, subsequent studies have been performed in patients with COPD and mild-to-moderate daytime hypoxemia, but the studies were underpowered to assess mortality and the impact of oxygen therapy on hospitalization, exercise performance, and quality of life were unclear.
Dr. Wise, professor of medicine and director of research, in the division of pulmonary and critical care medicine, Johns Hopkins University, Baltimore, and his fellow LOTT researchers examined whether longterm treatment with supplemental oxygen would extend life and avoid hospitalization among patients who had stable COPD with moderate resting desaturation – defined as an SpO2 of 89% to 93% – and patients who had stable COPD with moderate exercise-induced desaturation during the 6-minute walk test – defined as an SpO2 of at least 80% for at least 5 minutes and less than 90% for 10 seconds or more.
The 738 study participants, about 75% of whom were men, were randomly assigned at one of 42 centers either to receive (368) or not to receive (370) longterm supplemental oxygen. In the supplemental oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep (N Engl J Med. 2016;375:1617-27. DOI: 10.1056/NEJMoa1604344).
The groups were balanced for oxygen-desaturation type: 60 (16%) and 73 (20%) had oxygen desaturation only at rest, 171 (46%) and 148 (40%) had oxygen desaturation only upon exercise, and 139 (38%) and 147 (40%) had oxygen desaturation at rest and upon exercise. Patients were followed for 1 to 6 years.
Supplemental oxygen, regardless of prescription type or adherence, failed to benefit patients overall or any subgroup of patients with stable COPD and moderate desaturation. The results were similar for all groups based on measures of time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = .52), hospitalization for a COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17), non–COPD-related hospitalizations (rate ratio, 1.03; 95% CI, 0.90 to 1.18), the rate of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), and the rate of all COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19). Additionally, patients who did and did not receive oxygen treatment did not differ based on changes on measures of quality of life, depression, anxiety, or functional status.
Oxygen treatment also was not without risk. Among the 51 adverse events attributed to the use of supplemental oxygen were 23 reports of tripping over equipment, including two cases that necessitated hospitalization. There were five patients who reported six cases of fires or burns, including one who had to be hospitalized.
The researchers acknowledged that some patients may not have enrolled in the trial because they were too ill or felt that oxygen was beneficial. “Highly symptomatic patients who declined enrollment might have had a different response to oxygen than what we observed in the enrolled patients,” they noted.
Additionally, uniform devices weren’t used for oxygen delivery, so the amount of oxygen delivered may have varied, and the study did not evaluate the immediate effects of oxygen on symptoms or exercise performance. Nocturnal oxygen saturation was not measured, and “some patients with COPD and severe nocturnal desaturation might benefit from nocturnal oxygen supplementation,” they pointed out. Moreover, “patients’ self-reported adherence may have been an overestimate of their actual oxygen use,” they added, noting, however, that there was good agreement with use “as measured by means of serial meter readings on the concentrator.”
Based on the results, the authors concluded, “the consistency of the null findings strengthens the overall conclusion that long-term supplemental oxygen in patients with stable COPD and resting or exercise-induced moderate desaturation has no benefit with regard to the multiple outcomes measured.”
LOTT was funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services. LOTT researchers reported relationships with a wide variety of drug companies.
mdales@frontlinemedcom.com
On Twitter @maryjodales
Longterm supplemental oxygen had no benefit on multiple outcome measures in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation, Robert Wise, MD, and his colleagues in The Long-Term Oxygen Treatment Trial (LOTT) Research Group reported.
Recommendations that supplemental oxygen be administered to patients with severe desaturation – an oxyhemoglobin saturation of less than 89% on pulse oximetry (SpO2) – date to two trials performed in the 1970s. Since that time, subsequent studies have been performed in patients with COPD and mild-to-moderate daytime hypoxemia, but the studies were underpowered to assess mortality and the impact of oxygen therapy on hospitalization, exercise performance, and quality of life were unclear.
Dr. Wise, professor of medicine and director of research, in the division of pulmonary and critical care medicine, Johns Hopkins University, Baltimore, and his fellow LOTT researchers examined whether longterm treatment with supplemental oxygen would extend life and avoid hospitalization among patients who had stable COPD with moderate resting desaturation – defined as an SpO2 of 89% to 93% – and patients who had stable COPD with moderate exercise-induced desaturation during the 6-minute walk test – defined as an SpO2 of at least 80% for at least 5 minutes and less than 90% for 10 seconds or more.
The 738 study participants, about 75% of whom were men, were randomly assigned at one of 42 centers either to receive (368) or not to receive (370) longterm supplemental oxygen. In the supplemental oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep (N Engl J Med. 2016;375:1617-27. DOI: 10.1056/NEJMoa1604344).
The groups were balanced for oxygen-desaturation type: 60 (16%) and 73 (20%) had oxygen desaturation only at rest, 171 (46%) and 148 (40%) had oxygen desaturation only upon exercise, and 139 (38%) and 147 (40%) had oxygen desaturation at rest and upon exercise. Patients were followed for 1 to 6 years.
Supplemental oxygen, regardless of prescription type or adherence, failed to benefit patients overall or any subgroup of patients with stable COPD and moderate desaturation. The results were similar for all groups based on measures of time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = .52), hospitalization for a COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17), non–COPD-related hospitalizations (rate ratio, 1.03; 95% CI, 0.90 to 1.18), the rate of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), and the rate of all COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19). Additionally, patients who did and did not receive oxygen treatment did not differ based on changes on measures of quality of life, depression, anxiety, or functional status.
Oxygen treatment also was not without risk. Among the 51 adverse events attributed to the use of supplemental oxygen were 23 reports of tripping over equipment, including two cases that necessitated hospitalization. There were five patients who reported six cases of fires or burns, including one who had to be hospitalized.
The researchers acknowledged that some patients may not have enrolled in the trial because they were too ill or felt that oxygen was beneficial. “Highly symptomatic patients who declined enrollment might have had a different response to oxygen than what we observed in the enrolled patients,” they noted.
Additionally, uniform devices weren’t used for oxygen delivery, so the amount of oxygen delivered may have varied, and the study did not evaluate the immediate effects of oxygen on symptoms or exercise performance. Nocturnal oxygen saturation was not measured, and “some patients with COPD and severe nocturnal desaturation might benefit from nocturnal oxygen supplementation,” they pointed out. Moreover, “patients’ self-reported adherence may have been an overestimate of their actual oxygen use,” they added, noting, however, that there was good agreement with use “as measured by means of serial meter readings on the concentrator.”
Based on the results, the authors concluded, “the consistency of the null findings strengthens the overall conclusion that long-term supplemental oxygen in patients with stable COPD and resting or exercise-induced moderate desaturation has no benefit with regard to the multiple outcomes measured.”
LOTT was funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services. LOTT researchers reported relationships with a wide variety of drug companies.
mdales@frontlinemedcom.com
On Twitter @maryjodales
FROM NEJM
Key clinical point:
Major finding: The results were similar for all groups based on measures of time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = .52).
Data source: 738 study participants were randomly assigned to receive (368) or not to receive (370) longterm supplemental oxygen in The Long-Term Oxygen Treatment Trial (LOTT).
Disclosures: LOTT was funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services. LOTT researchers reported relationships with a wide variety of drug companies.