Pharmacology

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

The immunotherapy blinatumomab improves short-term outcomes when added to standard chemotherapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL), according to a report in the New England Journal of Medicine.

Two-year disease-free and overall survival measures, as well as the percentage of children who had complete minimal residual disease (MRD) responses, were substantially higher among the 30 infants in the study than in historical controls treated with the same chemotherapy backbone in an earlier trial, Interfant-06.

“These outcome data are very promising, given the poor survival and lack of improvements in outcomes among infants with KMT2A-rearranged ALL in recent decades,” said the investigators, led by Inge M. van der Sluis, MD, PhD, a hematologist-oncologist at Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands.

“The low incidence of relapse after treatment with blinatumomab is remarkable, given that in historical controls relapses occur frequently and early during therapy,” the investigators stated. Although the “follow-up time was relatively short” in the study, “it included the period historically defined” as being at high risk of relapse, they said.

The team suggested that future research should assess whether infants benefit from multiple courses of blinatumomab, rather than the one course used in the study, and whether blinatumomab plus chemotherapy can replace stem cell transplants for high-risk infants.
 

Pediatric community responds

There was excitement on Twitter about the results; a number of pediatric blood cancer specialists were impressed and posted the study on that platform. Comments included, “Wow! After years of stagnation, a huge step forward for infant leukemia” and “great news for infant lymphoblastic leukemia.”

Akshay Sharma, MBBS, a pediatric bone marrow transplant and cellular therapy specialist at St. Jude Children’s Research Hospital, Memphis, also posted. He said in an interview that the findings are “very exciting.”

The “outcomes of children diagnosed with leukemia in their infancy, particularly if they have a KMT2A rearrangement, have been dismal. This is terrific progress and a testament to the role that immunotherapy and novel agents will be playing in treatment of several malignant diseases in the decade to come,” he said.

Another poster, Pratik “Tik” Patel, MD, a pediatric hematology/oncology fellow at Emory University in Atlanta, told this news organization that the study “is welcome news to pediatric oncologists” and highlights “the success in incorporating newer immune-based therapeutics upfront in treatment rather than in relapsed/refractory settings.”

The National Cancer Institute–funded Children’s Oncology Group is thinking the same way. The group is launching a large, randomized trial to test if adding blinatumomab to chemotherapy upfront for B-cell acute lymphoblastic leukemia and lymphoblastic lymphoma improves outcomes in children and young adults aged 1-31 years. Results are due after 2029.
 

Study details

Blinatumomab is an expensive “T-cell engager” that helps cytotoxic CD3+T cells link to and destroy leukemic CD19+ B cells. Past studies have shown that it’s safe and works in older children and adults with B-lineage ALL after intensive chemotherapy, but until now the approach hadn’t been tested in infants, the investigators said.

The 30 subjects in the study were under a year old and newly diagnosed with KMT2A-rearranged ALL. They were treated with the Interfant-06 chemotherapy regimen – cytosine arabinoside and other agents – plus one postinduction course of blinatumomab at 15 micrograms/m² per day as a 4-week continuous infusion. Eight of nine high-risk patients had allogeneic hematopoietic stem cell transplants.

Overall survival was 93.3% over a median follow up of 26.3 months, substantially higher than the 65.8% in the Interfant-06 trial. Two-year disease-free survival was 81.6% versus 49.4% in Interfant-06.

Sixteen patients (53%) were MRD negative after blinatumomab infusion and 12 (40%) had low levels of MRD. All of the children who continued chemotherapy went on to become MRD negative.

There were no permanent blinatumomab discontinuations and no treatment related deaths. Serious toxic effects were consistent with those in older patients and included four fevers, four infections, and one case each of hypertension and vomiting.

There were no cases of severe cytokine release syndrome (CRS) because of the low tumor burden of the subjects. Likewise, there were no obvious neurologic adverse events – like CRS, a particular concern with blinatumomab – but “we cannot rule out underreporting of mild neurologic symptoms that may have been unrecognized in infants,” the investigators said.

Patients who relapsed in the study had CNS involvement at relapse. “This underscores the need for adequate intrathecal chemotherapy during the blinatumomab infusion, because the efficacy of blinatumomab for the treatment of CNS leukemia may be limited,” they said.

The work was supported by Amgen, the maker of blinatumomab, as well as the Princess Maxima Center Foundation, the Danish Childhood Cancer Foundation, and others. Dr. Sluis is a consultant and researcher for Amgen. Five other authors were also consultants/advisers/researchers for the company. Dr. Sharma and Dr. Patel didn’t have any relevant disclosures.

The immunotherapy blinatumomab improves short-term outcomes when added to standard chemotherapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL), according to a report in the New England Journal of Medicine.

Two-year disease-free and overall survival measures, as well as the percentage of children who had complete minimal residual disease (MRD) responses, were substantially higher among the 30 infants in the study than in historical controls treated with the same chemotherapy backbone in an earlier trial, Interfant-06.

“These outcome data are very promising, given the poor survival and lack of improvements in outcomes among infants with KMT2A-rearranged ALL in recent decades,” said the investigators, led by Inge M. van der Sluis, MD, PhD, a hematologist-oncologist at Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands.

“The low incidence of relapse after treatment with blinatumomab is remarkable, given that in historical controls relapses occur frequently and early during therapy,” the investigators stated. Although the “follow-up time was relatively short” in the study, “it included the period historically defined” as being at high risk of relapse, they said.

The team suggested that future research should assess whether infants benefit from multiple courses of blinatumomab, rather than the one course used in the study, and whether blinatumomab plus chemotherapy can replace stem cell transplants for high-risk infants.
 

Pediatric community responds

There was excitement on Twitter about the results; a number of pediatric blood cancer specialists were impressed and posted the study on that platform. Comments included, “Wow! After years of stagnation, a huge step forward for infant leukemia” and “great news for infant lymphoblastic leukemia.”

Akshay Sharma, MBBS, a pediatric bone marrow transplant and cellular therapy specialist at St. Jude Children’s Research Hospital, Memphis, also posted. He said in an interview that the findings are “very exciting.”

The “outcomes of children diagnosed with leukemia in their infancy, particularly if they have a KMT2A rearrangement, have been dismal. This is terrific progress and a testament to the role that immunotherapy and novel agents will be playing in treatment of several malignant diseases in the decade to come,” he said.

Another poster, Pratik “Tik” Patel, MD, a pediatric hematology/oncology fellow at Emory University in Atlanta, told this news organization that the study “is welcome news to pediatric oncologists” and highlights “the success in incorporating newer immune-based therapeutics upfront in treatment rather than in relapsed/refractory settings.”

The National Cancer Institute–funded Children’s Oncology Group is thinking the same way. The group is launching a large, randomized trial to test if adding blinatumomab to chemotherapy upfront for B-cell acute lymphoblastic leukemia and lymphoblastic lymphoma improves outcomes in children and young adults aged 1-31 years. Results are due after 2029.
 

Study details

Blinatumomab is an expensive “T-cell engager” that helps cytotoxic CD3+T cells link to and destroy leukemic CD19+ B cells. Past studies have shown that it’s safe and works in older children and adults with B-lineage ALL after intensive chemotherapy, but until now the approach hadn’t been tested in infants, the investigators said.

The 30 subjects in the study were under a year old and newly diagnosed with KMT2A-rearranged ALL. They were treated with the Interfant-06 chemotherapy regimen – cytosine arabinoside and other agents – plus one postinduction course of blinatumomab at 15 micrograms/m² per day as a 4-week continuous infusion. Eight of nine high-risk patients had allogeneic hematopoietic stem cell transplants.

Overall survival was 93.3% over a median follow up of 26.3 months, substantially higher than the 65.8% in the Interfant-06 trial. Two-year disease-free survival was 81.6% versus 49.4% in Interfant-06.

Sixteen patients (53%) were MRD negative after blinatumomab infusion and 12 (40%) had low levels of MRD. All of the children who continued chemotherapy went on to become MRD negative.

There were no permanent blinatumomab discontinuations and no treatment related deaths. Serious toxic effects were consistent with those in older patients and included four fevers, four infections, and one case each of hypertension and vomiting.

There were no cases of severe cytokine release syndrome (CRS) because of the low tumor burden of the subjects. Likewise, there were no obvious neurologic adverse events – like CRS, a particular concern with blinatumomab – but “we cannot rule out underreporting of mild neurologic symptoms that may have been unrecognized in infants,” the investigators said.

Patients who relapsed in the study had CNS involvement at relapse. “This underscores the need for adequate intrathecal chemotherapy during the blinatumomab infusion, because the efficacy of blinatumomab for the treatment of CNS leukemia may be limited,” they said.

The work was supported by Amgen, the maker of blinatumomab, as well as the Princess Maxima Center Foundation, the Danish Childhood Cancer Foundation, and others. Dr. Sluis is a consultant and researcher for Amgen. Five other authors were also consultants/advisers/researchers for the company. Dr. Sharma and Dr. Patel didn’t have any relevant disclosures.

The immunotherapy blinatumomab improves short-term outcomes when added to standard chemotherapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL), according to a report in the New England Journal of Medicine.

Two-year disease-free and overall survival measures, as well as the percentage of children who had complete minimal residual disease (MRD) responses, were substantially higher among the 30 infants in the study than in historical controls treated with the same chemotherapy backbone in an earlier trial, Interfant-06.

“These outcome data are very promising, given the poor survival and lack of improvements in outcomes among infants with KMT2A-rearranged ALL in recent decades,” said the investigators, led by Inge M. van der Sluis, MD, PhD, a hematologist-oncologist at Princess Maxima Center for Pediatric Oncology in Utrecht, the Netherlands.

“The low incidence of relapse after treatment with blinatumomab is remarkable, given that in historical controls relapses occur frequently and early during therapy,” the investigators stated. Although the “follow-up time was relatively short” in the study, “it included the period historically defined” as being at high risk of relapse, they said.

The team suggested that future research should assess whether infants benefit from multiple courses of blinatumomab, rather than the one course used in the study, and whether blinatumomab plus chemotherapy can replace stem cell transplants for high-risk infants.
 

Pediatric community responds

There was excitement on Twitter about the results; a number of pediatric blood cancer specialists were impressed and posted the study on that platform. Comments included, “Wow! After years of stagnation, a huge step forward for infant leukemia” and “great news for infant lymphoblastic leukemia.”

Akshay Sharma, MBBS, a pediatric bone marrow transplant and cellular therapy specialist at St. Jude Children’s Research Hospital, Memphis, also posted. He said in an interview that the findings are “very exciting.”

The “outcomes of children diagnosed with leukemia in their infancy, particularly if they have a KMT2A rearrangement, have been dismal. This is terrific progress and a testament to the role that immunotherapy and novel agents will be playing in treatment of several malignant diseases in the decade to come,” he said.

Another poster, Pratik “Tik” Patel, MD, a pediatric hematology/oncology fellow at Emory University in Atlanta, told this news organization that the study “is welcome news to pediatric oncologists” and highlights “the success in incorporating newer immune-based therapeutics upfront in treatment rather than in relapsed/refractory settings.”

The National Cancer Institute–funded Children’s Oncology Group is thinking the same way. The group is launching a large, randomized trial to test if adding blinatumomab to chemotherapy upfront for B-cell acute lymphoblastic leukemia and lymphoblastic lymphoma improves outcomes in children and young adults aged 1-31 years. Results are due after 2029.
 

Study details

Blinatumomab is an expensive “T-cell engager” that helps cytotoxic CD3+T cells link to and destroy leukemic CD19+ B cells. Past studies have shown that it’s safe and works in older children and adults with B-lineage ALL after intensive chemotherapy, but until now the approach hadn’t been tested in infants, the investigators said.

The 30 subjects in the study were under a year old and newly diagnosed with KMT2A-rearranged ALL. They were treated with the Interfant-06 chemotherapy regimen – cytosine arabinoside and other agents – plus one postinduction course of blinatumomab at 15 micrograms/m² per day as a 4-week continuous infusion. Eight of nine high-risk patients had allogeneic hematopoietic stem cell transplants.

Overall survival was 93.3% over a median follow up of 26.3 months, substantially higher than the 65.8% in the Interfant-06 trial. Two-year disease-free survival was 81.6% versus 49.4% in Interfant-06.

Sixteen patients (53%) were MRD negative after blinatumomab infusion and 12 (40%) had low levels of MRD. All of the children who continued chemotherapy went on to become MRD negative.

There were no permanent blinatumomab discontinuations and no treatment related deaths. Serious toxic effects were consistent with those in older patients and included four fevers, four infections, and one case each of hypertension and vomiting.

There were no cases of severe cytokine release syndrome (CRS) because of the low tumor burden of the subjects. Likewise, there were no obvious neurologic adverse events – like CRS, a particular concern with blinatumomab – but “we cannot rule out underreporting of mild neurologic symptoms that may have been unrecognized in infants,” the investigators said.

Patients who relapsed in the study had CNS involvement at relapse. “This underscores the need for adequate intrathecal chemotherapy during the blinatumomab infusion, because the efficacy of blinatumomab for the treatment of CNS leukemia may be limited,” they said.

The work was supported by Amgen, the maker of blinatumomab, as well as the Princess Maxima Center Foundation, the Danish Childhood Cancer Foundation, and others. Dr. Sluis is a consultant and researcher for Amgen. Five other authors were also consultants/advisers/researchers for the company. Dr. Sharma and Dr. Patel didn’t have any relevant disclosures.

The Food and Drug Administration has asked the manufacturer of the investigational drug for alopecia areata, deuruxolitinib to stop trials of the 12-mg dose because of the potential for thrombotic events, the company said in a press release on May 2.

The announcement came after a pulmonary embolism occurred with the 12-mg twice-daily dose in one of the long-term open-label extension (OLE) studies, the company, Sun Pharmaceutical Industries, said.

The company stated that the FDA has placed the Investigational New Drug testing for deuruxolitinib on partial clinical hold, and the agency is requiring that study participants who are currently on the 12-mg twice-daily dose in the OLE studies stop taking that dose. The hold covers only the 12-mg dose.
 

No hold on 8-mg dose

“There have been no thrombotic events reported to date for the 8-mg b.i.d. dose and U.S. FDA has not placed the 8-mg b.i.d. dose on hold,” the company said in the statement.

The statement added, “We are taking immediate steps to transition the patients in the OLE studies to the 8-mg b.i.d. dose arm in the ongoing studies.”

The company said that no thromboembolic events were observed in the phase 2 or phase 3 trials and said that it will work closely with the FDA to address its concerns. A formal letter detailing the FDA’s concerns is expected within 30 days.

Deuruxolitinib is an investigational oral selective inhibitor of Janus kinase 1 (JAK1) and JAK2 enzymes.

The FDA has granted deuruxolitinib breakthrough therapy designation for the treatment of adult patients with moderate to severe alopecia areata as well as fast-track designation for the treatment of alopecia areata.

In March, this news organization reported from the annual meeting of the American Academy of Dermatology that, based on phase 3 studies that demonstrate robust hair growth in about one-third of patients, deuruxolitinib has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received FDA approval almost 1 year ago.

Also at the AAD annual meeting, this news organization reported that principal investigator Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn., in his presentation on the results of THRIVE-AA2, one of the two phase 3 trials of deuruxolitinib, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.” Dr King also was a principal investigator in studies of baricitinib.

With one exception, labeling for baricitinib and other JAK inhibitors with dermatologic indications includes a boxed warning listing serious adverse events including the risk for major adverse cardiac events and thrombosis, including pulmonary embolism, based on the risks in a rheumatoid arthritis study.

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

The Food and Drug Administration has asked the manufacturer of the investigational drug for alopecia areata, deuruxolitinib to stop trials of the 12-mg dose because of the potential for thrombotic events, the company said in a press release on May 2.

The announcement came after a pulmonary embolism occurred with the 12-mg twice-daily dose in one of the long-term open-label extension (OLE) studies, the company, Sun Pharmaceutical Industries, said.

The company stated that the FDA has placed the Investigational New Drug testing for deuruxolitinib on partial clinical hold, and the agency is requiring that study participants who are currently on the 12-mg twice-daily dose in the OLE studies stop taking that dose. The hold covers only the 12-mg dose.
 

No hold on 8-mg dose

“There have been no thrombotic events reported to date for the 8-mg b.i.d. dose and U.S. FDA has not placed the 8-mg b.i.d. dose on hold,” the company said in the statement.

The statement added, “We are taking immediate steps to transition the patients in the OLE studies to the 8-mg b.i.d. dose arm in the ongoing studies.”

The company said that no thromboembolic events were observed in the phase 2 or phase 3 trials and said that it will work closely with the FDA to address its concerns. A formal letter detailing the FDA’s concerns is expected within 30 days.

Deuruxolitinib is an investigational oral selective inhibitor of Janus kinase 1 (JAK1) and JAK2 enzymes.

The FDA has granted deuruxolitinib breakthrough therapy designation for the treatment of adult patients with moderate to severe alopecia areata as well as fast-track designation for the treatment of alopecia areata.

In March, this news organization reported from the annual meeting of the American Academy of Dermatology that, based on phase 3 studies that demonstrate robust hair growth in about one-third of patients, deuruxolitinib has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received FDA approval almost 1 year ago.

Also at the AAD annual meeting, this news organization reported that principal investigator Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn., in his presentation on the results of THRIVE-AA2, one of the two phase 3 trials of deuruxolitinib, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.” Dr King also was a principal investigator in studies of baricitinib.

With one exception, labeling for baricitinib and other JAK inhibitors with dermatologic indications includes a boxed warning listing serious adverse events including the risk for major adverse cardiac events and thrombosis, including pulmonary embolism, based on the risks in a rheumatoid arthritis study.

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

The Food and Drug Administration has asked the manufacturer of the investigational drug for alopecia areata, deuruxolitinib to stop trials of the 12-mg dose because of the potential for thrombotic events, the company said in a press release on May 2.

The announcement came after a pulmonary embolism occurred with the 12-mg twice-daily dose in one of the long-term open-label extension (OLE) studies, the company, Sun Pharmaceutical Industries, said.

The company stated that the FDA has placed the Investigational New Drug testing for deuruxolitinib on partial clinical hold, and the agency is requiring that study participants who are currently on the 12-mg twice-daily dose in the OLE studies stop taking that dose. The hold covers only the 12-mg dose.
 

No hold on 8-mg dose

“There have been no thrombotic events reported to date for the 8-mg b.i.d. dose and U.S. FDA has not placed the 8-mg b.i.d. dose on hold,” the company said in the statement.

The statement added, “We are taking immediate steps to transition the patients in the OLE studies to the 8-mg b.i.d. dose arm in the ongoing studies.”

The company said that no thromboembolic events were observed in the phase 2 or phase 3 trials and said that it will work closely with the FDA to address its concerns. A formal letter detailing the FDA’s concerns is expected within 30 days.

Deuruxolitinib is an investigational oral selective inhibitor of Janus kinase 1 (JAK1) and JAK2 enzymes.

The FDA has granted deuruxolitinib breakthrough therapy designation for the treatment of adult patients with moderate to severe alopecia areata as well as fast-track designation for the treatment of alopecia areata.

In March, this news organization reported from the annual meeting of the American Academy of Dermatology that, based on phase 3 studies that demonstrate robust hair growth in about one-third of patients, deuruxolitinib has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received FDA approval almost 1 year ago.

Also at the AAD annual meeting, this news organization reported that principal investigator Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn., in his presentation on the results of THRIVE-AA2, one of the two phase 3 trials of deuruxolitinib, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.” Dr King also was a principal investigator in studies of baricitinib.

With one exception, labeling for baricitinib and other JAK inhibitors with dermatologic indications includes a boxed warning listing serious adverse events including the risk for major adverse cardiac events and thrombosis, including pulmonary embolism, based on the risks in a rheumatoid arthritis study.

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

Among patients with atrial fibrillation (AFib), initiation of statins soon after diagnosis was protective against stroke and related vascular events, and longer duration of use was associated with greater protection, a new cohort study shows.

Statin use was associated with lower risks of ischemic stroke or systemic embolism, hemorrhagic stroke, and transient ischemic attack (TIA), regardless of whether patients were also taking anticoagulant medications.

Lead author Jiayi Huang, a PhD student at Hong Kong University at Shenzhen (China) Hospital, concluded that the study’s findings support the use of statins to prevent stroke for patients with new-onset AFib.

“The findings have important clinical implications, particularly given that in atrial fibrillation, patients’ ischemic strokes are often fatal or disabling and have a high risk of recurrence,” she said.

The results were presented in a moderated poster session at the European Heart Rhythm Association 2023 Congress.
 

Widely prescribed

Anticoagulant drugs are prescribed to lower the fivefold increased risk of stroke among individuals with AFib, compared with those without AFib, but the therapy does not eliminate the higher risk, Ms. Huang explained. And although statins are widely prescribed to reduce the likelihood of myocardial infarction and stroke, “the benefit of statins for stroke prevention in patients with atrial fibrillation has been unclear.”

Ms. Huang and colleagues analyzed data from 51,472 patients newly diagnosed with AFib between 2010 and 2018. The population was divided into statin users (n = 11,866), defined as patients who had taken statins for at least 19 consecutive days in the first year after AFib diagnosis, and statin nonusers (n = 39,606), based on whether they were prescribed statin therapy after their first diagnosis of AFib.

The median age of the cohort was 74.9 years, and 47.7% were women. The investigators used statistical methods to balance baseline covariates between the two groups.

The primary outcomes were ischemic stroke or systemic embolism, hemorrhagic stroke, and TIA. Median follow-up was 5.1 years.

Statin use was associated with a significantly lower risk of all outcomes, compared with nonuse. Statin users had a 17% reduced risk of ischemic stroke or systemic embolism, a 7% reduced risk of hemorrhagic stroke, and a 15% rate of reduced risk of TIA, Ms. Huang reported.

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

Among patients with atrial fibrillation (AFib), initiation of statins soon after diagnosis was protective against stroke and related vascular events, and longer duration of use was associated with greater protection, a new cohort study shows.

Statin use was associated with lower risks of ischemic stroke or systemic embolism, hemorrhagic stroke, and transient ischemic attack (TIA), regardless of whether patients were also taking anticoagulant medications.

Lead author Jiayi Huang, a PhD student at Hong Kong University at Shenzhen (China) Hospital, concluded that the study’s findings support the use of statins to prevent stroke for patients with new-onset AFib.

“The findings have important clinical implications, particularly given that in atrial fibrillation, patients’ ischemic strokes are often fatal or disabling and have a high risk of recurrence,” she said.

The results were presented in a moderated poster session at the European Heart Rhythm Association 2023 Congress.
 

Widely prescribed

Anticoagulant drugs are prescribed to lower the fivefold increased risk of stroke among individuals with AFib, compared with those without AFib, but the therapy does not eliminate the higher risk, Ms. Huang explained. And although statins are widely prescribed to reduce the likelihood of myocardial infarction and stroke, “the benefit of statins for stroke prevention in patients with atrial fibrillation has been unclear.”

Ms. Huang and colleagues analyzed data from 51,472 patients newly diagnosed with AFib between 2010 and 2018. The population was divided into statin users (n = 11,866), defined as patients who had taken statins for at least 19 consecutive days in the first year after AFib diagnosis, and statin nonusers (n = 39,606), based on whether they were prescribed statin therapy after their first diagnosis of AFib.

The median age of the cohort was 74.9 years, and 47.7% were women. The investigators used statistical methods to balance baseline covariates between the two groups.

The primary outcomes were ischemic stroke or systemic embolism, hemorrhagic stroke, and TIA. Median follow-up was 5.1 years.

Statin use was associated with a significantly lower risk of all outcomes, compared with nonuse. Statin users had a 17% reduced risk of ischemic stroke or systemic embolism, a 7% reduced risk of hemorrhagic stroke, and a 15% rate of reduced risk of TIA, Ms. Huang reported.

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

Among patients with atrial fibrillation (AFib), initiation of statins soon after diagnosis was protective against stroke and related vascular events, and longer duration of use was associated with greater protection, a new cohort study shows.

Statin use was associated with lower risks of ischemic stroke or systemic embolism, hemorrhagic stroke, and transient ischemic attack (TIA), regardless of whether patients were also taking anticoagulant medications.

Lead author Jiayi Huang, a PhD student at Hong Kong University at Shenzhen (China) Hospital, concluded that the study’s findings support the use of statins to prevent stroke for patients with new-onset AFib.

“The findings have important clinical implications, particularly given that in atrial fibrillation, patients’ ischemic strokes are often fatal or disabling and have a high risk of recurrence,” she said.

The results were presented in a moderated poster session at the European Heart Rhythm Association 2023 Congress.
 

Widely prescribed

Anticoagulant drugs are prescribed to lower the fivefold increased risk of stroke among individuals with AFib, compared with those without AFib, but the therapy does not eliminate the higher risk, Ms. Huang explained. And although statins are widely prescribed to reduce the likelihood of myocardial infarction and stroke, “the benefit of statins for stroke prevention in patients with atrial fibrillation has been unclear.”

Ms. Huang and colleagues analyzed data from 51,472 patients newly diagnosed with AFib between 2010 and 2018. The population was divided into statin users (n = 11,866), defined as patients who had taken statins for at least 19 consecutive days in the first year after AFib diagnosis, and statin nonusers (n = 39,606), based on whether they were prescribed statin therapy after their first diagnosis of AFib.

The median age of the cohort was 74.9 years, and 47.7% were women. The investigators used statistical methods to balance baseline covariates between the two groups.

The primary outcomes were ischemic stroke or systemic embolism, hemorrhagic stroke, and TIA. Median follow-up was 5.1 years.

Statin use was associated with a significantly lower risk of all outcomes, compared with nonuse. Statin users had a 17% reduced risk of ischemic stroke or systemic embolism, a 7% reduced risk of hemorrhagic stroke, and a 15% rate of reduced risk of TIA, Ms. Huang reported.

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

Adults with cancer experienced significant reductions in pain after taking medicinal cannabis, in a study.

Physician-prescribed cannabis, particularly cannabinoids, has been shown to ease cancer-related pain in adult cancer patients, who often find inadequate pain relief from medications including opioids, Saro Aprikian, MSc, a medical student at the Royal College of Surgeons, Dublin, and colleagues, wrote in their paper.

However, real-world data on the safety and effectiveness of cannabis in the cancer population and the impact on use of other medications are lacking, the researchers said.

In the study, published in BMJ Supportive & Palliative Care, the researchers reviewed data from 358 adults with cancer who were part of a multicenter cannabis registry in Canada between May 2015 and October 2018.

The average age of the patients was 57.6 years, and 48% were men. The top three cancer diagnoses in the study population were genitorurinary, breast, and colorectal.

Pain was the most common reason for obtaining a medical cannabis prescription, cited by 72.4% of patients.

Data were collected at follow-up visits conducted every 3 months over 1 year. Pain was assessed via the Brief Pain Inventory (BPI) and revised Edmonton Symptom Assessment System (ESAS-r) questionnaires and compared to baseline values. Patients rated their pain intensity on a sliding scale of 0 (none) to 10 (worst possible). Pain relief was rated on a scale of 0% (none) to 100% (complete).

Compared to baseline scores, patients showed significant decreases at 3, 6 and 9 months for BPI worst pain (5.5 at baseline, 3.6 for 3, 6, and 9 months) average pain (4.1 at baseline, 2.4, 2.3, and 2.7 for 3, 6, and 9 months, respectively), overall pain severity (2.7 at baseline, 2.3, 2.3, and 2.4 at 3, 6, and 9 months, respectively), and pain interference with daily life (4.3 at baseline, 2.4, 2.2, and 2.4 at 3, 6, and 9 months, respectively; P less than .01 for all four pain measures).

“Pain severity as reported in the ESAS-r decreased significantly at 3-month, 6-month and 9-month follow-ups,” the researchers noted.

In addition, total medication burden based on the medication quantification scale (MQS) and morphine equivalent daily dose (MEDD) were recorded at 3, 6, 9, and 12 months. MQS scores decreased compared to baseline at 3, 6, 9, and 12 months in 10%, 23.5%, 26.2%, and 31.6% of patients, respectively. Also compared with baseline, 11.1%, 31.3%, and 14.3% of patients reported decreases in MEDD scores at 3, 6, and 9 months, respectively.

Overall, products with equal amounts of active ingredients tetrahydrocannabinol (THC) and cannabidiol (CBD) were more effective than were those with a predominance of either THC or CBD, the researchers wrote.

Medical cannabis was well-tolerated; a total of 15 moderate to severe side effects were reported by 11 patients, 13 of which were minor. The most common side effects were sleepiness and fatigue, and five patients discontinued their medical cannabis because of side effects. The two serious side effects reported during the study period – pneumonia and a cardiovascular event – were deemed unlikely related to the patients’ medicinal cannabis use.

The findings were limited by several factors, including the observational design, which prevented conclusions about causality, the researchers noted. Other limitations included the loss of many patients to follow-up and incomplete data on other prescription medications in many cases.

The results support the use of medical cannabis by cancer patients as an adjunct pain relief strategy and a way to potentially reduce the use of other medications such as opioids, the authors concluded.

The study was supported by the Canadian Consortium for the Investigation of Cannabinoids, Collège des Médecins du Québec, and the Canopy Growth Corporation. The researchers had no financial conflicts to disclose.

Adults with cancer experienced significant reductions in pain after taking medicinal cannabis, in a study.

Physician-prescribed cannabis, particularly cannabinoids, has been shown to ease cancer-related pain in adult cancer patients, who often find inadequate pain relief from medications including opioids, Saro Aprikian, MSc, a medical student at the Royal College of Surgeons, Dublin, and colleagues, wrote in their paper.

However, real-world data on the safety and effectiveness of cannabis in the cancer population and the impact on use of other medications are lacking, the researchers said.

In the study, published in BMJ Supportive & Palliative Care, the researchers reviewed data from 358 adults with cancer who were part of a multicenter cannabis registry in Canada between May 2015 and October 2018.

The average age of the patients was 57.6 years, and 48% were men. The top three cancer diagnoses in the study population were genitorurinary, breast, and colorectal.

Pain was the most common reason for obtaining a medical cannabis prescription, cited by 72.4% of patients.

Data were collected at follow-up visits conducted every 3 months over 1 year. Pain was assessed via the Brief Pain Inventory (BPI) and revised Edmonton Symptom Assessment System (ESAS-r) questionnaires and compared to baseline values. Patients rated their pain intensity on a sliding scale of 0 (none) to 10 (worst possible). Pain relief was rated on a scale of 0% (none) to 100% (complete).

Compared to baseline scores, patients showed significant decreases at 3, 6 and 9 months for BPI worst pain (5.5 at baseline, 3.6 for 3, 6, and 9 months) average pain (4.1 at baseline, 2.4, 2.3, and 2.7 for 3, 6, and 9 months, respectively), overall pain severity (2.7 at baseline, 2.3, 2.3, and 2.4 at 3, 6, and 9 months, respectively), and pain interference with daily life (4.3 at baseline, 2.4, 2.2, and 2.4 at 3, 6, and 9 months, respectively; P less than .01 for all four pain measures).

“Pain severity as reported in the ESAS-r decreased significantly at 3-month, 6-month and 9-month follow-ups,” the researchers noted.

In addition, total medication burden based on the medication quantification scale (MQS) and morphine equivalent daily dose (MEDD) were recorded at 3, 6, 9, and 12 months. MQS scores decreased compared to baseline at 3, 6, 9, and 12 months in 10%, 23.5%, 26.2%, and 31.6% of patients, respectively. Also compared with baseline, 11.1%, 31.3%, and 14.3% of patients reported decreases in MEDD scores at 3, 6, and 9 months, respectively.

Overall, products with equal amounts of active ingredients tetrahydrocannabinol (THC) and cannabidiol (CBD) were more effective than were those with a predominance of either THC or CBD, the researchers wrote.

Medical cannabis was well-tolerated; a total of 15 moderate to severe side effects were reported by 11 patients, 13 of which were minor. The most common side effects were sleepiness and fatigue, and five patients discontinued their medical cannabis because of side effects. The two serious side effects reported during the study period – pneumonia and a cardiovascular event – were deemed unlikely related to the patients’ medicinal cannabis use.

The findings were limited by several factors, including the observational design, which prevented conclusions about causality, the researchers noted. Other limitations included the loss of many patients to follow-up and incomplete data on other prescription medications in many cases.

The results support the use of medical cannabis by cancer patients as an adjunct pain relief strategy and a way to potentially reduce the use of other medications such as opioids, the authors concluded.

The study was supported by the Canadian Consortium for the Investigation of Cannabinoids, Collège des Médecins du Québec, and the Canopy Growth Corporation. The researchers had no financial conflicts to disclose.

Adults with cancer experienced significant reductions in pain after taking medicinal cannabis, in a study.

Physician-prescribed cannabis, particularly cannabinoids, has been shown to ease cancer-related pain in adult cancer patients, who often find inadequate pain relief from medications including opioids, Saro Aprikian, MSc, a medical student at the Royal College of Surgeons, Dublin, and colleagues, wrote in their paper.

However, real-world data on the safety and effectiveness of cannabis in the cancer population and the impact on use of other medications are lacking, the researchers said.

In the study, published in BMJ Supportive & Palliative Care, the researchers reviewed data from 358 adults with cancer who were part of a multicenter cannabis registry in Canada between May 2015 and October 2018.

The average age of the patients was 57.6 years, and 48% were men. The top three cancer diagnoses in the study population were genitorurinary, breast, and colorectal.

Pain was the most common reason for obtaining a medical cannabis prescription, cited by 72.4% of patients.

Data were collected at follow-up visits conducted every 3 months over 1 year. Pain was assessed via the Brief Pain Inventory (BPI) and revised Edmonton Symptom Assessment System (ESAS-r) questionnaires and compared to baseline values. Patients rated their pain intensity on a sliding scale of 0 (none) to 10 (worst possible). Pain relief was rated on a scale of 0% (none) to 100% (complete).

Compared to baseline scores, patients showed significant decreases at 3, 6 and 9 months for BPI worst pain (5.5 at baseline, 3.6 for 3, 6, and 9 months) average pain (4.1 at baseline, 2.4, 2.3, and 2.7 for 3, 6, and 9 months, respectively), overall pain severity (2.7 at baseline, 2.3, 2.3, and 2.4 at 3, 6, and 9 months, respectively), and pain interference with daily life (4.3 at baseline, 2.4, 2.2, and 2.4 at 3, 6, and 9 months, respectively; P less than .01 for all four pain measures).

“Pain severity as reported in the ESAS-r decreased significantly at 3-month, 6-month and 9-month follow-ups,” the researchers noted.

In addition, total medication burden based on the medication quantification scale (MQS) and morphine equivalent daily dose (MEDD) were recorded at 3, 6, 9, and 12 months. MQS scores decreased compared to baseline at 3, 6, 9, and 12 months in 10%, 23.5%, 26.2%, and 31.6% of patients, respectively. Also compared with baseline, 11.1%, 31.3%, and 14.3% of patients reported decreases in MEDD scores at 3, 6, and 9 months, respectively.

Overall, products with equal amounts of active ingredients tetrahydrocannabinol (THC) and cannabidiol (CBD) were more effective than were those with a predominance of either THC or CBD, the researchers wrote.

Medical cannabis was well-tolerated; a total of 15 moderate to severe side effects were reported by 11 patients, 13 of which were minor. The most common side effects were sleepiness and fatigue, and five patients discontinued their medical cannabis because of side effects. The two serious side effects reported during the study period – pneumonia and a cardiovascular event – were deemed unlikely related to the patients’ medicinal cannabis use.

The findings were limited by several factors, including the observational design, which prevented conclusions about causality, the researchers noted. Other limitations included the loss of many patients to follow-up and incomplete data on other prescription medications in many cases.

The results support the use of medical cannabis by cancer patients as an adjunct pain relief strategy and a way to potentially reduce the use of other medications such as opioids, the authors concluded.

The study was supported by the Canadian Consortium for the Investigation of Cannabinoids, Collège des Médecins du Québec, and the Canopy Growth Corporation. The researchers had no financial conflicts to disclose.

SAN DIEGO – For patients with obesity, surgery, lifestyle changes, and pharmacologic interventions are all treatment options, but antiobesity medications provide a better risk-to-benefit ratio, according to a presenter at the annual meeting of the American College of Physicians.

Lifestyle changes result in the least weight loss and may be safest, while surgery provides the most weight loss and has the greatest risk. Antiobesity medications, especially the newer ones used in combination with lifestyle changes, can provide significant and sustained weight loss with manageable side effects, said Daniel Bessesen, MD, a professor in the endocrinology, diabetes, and metabolism at University of Colorado at Denver, Aurora.

New and more effective antiobesity medications have given internists more potential options to discuss with their patients, Dr. Bessesen said. He reviewed the pros and cons of the different options.

Medications are indicated for patients with a body mass index greater than 30, including those with a weight-related comorbidity, Dr. Bessesen said. The average weight loss is 5%-15% over 3-6 months but may vary greatly. Insurance often does not cover the medication costs.
 

Older FDA-approved antiobesity medications

Phentermine is the most widely prescribed antiobesity medication, partly because it is the only option most people can afford out of pocket. Dr. Bessesen presented recent data showing that long-term use of phentermine was associated with greater weight loss and that patients continuously taking phentermine for 24 months lost 7.5% of their weight.

Phentermine suppresses appetite by increasing norepinephrine production. Dr. Bessesen warned that internists should be careful when prescribing it to patients with mental conditions, because it acts as a stimulant. Early studies raised concerns about the risk of cardiovascular disease (CVD) in patients taking phentermine. However, analysis of data from over 13,000 individuals showed no evidence of a relationship between phentermine exposure and CVD events.

“These data provide some reassurance that it could be used in patients with CVD risk,” he noted. Phentermine can also be combined with topiramate extended release, a combination that provides greater efficacy (up to 10% weight loss) with fewer side effects. However, this combination is less effective in patients with diabetes than in those without.

Additional treatment options included orlistat and naltrexone sustained release/bupropion SR. Orlistat is a good treatment alternative for patients with constipation and is the safest option among older anti-obesity medications, whereas naltrexone SR/bupropion SR may be useful in patients with food cravings. However, there is more variability in the individual-level benefit from these agents compared to phentermine and phentermine/topiramate ER, Dr. Bessesen said.
 

Newer anti‐obesity medications

Liraglutide, an agent used for the management of type 2 diabetes, has recently been approved for weight loss. Liraglutide causes moderate weight loss, and it may reduce the risk of CVD. However, there are tolerability issues, such as nausea and other risks, and Dr. Bessesen advises internists to “start at low doses and increase slowly.”

Semaglutide is the newest and most effective antiobesity drug approved by the Food and Drug Administration, providing sustained weight loss of 8% for up to 48 weeks after starting treatment. Although its efficacy is lower in patients with diabetes, Dr. Bessesen noted that “this is common for antiobesity agents, and clinicians should not refrain from prescribing it in this population.”

Setmelanotide is another new medication approved for chronic weight management in patients with monogenic obesity. This medication can be considered for patients with early-onset severe obesity with abnormal feeding behavior.

Commenting on barriers to access to new antiobesity medications, Dr. Bessesen said that “the high cost of these medications is a substantial problem, but as more companies become involved and products are on the market for a longer period of time, I am hopeful that prices will come down.”
 

Emerging antiobesity medications

Dr. Bessesen presented recent phase 3 data showing that treatment with tirzepatide provided sustained chronic loss and improved cardiometabolic measures with no diet. Tirzepatide, which targets receptors for glucagonlike peptide–1 and glucose-dependent insulinotropic polypeptide, is used for the management of type 2 diabetes and is expected to be reviewed soon by the FDA for its use in weight management.

A semaglutide/cagrilintide combination may also provide a new treatment option for patients with obesity. In a phase 1b trial, semaglutide/cagrilintide treatment resulted in up to 17% weight loss in patients with obesity who were otherwise healthy; however, phase 2 and 3 data are needed to confirm its efficacy.
 

A ‘holistic approach’

When deciding whether to prescribe antiobesity medications, Dr. Bessesen noted that medications are better than exercise alone. Factors to consider when deciding whether to prescribe drugs, as well as which ones, include costs, local regulatory guidelines, requirement for long-term use, and patient comorbidities.

He also stated that lifestyle changes, such as adopting healthy nutrition and exercising regularly, are also important and can enhance weight loss when combined with medications.

Richele Corrado, DO, MPH, agreed that lifestyle management in combination with medications may provide greater weight loss than each of these interventions alone.

“If you look at the data, exercise doesn’t help you lose much weight,” said Dr. Corrado, a staff internist and obesity medicine specialist at Walter Reed National Military Medical Center in Bethesda, Md., who spoke at the same session. She added that she has many patients who struggle to lose weight despite having a healthy lifestyle. “It’s important to discuss with these patients about medications and surgery.”

Dr. Bessesen noted that management of mental health and emotional well-being should also be an integral part of obesity management. “Treatment for obesity may be more successful when underlying psychological conditions such as depression, childhood sexual trauma, or anxiety are addressed and treated,” he said.

Dr. Bessesen was involved in the study of the efficacy of semaglutide/cagrilintide. He does not have any financial conflicts with the companies that make other mentioned medications. He has received research grants or contracts from Novo Nordisk, honoraria from Novo Nordisk, and consultantship from Eli Lilly. Dr. Corrado reported no relevant financial conflicts.

SAN DIEGO – For patients with obesity, surgery, lifestyle changes, and pharmacologic interventions are all treatment options, but antiobesity medications provide a better risk-to-benefit ratio, according to a presenter at the annual meeting of the American College of Physicians.

Lifestyle changes result in the least weight loss and may be safest, while surgery provides the most weight loss and has the greatest risk. Antiobesity medications, especially the newer ones used in combination with lifestyle changes, can provide significant and sustained weight loss with manageable side effects, said Daniel Bessesen, MD, a professor in the endocrinology, diabetes, and metabolism at University of Colorado at Denver, Aurora.

New and more effective antiobesity medications have given internists more potential options to discuss with their patients, Dr. Bessesen said. He reviewed the pros and cons of the different options.

Medications are indicated for patients with a body mass index greater than 30, including those with a weight-related comorbidity, Dr. Bessesen said. The average weight loss is 5%-15% over 3-6 months but may vary greatly. Insurance often does not cover the medication costs.
 

Older FDA-approved antiobesity medications

Phentermine is the most widely prescribed antiobesity medication, partly because it is the only option most people can afford out of pocket. Dr. Bessesen presented recent data showing that long-term use of phentermine was associated with greater weight loss and that patients continuously taking phentermine for 24 months lost 7.5% of their weight.

Phentermine suppresses appetite by increasing norepinephrine production. Dr. Bessesen warned that internists should be careful when prescribing it to patients with mental conditions, because it acts as a stimulant. Early studies raised concerns about the risk of cardiovascular disease (CVD) in patients taking phentermine. However, analysis of data from over 13,000 individuals showed no evidence of a relationship between phentermine exposure and CVD events.

“These data provide some reassurance that it could be used in patients with CVD risk,” he noted. Phentermine can also be combined with topiramate extended release, a combination that provides greater efficacy (up to 10% weight loss) with fewer side effects. However, this combination is less effective in patients with diabetes than in those without.

Additional treatment options included orlistat and naltrexone sustained release/bupropion SR. Orlistat is a good treatment alternative for patients with constipation and is the safest option among older anti-obesity medications, whereas naltrexone SR/bupropion SR may be useful in patients with food cravings. However, there is more variability in the individual-level benefit from these agents compared to phentermine and phentermine/topiramate ER, Dr. Bessesen said.
 

Newer anti‐obesity medications

Liraglutide, an agent used for the management of type 2 diabetes, has recently been approved for weight loss. Liraglutide causes moderate weight loss, and it may reduce the risk of CVD. However, there are tolerability issues, such as nausea and other risks, and Dr. Bessesen advises internists to “start at low doses and increase slowly.”

Semaglutide is the newest and most effective antiobesity drug approved by the Food and Drug Administration, providing sustained weight loss of 8% for up to 48 weeks after starting treatment. Although its efficacy is lower in patients with diabetes, Dr. Bessesen noted that “this is common for antiobesity agents, and clinicians should not refrain from prescribing it in this population.”

Setmelanotide is another new medication approved for chronic weight management in patients with monogenic obesity. This medication can be considered for patients with early-onset severe obesity with abnormal feeding behavior.

Commenting on barriers to access to new antiobesity medications, Dr. Bessesen said that “the high cost of these medications is a substantial problem, but as more companies become involved and products are on the market for a longer period of time, I am hopeful that prices will come down.”
 

Emerging antiobesity medications

Dr. Bessesen presented recent phase 3 data showing that treatment with tirzepatide provided sustained chronic loss and improved cardiometabolic measures with no diet. Tirzepatide, which targets receptors for glucagonlike peptide–1 and glucose-dependent insulinotropic polypeptide, is used for the management of type 2 diabetes and is expected to be reviewed soon by the FDA for its use in weight management.

A semaglutide/cagrilintide combination may also provide a new treatment option for patients with obesity. In a phase 1b trial, semaglutide/cagrilintide treatment resulted in up to 17% weight loss in patients with obesity who were otherwise healthy; however, phase 2 and 3 data are needed to confirm its efficacy.
 

A ‘holistic approach’

When deciding whether to prescribe antiobesity medications, Dr. Bessesen noted that medications are better than exercise alone. Factors to consider when deciding whether to prescribe drugs, as well as which ones, include costs, local regulatory guidelines, requirement for long-term use, and patient comorbidities.

He also stated that lifestyle changes, such as adopting healthy nutrition and exercising regularly, are also important and can enhance weight loss when combined with medications.

Richele Corrado, DO, MPH, agreed that lifestyle management in combination with medications may provide greater weight loss than each of these interventions alone.

“If you look at the data, exercise doesn’t help you lose much weight,” said Dr. Corrado, a staff internist and obesity medicine specialist at Walter Reed National Military Medical Center in Bethesda, Md., who spoke at the same session. She added that she has many patients who struggle to lose weight despite having a healthy lifestyle. “It’s important to discuss with these patients about medications and surgery.”

Dr. Bessesen noted that management of mental health and emotional well-being should also be an integral part of obesity management. “Treatment for obesity may be more successful when underlying psychological conditions such as depression, childhood sexual trauma, or anxiety are addressed and treated,” he said.

Dr. Bessesen was involved in the study of the efficacy of semaglutide/cagrilintide. He does not have any financial conflicts with the companies that make other mentioned medications. He has received research grants or contracts from Novo Nordisk, honoraria from Novo Nordisk, and consultantship from Eli Lilly. Dr. Corrado reported no relevant financial conflicts.

SAN DIEGO – For patients with obesity, surgery, lifestyle changes, and pharmacologic interventions are all treatment options, but antiobesity medications provide a better risk-to-benefit ratio, according to a presenter at the annual meeting of the American College of Physicians.

Lifestyle changes result in the least weight loss and may be safest, while surgery provides the most weight loss and has the greatest risk. Antiobesity medications, especially the newer ones used in combination with lifestyle changes, can provide significant and sustained weight loss with manageable side effects, said Daniel Bessesen, MD, a professor in the endocrinology, diabetes, and metabolism at University of Colorado at Denver, Aurora.

New and more effective antiobesity medications have given internists more potential options to discuss with their patients, Dr. Bessesen said. He reviewed the pros and cons of the different options.

Medications are indicated for patients with a body mass index greater than 30, including those with a weight-related comorbidity, Dr. Bessesen said. The average weight loss is 5%-15% over 3-6 months but may vary greatly. Insurance often does not cover the medication costs.
 

Older FDA-approved antiobesity medications

Phentermine is the most widely prescribed antiobesity medication, partly because it is the only option most people can afford out of pocket. Dr. Bessesen presented recent data showing that long-term use of phentermine was associated with greater weight loss and that patients continuously taking phentermine for 24 months lost 7.5% of their weight.

Phentermine suppresses appetite by increasing norepinephrine production. Dr. Bessesen warned that internists should be careful when prescribing it to patients with mental conditions, because it acts as a stimulant. Early studies raised concerns about the risk of cardiovascular disease (CVD) in patients taking phentermine. However, analysis of data from over 13,000 individuals showed no evidence of a relationship between phentermine exposure and CVD events.

“These data provide some reassurance that it could be used in patients with CVD risk,” he noted. Phentermine can also be combined with topiramate extended release, a combination that provides greater efficacy (up to 10% weight loss) with fewer side effects. However, this combination is less effective in patients with diabetes than in those without.

Additional treatment options included orlistat and naltrexone sustained release/bupropion SR. Orlistat is a good treatment alternative for patients with constipation and is the safest option among older anti-obesity medications, whereas naltrexone SR/bupropion SR may be useful in patients with food cravings. However, there is more variability in the individual-level benefit from these agents compared to phentermine and phentermine/topiramate ER, Dr. Bessesen said.
 

Newer anti‐obesity medications

Liraglutide, an agent used for the management of type 2 diabetes, has recently been approved for weight loss. Liraglutide causes moderate weight loss, and it may reduce the risk of CVD. However, there are tolerability issues, such as nausea and other risks, and Dr. Bessesen advises internists to “start at low doses and increase slowly.”

Semaglutide is the newest and most effective antiobesity drug approved by the Food and Drug Administration, providing sustained weight loss of 8% for up to 48 weeks after starting treatment. Although its efficacy is lower in patients with diabetes, Dr. Bessesen noted that “this is common for antiobesity agents, and clinicians should not refrain from prescribing it in this population.”

Setmelanotide is another new medication approved for chronic weight management in patients with monogenic obesity. This medication can be considered for patients with early-onset severe obesity with abnormal feeding behavior.

Commenting on barriers to access to new antiobesity medications, Dr. Bessesen said that “the high cost of these medications is a substantial problem, but as more companies become involved and products are on the market for a longer period of time, I am hopeful that prices will come down.”
 

Emerging antiobesity medications

Dr. Bessesen presented recent phase 3 data showing that treatment with tirzepatide provided sustained chronic loss and improved cardiometabolic measures with no diet. Tirzepatide, which targets receptors for glucagonlike peptide–1 and glucose-dependent insulinotropic polypeptide, is used for the management of type 2 diabetes and is expected to be reviewed soon by the FDA for its use in weight management.

A semaglutide/cagrilintide combination may also provide a new treatment option for patients with obesity. In a phase 1b trial, semaglutide/cagrilintide treatment resulted in up to 17% weight loss in patients with obesity who were otherwise healthy; however, phase 2 and 3 data are needed to confirm its efficacy.
 

A ‘holistic approach’

When deciding whether to prescribe antiobesity medications, Dr. Bessesen noted that medications are better than exercise alone. Factors to consider when deciding whether to prescribe drugs, as well as which ones, include costs, local regulatory guidelines, requirement for long-term use, and patient comorbidities.

He also stated that lifestyle changes, such as adopting healthy nutrition and exercising regularly, are also important and can enhance weight loss when combined with medications.

Richele Corrado, DO, MPH, agreed that lifestyle management in combination with medications may provide greater weight loss than each of these interventions alone.

“If you look at the data, exercise doesn’t help you lose much weight,” said Dr. Corrado, a staff internist and obesity medicine specialist at Walter Reed National Military Medical Center in Bethesda, Md., who spoke at the same session. She added that she has many patients who struggle to lose weight despite having a healthy lifestyle. “It’s important to discuss with these patients about medications and surgery.”

Dr. Bessesen noted that management of mental health and emotional well-being should also be an integral part of obesity management. “Treatment for obesity may be more successful when underlying psychological conditions such as depression, childhood sexual trauma, or anxiety are addressed and treated,” he said.

Dr. Bessesen was involved in the study of the efficacy of semaglutide/cagrilintide. He does not have any financial conflicts with the companies that make other mentioned medications. He has received research grants or contracts from Novo Nordisk, honoraria from Novo Nordisk, and consultantship from Eli Lilly. Dr. Corrado reported no relevant financial conflicts.

BOSTON – When it comes to relieving migraine, triptans, ergots, and antiemetics are the most effective classes of medications, a new real-world analysis of data on more than 3 million migraine attacks shows.

The findings “align with results of clinical trials and recommendations from clinical treatment guidelines” and provide insights to complement clinical practice, said study investigator Chia-Chun Chiang, MD, a neurologist with Mayo Clinic, Rochester, Minn.

The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
 

The power of big data

Despite a wide variety of acute migraine medications that are available, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking, Dr. Chiang explained.

“To the best of our knowledge, this is the first study that simultaneously compared multiple acute migraine medications using a Big Data analysis approach based on real-world patient-provided data,” she said.

The researchers extracted more than 10 million self-reported migraine attack records from a migraine smartphone app called Migraine Buddy, where users can document whether a treatment was helpful, somewhat helpful, unsure, or unhelpful.

They analyzed 25 acute medications among seven classes: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, combination analgesics (acetaminophen/aspirin/caffeine), ergots, antiemetics, and opioids. The newer gepants and ditan medication classes of medications were not included because of the relatively lower numbers of usage when data was extracted (2014-2020).

The researchers employed a two-level nested logistic regression model to analyze the odds of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user.

The final analysis included more than 3.1 million migraine attacks among 278,000 users globally.

Using ibuprofen as the reference, triptans, ergots, and antiemetics had the highest efficacy with mean odds ratios of 4.8, 3.02, and 2.67, respectively, followed by opioids (OR, 2.49), NSAIDs (OR, 1.94), combination analgesics (OR, 1.69), others (OR, 1.49), and acetaminophen (OR, 0.83).

Individual medications with the highest patient-reported effectiveness were eletriptan (Relpax; OR, 6.1), zolmitriptan (Zomig; OR, 5.7) and sumatriptan (Zecuity; OR, 5.2).

This migraine medication comparative effectiveness analysis, based on patient-reported outcomes, “supports and complements the treatment recommendations from national headache societies based on randomized controlled trials and meta-analyses and strongly supports the use of triptans,” Dr. Chiang said.
 

End of trial-and-error?

Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said “This is a great study of Big Data in that it shows the power of the smartphone to collect real-world data and smart researchers like at Mayo Clinic to analyze them.”

“The study sheds light on how different therapeutics compare with each other. The next iteration of this line of research, I would hope, would be to determine if particular medications are effective for a particular migraine population, and even down to individuals with migraine,” said Dr. Lakhan, who wasn’t involved in the study.

“Once those models are appropriately built, long gone will be the era of trial-and-error medicine,” Dr. Lakhan added.

The study had no specific funding. Dr. Chiang has served as a consultant for Satsuma. Dr. Lakhan reports no relevant financial relationships.

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

BOSTON – When it comes to relieving migraine, triptans, ergots, and antiemetics are the most effective classes of medications, a new real-world analysis of data on more than 3 million migraine attacks shows.

The findings “align with results of clinical trials and recommendations from clinical treatment guidelines” and provide insights to complement clinical practice, said study investigator Chia-Chun Chiang, MD, a neurologist with Mayo Clinic, Rochester, Minn.

The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
 

The power of big data

Despite a wide variety of acute migraine medications that are available, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking, Dr. Chiang explained.

“To the best of our knowledge, this is the first study that simultaneously compared multiple acute migraine medications using a Big Data analysis approach based on real-world patient-provided data,” she said.

The researchers extracted more than 10 million self-reported migraine attack records from a migraine smartphone app called Migraine Buddy, where users can document whether a treatment was helpful, somewhat helpful, unsure, or unhelpful.

They analyzed 25 acute medications among seven classes: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, combination analgesics (acetaminophen/aspirin/caffeine), ergots, antiemetics, and opioids. The newer gepants and ditan medication classes of medications were not included because of the relatively lower numbers of usage when data was extracted (2014-2020).

The researchers employed a two-level nested logistic regression model to analyze the odds of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user.

The final analysis included more than 3.1 million migraine attacks among 278,000 users globally.

Using ibuprofen as the reference, triptans, ergots, and antiemetics had the highest efficacy with mean odds ratios of 4.8, 3.02, and 2.67, respectively, followed by opioids (OR, 2.49), NSAIDs (OR, 1.94), combination analgesics (OR, 1.69), others (OR, 1.49), and acetaminophen (OR, 0.83).

Individual medications with the highest patient-reported effectiveness were eletriptan (Relpax; OR, 6.1), zolmitriptan (Zomig; OR, 5.7) and sumatriptan (Zecuity; OR, 5.2).

This migraine medication comparative effectiveness analysis, based on patient-reported outcomes, “supports and complements the treatment recommendations from national headache societies based on randomized controlled trials and meta-analyses and strongly supports the use of triptans,” Dr. Chiang said.
 

End of trial-and-error?

Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said “This is a great study of Big Data in that it shows the power of the smartphone to collect real-world data and smart researchers like at Mayo Clinic to analyze them.”

“The study sheds light on how different therapeutics compare with each other. The next iteration of this line of research, I would hope, would be to determine if particular medications are effective for a particular migraine population, and even down to individuals with migraine,” said Dr. Lakhan, who wasn’t involved in the study.

“Once those models are appropriately built, long gone will be the era of trial-and-error medicine,” Dr. Lakhan added.

The study had no specific funding. Dr. Chiang has served as a consultant for Satsuma. Dr. Lakhan reports no relevant financial relationships.

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

BOSTON – When it comes to relieving migraine, triptans, ergots, and antiemetics are the most effective classes of medications, a new real-world analysis of data on more than 3 million migraine attacks shows.

The findings “align with results of clinical trials and recommendations from clinical treatment guidelines” and provide insights to complement clinical practice, said study investigator Chia-Chun Chiang, MD, a neurologist with Mayo Clinic, Rochester, Minn.

The findings were presented at the 2023 annual meeting of the American Academy of Neurology.
 

The power of big data

Despite a wide variety of acute migraine medications that are available, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking, Dr. Chiang explained.

“To the best of our knowledge, this is the first study that simultaneously compared multiple acute migraine medications using a Big Data analysis approach based on real-world patient-provided data,” she said.

The researchers extracted more than 10 million self-reported migraine attack records from a migraine smartphone app called Migraine Buddy, where users can document whether a treatment was helpful, somewhat helpful, unsure, or unhelpful.

They analyzed 25 acute medications among seven classes: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, combination analgesics (acetaminophen/aspirin/caffeine), ergots, antiemetics, and opioids. The newer gepants and ditan medication classes of medications were not included because of the relatively lower numbers of usage when data was extracted (2014-2020).

The researchers employed a two-level nested logistic regression model to analyze the odds of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user.

The final analysis included more than 3.1 million migraine attacks among 278,000 users globally.

Using ibuprofen as the reference, triptans, ergots, and antiemetics had the highest efficacy with mean odds ratios of 4.8, 3.02, and 2.67, respectively, followed by opioids (OR, 2.49), NSAIDs (OR, 1.94), combination analgesics (OR, 1.69), others (OR, 1.49), and acetaminophen (OR, 0.83).

Individual medications with the highest patient-reported effectiveness were eletriptan (Relpax; OR, 6.1), zolmitriptan (Zomig; OR, 5.7) and sumatriptan (Zecuity; OR, 5.2).

This migraine medication comparative effectiveness analysis, based on patient-reported outcomes, “supports and complements the treatment recommendations from national headache societies based on randomized controlled trials and meta-analyses and strongly supports the use of triptans,” Dr. Chiang said.
 

End of trial-and-error?

Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said “This is a great study of Big Data in that it shows the power of the smartphone to collect real-world data and smart researchers like at Mayo Clinic to analyze them.”

“The study sheds light on how different therapeutics compare with each other. The next iteration of this line of research, I would hope, would be to determine if particular medications are effective for a particular migraine population, and even down to individuals with migraine,” said Dr. Lakhan, who wasn’t involved in the study.

“Once those models are appropriately built, long gone will be the era of trial-and-error medicine,” Dr. Lakhan added.

The study had no specific funding. Dr. Chiang has served as a consultant for Satsuma. Dr. Lakhan reports no relevant financial relationships.

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

Among patients with unresectable desmoplastic melanoma (DM), a prospective trial showed that single-agent treatment with the programmed death 1 (PD-1) inhibitor pembrolizumab led to a dramatic overall response rate.

The findings could represent a new standard of treatment for this extremely rare tumor.

The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.

The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.

“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.

The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.

“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.

Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.

It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.

“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.

She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
 

Study details and adverse events

Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.

The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.

The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.

Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.

Among patients with unresectable desmoplastic melanoma (DM), a prospective trial showed that single-agent treatment with the programmed death 1 (PD-1) inhibitor pembrolizumab led to a dramatic overall response rate.

The findings could represent a new standard of treatment for this extremely rare tumor.

The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.

The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.

“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.

The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.

“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.

Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.

It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.

“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.

She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
 

Study details and adverse events

Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.

The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.

The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.

Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.

Among patients with unresectable desmoplastic melanoma (DM), a prospective trial showed that single-agent treatment with the programmed death 1 (PD-1) inhibitor pembrolizumab led to a dramatic overall response rate.

The findings could represent a new standard of treatment for this extremely rare tumor.

The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.

The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.

“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.

The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.

“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.

Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.

It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.

“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.

She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
 

Study details and adverse events

Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.

The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.

The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.

Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.

Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.

As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.

The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.

The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.

Rates were the highest for ibrutinib, clofarabine, and ponatinib.

The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.

Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.

“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
 

Call for routine monitoring

The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.

To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.

Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.

“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.

The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”

Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
 

Details of the meta-analysis

The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.

The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.

The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.

The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.

The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).

For placebo, the annualized rate was 0.25 cases per 100 person-years.

The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.

One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.

No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
 

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

Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.

As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.

The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.

The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.

Rates were the highest for ibrutinib, clofarabine, and ponatinib.

The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.

Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.

“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
 

Call for routine monitoring

The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.

To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.

Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.

“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.

The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”

Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
 

Details of the meta-analysis

The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.

The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.

The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.

The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.

The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).

For placebo, the annualized rate was 0.25 cases per 100 person-years.

The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.

One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.

No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
 

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

Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.

As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.

The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.

The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.

Rates were the highest for ibrutinib, clofarabine, and ponatinib.

The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.

Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.

“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
 

Call for routine monitoring

The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.

To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.

Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.

“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.

The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”

Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
 

Details of the meta-analysis

The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.

The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.

The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.

The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.

The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).

For placebo, the annualized rate was 0.25 cases per 100 person-years.

The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.

One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.

No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
 

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

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.