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Final ASCEND study data: Acalabrutinib beat standard of care for r/r CLL
Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.
The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.
The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.
The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
Overall responses
The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.
The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.
The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
Adverse events
AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.
The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.
Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
Confirmatory results
“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.
“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”
This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.
SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.
Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.
The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.
The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.
The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
Overall responses
The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.
The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.
The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
Adverse events
AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.
The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.
Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
Confirmatory results
“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.
“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”
This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.
SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.
Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.
The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.
The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.
The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
Overall responses
The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.
The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.
The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
Adverse events
AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.
The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.
Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
Confirmatory results
“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.
“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”
This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.
SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.
FROM SOHO 2020
ESMO offers new clinical practice guideline for CLL
An updated European Society for Medical Oncology (ESMO) clinical practice guidelines were released to provide key recommendations on the management of chronic lymphocytic leukemia (CLL).
The guidelines were developed by a multidisciplinary group of experts from different institutions and countries in Europe and provide levels of evidence and grades of recommendation where applicable for issues regarding prognosis and treatment decisions in CLL. Such decisions depend on genetic and clinical factors such as age, stage, and comorbidities. The guidelines also focus on new therapies targeting B-cell-receptor pathways or defect mechanism of apoptosis, which have been found to induce long-lasting remissions. The guidelines were endorsed by the European Hematology Association (EHA) through the Scientific Working Group on CLL/European Research Initiative on CLL (ERIC), according to the report published online the Annals of Oncology.
These clinical practice guidelines were developed in accordance with the ESMO standard operating procedures for clinical practice guidelines development with use of relevant literature selected by the expert authors. Statements without grading were considered justified as standard clinical practice by the experts and the ESMO faculty.
Below are some highlights of the guidelines, which cover a wide array of topics regarding the diagnosis, staging, treatment, and progression of CLL disease.
Diagnosis
The guidelines indicate that CLL diagnosis is usually possible by immunophenotyping of peripheral blood only and that lymph node (LN) biopsy and/or bone marrow biopsy may be helpful if immunophenotyping is not conclusive for the diagnosis of CLL, according to Barbara Eichhorst, MD, of the University of Cologne (Germany) and colleagues on behalf of the ESMO guidelines committee.
Staging and risk assessment
Early asymptomatic-stage disease does not need further risk assessment, but after the first year, when all patients should be seen at 3-monthly intervals, patients can be followed every 3-12 months. The interval would depend on burden and dynamics of the disease obtained by the using history and physical examinations, including a careful palpation of all LN areas, spleen, and liver, as well as assessing complete blood cell count and differential count, according to the report.
Advanced- and symptomatic-stage disease requires a broader examination including imaging, history and status of relevant infections, and fluorescent in situ hybridization (FISH) assays for the detection of deletion of the chromosome 17 (del[17p]) affecting the tumor protein p53 expression and, in the absence of del(17p), TP53 sequencing for detection of TP53 gene mutation, according to the authors.
Prognostication
Two clinical staging systems are typically used in CLL. Both Binet and Rai staging systems separate three groups of patients with different prognosis, although “as a consequence of more effective therapy, the overall survival (OS) of patients with advanced stage has improved and the relevance of the staging systems for prognostication has decreased,” according to the report.
The recent addition of genetic markers has also proved highly relevant to identifying patients with different prognoses and to guide treatment.
Therapy
Although CLL is an incurable disease, choice and application of treatment are strongly tied to the length of survival, according to the authors. The guidelines recommend Binet and Rai staging with clinical symptoms as relevant for treatment indication. In addition, the identification of del(17p), TP53 mutations, and IGHV status are relevant for choice of therapy and should be assessed prior to treatment.
The guidelines discuss specific treatment modalities for various stages of the disease, from early stages to relapse.
For frontline therapy, different treatment strategies are available including continuous treatment with Bruton tyrosine kinase (BTK)–inhibitors, such as ibrutinib, until progression or time-limited therapy with ChT backbone and CD20 antibodies. In addition, the Food and Drug Administration and European Medicines Agency have recently approved the combination of venetoclax plus obinutuzumab for first-line therapy of CLL.
Treatment decisions should include an assessment of IGHV and TP53 status, as well as patient-related factors such as comedication, comorbidities, preferences, drug availability, and potential of treatment adherence, according to the guidelines.
In case of symptomatic relapse within 3 years after fixed-duration therapy or nonresponse to therapy, the guidelines recommend that the therapeutic regimen should be changed, regardless of the type of first-line either to venetoclax plus rituximab for 24 months or to ibrutinib, acalabrutinib, or other BTK inhibitors (if available) as continuous therapy.
The guidelines also discuss the possible roles for hematopoietic stem cell transplantation and cellular therapies, as well as the treatment of the various complications that can arise in patients with CLL, and dealing with various aspects of disease progression.
No external funds were provided for the production of the guidelines. The authors of the report and members of the ESMO Guidelines Committee reported numerous disclosures regarding pharmaceutical and biotechnology companies.
SOURCE: Eichhorst B et al. Ann Oncol. 2020 Oct 19. doi: 10.1016/j.annonc.2020.09.019.
An updated European Society for Medical Oncology (ESMO) clinical practice guidelines were released to provide key recommendations on the management of chronic lymphocytic leukemia (CLL).
The guidelines were developed by a multidisciplinary group of experts from different institutions and countries in Europe and provide levels of evidence and grades of recommendation where applicable for issues regarding prognosis and treatment decisions in CLL. Such decisions depend on genetic and clinical factors such as age, stage, and comorbidities. The guidelines also focus on new therapies targeting B-cell-receptor pathways or defect mechanism of apoptosis, which have been found to induce long-lasting remissions. The guidelines were endorsed by the European Hematology Association (EHA) through the Scientific Working Group on CLL/European Research Initiative on CLL (ERIC), according to the report published online the Annals of Oncology.
These clinical practice guidelines were developed in accordance with the ESMO standard operating procedures for clinical practice guidelines development with use of relevant literature selected by the expert authors. Statements without grading were considered justified as standard clinical practice by the experts and the ESMO faculty.
Below are some highlights of the guidelines, which cover a wide array of topics regarding the diagnosis, staging, treatment, and progression of CLL disease.
Diagnosis
The guidelines indicate that CLL diagnosis is usually possible by immunophenotyping of peripheral blood only and that lymph node (LN) biopsy and/or bone marrow biopsy may be helpful if immunophenotyping is not conclusive for the diagnosis of CLL, according to Barbara Eichhorst, MD, of the University of Cologne (Germany) and colleagues on behalf of the ESMO guidelines committee.
Staging and risk assessment
Early asymptomatic-stage disease does not need further risk assessment, but after the first year, when all patients should be seen at 3-monthly intervals, patients can be followed every 3-12 months. The interval would depend on burden and dynamics of the disease obtained by the using history and physical examinations, including a careful palpation of all LN areas, spleen, and liver, as well as assessing complete blood cell count and differential count, according to the report.
Advanced- and symptomatic-stage disease requires a broader examination including imaging, history and status of relevant infections, and fluorescent in situ hybridization (FISH) assays for the detection of deletion of the chromosome 17 (del[17p]) affecting the tumor protein p53 expression and, in the absence of del(17p), TP53 sequencing for detection of TP53 gene mutation, according to the authors.
Prognostication
Two clinical staging systems are typically used in CLL. Both Binet and Rai staging systems separate three groups of patients with different prognosis, although “as a consequence of more effective therapy, the overall survival (OS) of patients with advanced stage has improved and the relevance of the staging systems for prognostication has decreased,” according to the report.
The recent addition of genetic markers has also proved highly relevant to identifying patients with different prognoses and to guide treatment.
Therapy
Although CLL is an incurable disease, choice and application of treatment are strongly tied to the length of survival, according to the authors. The guidelines recommend Binet and Rai staging with clinical symptoms as relevant for treatment indication. In addition, the identification of del(17p), TP53 mutations, and IGHV status are relevant for choice of therapy and should be assessed prior to treatment.
The guidelines discuss specific treatment modalities for various stages of the disease, from early stages to relapse.
For frontline therapy, different treatment strategies are available including continuous treatment with Bruton tyrosine kinase (BTK)–inhibitors, such as ibrutinib, until progression or time-limited therapy with ChT backbone and CD20 antibodies. In addition, the Food and Drug Administration and European Medicines Agency have recently approved the combination of venetoclax plus obinutuzumab for first-line therapy of CLL.
Treatment decisions should include an assessment of IGHV and TP53 status, as well as patient-related factors such as comedication, comorbidities, preferences, drug availability, and potential of treatment adherence, according to the guidelines.
In case of symptomatic relapse within 3 years after fixed-duration therapy or nonresponse to therapy, the guidelines recommend that the therapeutic regimen should be changed, regardless of the type of first-line either to venetoclax plus rituximab for 24 months or to ibrutinib, acalabrutinib, or other BTK inhibitors (if available) as continuous therapy.
The guidelines also discuss the possible roles for hematopoietic stem cell transplantation and cellular therapies, as well as the treatment of the various complications that can arise in patients with CLL, and dealing with various aspects of disease progression.
No external funds were provided for the production of the guidelines. The authors of the report and members of the ESMO Guidelines Committee reported numerous disclosures regarding pharmaceutical and biotechnology companies.
SOURCE: Eichhorst B et al. Ann Oncol. 2020 Oct 19. doi: 10.1016/j.annonc.2020.09.019.
An updated European Society for Medical Oncology (ESMO) clinical practice guidelines were released to provide key recommendations on the management of chronic lymphocytic leukemia (CLL).
The guidelines were developed by a multidisciplinary group of experts from different institutions and countries in Europe and provide levels of evidence and grades of recommendation where applicable for issues regarding prognosis and treatment decisions in CLL. Such decisions depend on genetic and clinical factors such as age, stage, and comorbidities. The guidelines also focus on new therapies targeting B-cell-receptor pathways or defect mechanism of apoptosis, which have been found to induce long-lasting remissions. The guidelines were endorsed by the European Hematology Association (EHA) through the Scientific Working Group on CLL/European Research Initiative on CLL (ERIC), according to the report published online the Annals of Oncology.
These clinical practice guidelines were developed in accordance with the ESMO standard operating procedures for clinical practice guidelines development with use of relevant literature selected by the expert authors. Statements without grading were considered justified as standard clinical practice by the experts and the ESMO faculty.
Below are some highlights of the guidelines, which cover a wide array of topics regarding the diagnosis, staging, treatment, and progression of CLL disease.
Diagnosis
The guidelines indicate that CLL diagnosis is usually possible by immunophenotyping of peripheral blood only and that lymph node (LN) biopsy and/or bone marrow biopsy may be helpful if immunophenotyping is not conclusive for the diagnosis of CLL, according to Barbara Eichhorst, MD, of the University of Cologne (Germany) and colleagues on behalf of the ESMO guidelines committee.
Staging and risk assessment
Early asymptomatic-stage disease does not need further risk assessment, but after the first year, when all patients should be seen at 3-monthly intervals, patients can be followed every 3-12 months. The interval would depend on burden and dynamics of the disease obtained by the using history and physical examinations, including a careful palpation of all LN areas, spleen, and liver, as well as assessing complete blood cell count and differential count, according to the report.
Advanced- and symptomatic-stage disease requires a broader examination including imaging, history and status of relevant infections, and fluorescent in situ hybridization (FISH) assays for the detection of deletion of the chromosome 17 (del[17p]) affecting the tumor protein p53 expression and, in the absence of del(17p), TP53 sequencing for detection of TP53 gene mutation, according to the authors.
Prognostication
Two clinical staging systems are typically used in CLL. Both Binet and Rai staging systems separate three groups of patients with different prognosis, although “as a consequence of more effective therapy, the overall survival (OS) of patients with advanced stage has improved and the relevance of the staging systems for prognostication has decreased,” according to the report.
The recent addition of genetic markers has also proved highly relevant to identifying patients with different prognoses and to guide treatment.
Therapy
Although CLL is an incurable disease, choice and application of treatment are strongly tied to the length of survival, according to the authors. The guidelines recommend Binet and Rai staging with clinical symptoms as relevant for treatment indication. In addition, the identification of del(17p), TP53 mutations, and IGHV status are relevant for choice of therapy and should be assessed prior to treatment.
The guidelines discuss specific treatment modalities for various stages of the disease, from early stages to relapse.
For frontline therapy, different treatment strategies are available including continuous treatment with Bruton tyrosine kinase (BTK)–inhibitors, such as ibrutinib, until progression or time-limited therapy with ChT backbone and CD20 antibodies. In addition, the Food and Drug Administration and European Medicines Agency have recently approved the combination of venetoclax plus obinutuzumab for first-line therapy of CLL.
Treatment decisions should include an assessment of IGHV and TP53 status, as well as patient-related factors such as comedication, comorbidities, preferences, drug availability, and potential of treatment adherence, according to the guidelines.
In case of symptomatic relapse within 3 years after fixed-duration therapy or nonresponse to therapy, the guidelines recommend that the therapeutic regimen should be changed, regardless of the type of first-line either to venetoclax plus rituximab for 24 months or to ibrutinib, acalabrutinib, or other BTK inhibitors (if available) as continuous therapy.
The guidelines also discuss the possible roles for hematopoietic stem cell transplantation and cellular therapies, as well as the treatment of the various complications that can arise in patients with CLL, and dealing with various aspects of disease progression.
No external funds were provided for the production of the guidelines. The authors of the report and members of the ESMO Guidelines Committee reported numerous disclosures regarding pharmaceutical and biotechnology companies.
SOURCE: Eichhorst B et al. Ann Oncol. 2020 Oct 19. doi: 10.1016/j.annonc.2020.09.019.
FROM ANNALS OF ONCOLOGY
Older age, r/r disease in lymphoma patients tied to increased COVID-19 death rate
Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.
Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.
These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.
The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
Promising results for many
There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.
With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.
The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).
Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.
“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.
The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.
SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.
Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.
Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.
These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.
The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
Promising results for many
There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.
With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.
The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).
Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.
“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.
The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.
SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.
Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.
Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.
These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.
The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
Promising results for many
There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.
With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.
The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).
Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.
“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.
The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.
SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.
FROM ECLINICALMEDICINE
Efforts to close the ‘AYA gap’ in lymphoma
In the 1970s, cancer survival was poor for young children and older adults in the United States, as shown by data published in the Journal of the National Cancer Institute.
Great progress has been made since the 1970s, but improvements in outcome have been less impressive for cancer patients aged 15-39 years, as shown by research published in Cancer. 
Patients aged 15-39 years have been designated by the National Institutes of Health (NIH) as “adolescents and young adults (AYAs),” and the lag in survival benefit has been termed “the AYA gap.”
The AYA gap persists in lymphoma patients, and an expert panel recently outlined differences between lymphoma in AYAs and lymphoma in other age groups.
The experts spoke at a special session of the AACR Virtual Meeting: Advances in Malignant Lymphoma moderated by Somali M. Smith, MD, of the University of Chicago.
Factors that contribute to the AYA gap
About 89,000 AYAs are diagnosed with cancer each year in the United States, according to data from the National Cancer Institute (NCI). Lymphomas and thyroid cancer are the most common cancers among younger AYAs, aged 15-24 years.
In a report commissioned by the NIH in 2006, many factors contributing to the AYA gap were identified. Chief among them were:
- Limitations in access to care.
- Delayed diagnosis.
- Inconsistency in treatment and follow-up.
- Long-term toxicity (fertility, second malignancies, and cardiovascular disease).
These factors compromise health-related survival, even when cancer-specific survival is improved.
Panelist Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., noted that there are additional unique challenges for AYAs with cancer. These include:
- Pubertal changes.
- Developmental transition to independence.
- Societal impediments such as insurance coverage and disparities in access to specialized centers.
- Psychosocial factors such as health literacy and adherence to treatment and follow-up.
Focusing on lymphoma specifically, Dr. Kelly noted that lymphoma biology differs across the age spectrum and by race and ethnicity. Both tumor and host factors require further study, she said.
Clinical trial access for AYAs
Dr. Kelly emphasized that, unfortunately, clinical research participation is low among AYAs. A major impediment is that adult clinical trials historically required participants to be at least 18 years old.
In addition, there has not been a focused effort to educate AYAs about regulatory safeguards to ensure safety and the promise of enhanced benefit to them in NCI Cancer Trials Network (NCTN) trials. As a result, the refusal rate is high.
A multi-stakeholder workshop, convened in May 2016 by the American Society of Clinical Oncology and Friends of Cancer Research, outlined opportunities for expanding trial eligibility to include children younger than 18 years in first-in-human and other adult cancer clinical trials, enhancing their access to new agents, without compromising safety.
Recently, collaborative efforts between the adult and children’s NCTN research groups have included AYAs in studies addressing cancers that span the age spectrum, including lymphoma.
However, as Dr. Kelly noted, there are differences in AYA lymphoid malignancy types with a transition from more pediatric to more adult types.
Hodgkin lymphoma and primary mediastinal B-cell lymphoma
Panelist Lisa G. Roth, MD, of Weill Cornell Medicine, New York, reviewed the genomic landscape of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL).
Dr. Roth explained that both HL and PMBCL are derived from thymic B cells, predominantly affect the mediastinum, and are CD30-positive lymphomas. Both are characterized by upregulation of JAK/STAT and NF-kappaB as well as overexpression of PD-L1.
Dr. Roth noted that HL is challenging to sequence by standard methods because Reed Sternberg (HRS) cells represent less than 1% of the cellular infiltrate. Recurrently mutated genes in HL cluster by histologic subtype.
Whole-exome sequencing of HRS cells show loss of beta-2 microglobulin and MHC-1 expression, HLA-B, NF-kappaB signaling, and JAK-STAT signaling, according to data published in Blood Advances in 2019.
Dr. Roth’s lab performed immunohistochemistry on tissue microarrays in 145 cases of HL (unpublished data). Results showed that loss of beta-2 microglobulin is more common in younger HL patients. For other alterations, there were too few cases to know.
Dr. Roth’s lab is a member of a pediatric/AYA HL sequencing multi-institutional consortium that has been able to extract DNA and RNA from samples submitted for whole-exome sequencing. The consortium’s goal is to shed light on implications of other genomic alterations that may differ by age in HL patients.
Dr. Roth cited research showing that PMBCL shares molecular alterations similar to those of HL. Alterations in PMBCL suggest dysregulated cellular signaling and immune evasion mechanisms (e.g., deletions in MHC type 1 and 2, beta-2 microglobulin, JAK-STAT, and NF-kappaB mutations) that provide opportunities to study novel agents, according to data published in Blood in 2019.
By early 2021, the S1826 and ANHL1931 studies, which have no age restriction, will be available to AYA lymphoma patients with HL and PMBCL, respectively, Dr. Roth said.
Follicular lymphoma: Clinical features by age
Panelist Abner Louissaint Jr, MD, PhD, of Massachusetts General Hospital in Boston, discussed age-related differences in follicular lymphoma (FL).
He noted that FL typically presents at an advanced stage, with low- or high-grade histology. It is increasingly common in adults in their 50s and 60s, representing 20% of all lymphomas. FL is rare in children and AYAs.
Dr. Louissaint explained that the typical flow cytometric findings in FL are BCL2 translocations, occurring in up to 85%-90% of low-grade and 50% of high-grade cases. The t(14;18)(q32;q21) translocation juxtaposes BCL2 on 18q21 to regulatory sequences and enhances the expression of elements of the Ig heavy chain.
Malignant cells in FL patients express CD20, CD10, CD21, and BCL2 (in contrast to normal germinal centers) and overexpress BCL6 (in contrast to normal follicles), Dr. Louissaint noted. He said the Ki-67 proliferative index of the malignant cells is typically low.
Pediatric-type FL is rare, but case series show clinical, pathologic, and molecular features that are distinctive from adult FL, Dr. Louissaint explained.
He then discussed the features of pediatric-type FL in multiple domains. In the clinical domain, there is a male predilection, and stage tends to be low. There is frequent involvement of nodes of the head and neck region and rare involvement of internal lymph node chains.
Pathologically, the malignant cells appear high grade, with architectural effacement, expansile follicular pattern, large lymphocyte size, and an elevated proliferation index. In contrast to adult FL, malignant cells in pediatric-type FL lack aberrant BCL2 expression.
Most importantly, for pediatric-type FL, the prognosis is excellent with durable remissions after surgical excision, Dr. Louissaint said.
Follicular lymphoma: Molecular features by age
Because of the excellent prognosis in pediatric-type FL, it is important to assess whether young adults with FL have adult-type or pediatric-type lesions, Dr. Louissaint said.
He cited many studies showing differences in adult and pediatric-type FL. In adult FL, the mutational landscape is characterized by frequent chromatin-modifying mutations in genes such as CREBBP, KM22D, and EP300.
In contrast, in pediatric-type FL, there are frequent activating MAPK pathway mutations, including mutations in the negative regulatory domain of MAP2K1. These mutations are not seen in adult FL.
Dr. Louissaint noted that there may be mutations in epigenetic modifiers (CREBBP, TNFRSF14) in both adult and pediatric-type FL. However, CREBBP is very unusual in pediatric-type FL and common in adult FL. This suggests the alterations in pediatric-type FL do not simply represent an early stage of the same disease as adult FL.
Despite a high proliferating fraction and absence of BCL2/BCL6/IRF4 rearrangements in pediatric-type FL, the presence of these features was associated with dramatic difference in progression-free survival, according to research published in Blood in 2012.
A distinct entity
In 2016, the World Health Organization recognized pediatric-type FL as a distinct entity, with the following diagnostic criteria (published in Blood):
- At least partial effacement of nodal architecture, expansile follicles, intermediate-size blastoid cells, and no component of diffuse large B-cell lymphoma.
- Immunohistochemistry showing BCL6 positivity, BCL2 negativity or weak positivity, and a high proliferative fraction.
- Genomic studies showing no BCL2 amplification.
- Clinical features of nodal disease in the head and neck region, early clinical stage, age younger than 40 years, typically in a male with no internal nodes involved.
When FL occurs in AYAs, the diagnostic findings of pediatric-type FL suggest the patient will do well with conservative management (e.g., excision alone), Dr. Louissaint noted.
Two sizes do not fit all
The strategies that have improved cancer outcomes since the 1970s for children and older adults have been much less successful for AYAs with cancer.
As an oncologic community, we should not allow the AYA gap to persist. As always, the solutions are likely to involve focused clinical research, education, and communication. Effort will need to be targeted specifically to the AYA population.
Since health-related mortality is high even when cancer-specific outcomes improve, adopting and maintaining a healthy lifestyle must be a key part of the discussion with these young patients.
The biologic differences associated with AYA lymphomas demand participation in clinical trials.
Oncologists should vigorously support removing impediments to the participation of AYAs in prospective clinical trials, stratified (but unrestricted) by age, with careful analysis of patient-reported outcomes, late adverse effects, and biospecimen collection.
As Dr. Kelly noted in the question-and-answer period, the Children’s Oncology Group has an existing biobank of paraffin-embedded tumor samples, DNA from lymphoma specimens, plasma, and sera with clinically annotated data that can be given to investigators upon request and justification.
Going beyond eligibility for clinical trials
Unfortunately, we will likely find that broadening eligibility criteria is the “low-hanging fruit.” There are protocol-, patient-, and physician-related obstacles, according to a review published in Cancer in 2019.
Patient-related obstacles include fear of toxicity, uncertainty about placebos, a steep learning curve for health literacy, insurance-related impediments, and other access-related issues.
Discussions will need to be tailored to the AYA population. Frank, early conversations about fertility, sexuality, financial hardship, career advancement, work-life balance, and cognitive risks may not only facilitate treatment planning but also encourage the trust that is essential for patients to enroll in trials.
The investment in time, multidisciplinary staff and physician involvement, and potential delays in treatment initiation may be painful and inconvenient, but the benefits for long-term health outcomes and personal-professional relationships will be gratifying beyond measure.
Dr. Smith disclosed relationships with Genentech/Roche, Celgene, TGTX, Karyopharm, Janssen, and Bantem. Dr. Roth disclosed relationships with Janssen, ADC Therapeutics, and Celgene. Dr. Kelly and Dr. Louissaint had no financial relationships to disclose.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
In the 1970s, cancer survival was poor for young children and older adults in the United States, as shown by data published in the Journal of the National Cancer Institute.
Great progress has been made since the 1970s, but improvements in outcome have been less impressive for cancer patients aged 15-39 years, as shown by research published in Cancer.
Patients aged 15-39 years have been designated by the National Institutes of Health (NIH) as “adolescents and young adults (AYAs),” and the lag in survival benefit has been termed “the AYA gap.”
The AYA gap persists in lymphoma patients, and an expert panel recently outlined differences between lymphoma in AYAs and lymphoma in other age groups.
The experts spoke at a special session of the AACR Virtual Meeting: Advances in Malignant Lymphoma moderated by Somali M. Smith, MD, of the University of Chicago.
Factors that contribute to the AYA gap
About 89,000 AYAs are diagnosed with cancer each year in the United States, according to data from the National Cancer Institute (NCI). Lymphomas and thyroid cancer are the most common cancers among younger AYAs, aged 15-24 years.
In a report commissioned by the NIH in 2006, many factors contributing to the AYA gap were identified. Chief among them were:
- Limitations in access to care.
- Delayed diagnosis.
- Inconsistency in treatment and follow-up.
- Long-term toxicity (fertility, second malignancies, and cardiovascular disease).
These factors compromise health-related survival, even when cancer-specific survival is improved.
Panelist Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., noted that there are additional unique challenges for AYAs with cancer. These include:
- Pubertal changes.
- Developmental transition to independence.
- Societal impediments such as insurance coverage and disparities in access to specialized centers.
- Psychosocial factors such as health literacy and adherence to treatment and follow-up.
Focusing on lymphoma specifically, Dr. Kelly noted that lymphoma biology differs across the age spectrum and by race and ethnicity. Both tumor and host factors require further study, she said.
Clinical trial access for AYAs
Dr. Kelly emphasized that, unfortunately, clinical research participation is low among AYAs. A major impediment is that adult clinical trials historically required participants to be at least 18 years old.
In addition, there has not been a focused effort to educate AYAs about regulatory safeguards to ensure safety and the promise of enhanced benefit to them in NCI Cancer Trials Network (NCTN) trials. As a result, the refusal rate is high.
A multi-stakeholder workshop, convened in May 2016 by the American Society of Clinical Oncology and Friends of Cancer Research, outlined opportunities for expanding trial eligibility to include children younger than 18 years in first-in-human and other adult cancer clinical trials, enhancing their access to new agents, without compromising safety.
Recently, collaborative efforts between the adult and children’s NCTN research groups have included AYAs in studies addressing cancers that span the age spectrum, including lymphoma.
However, as Dr. Kelly noted, there are differences in AYA lymphoid malignancy types with a transition from more pediatric to more adult types.
Hodgkin lymphoma and primary mediastinal B-cell lymphoma
Panelist Lisa G. Roth, MD, of Weill Cornell Medicine, New York, reviewed the genomic landscape of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL).
Dr. Roth explained that both HL and PMBCL are derived from thymic B cells, predominantly affect the mediastinum, and are CD30-positive lymphomas. Both are characterized by upregulation of JAK/STAT and NF-kappaB as well as overexpression of PD-L1.
Dr. Roth noted that HL is challenging to sequence by standard methods because Reed Sternberg (HRS) cells represent less than 1% of the cellular infiltrate. Recurrently mutated genes in HL cluster by histologic subtype.
Whole-exome sequencing of HRS cells show loss of beta-2 microglobulin and MHC-1 expression, HLA-B, NF-kappaB signaling, and JAK-STAT signaling, according to data published in Blood Advances in 2019.
Dr. Roth’s lab performed immunohistochemistry on tissue microarrays in 145 cases of HL (unpublished data). Results showed that loss of beta-2 microglobulin is more common in younger HL patients. For other alterations, there were too few cases to know.
Dr. Roth’s lab is a member of a pediatric/AYA HL sequencing multi-institutional consortium that has been able to extract DNA and RNA from samples submitted for whole-exome sequencing. The consortium’s goal is to shed light on implications of other genomic alterations that may differ by age in HL patients.
Dr. Roth cited research showing that PMBCL shares molecular alterations similar to those of HL. Alterations in PMBCL suggest dysregulated cellular signaling and immune evasion mechanisms (e.g., deletions in MHC type 1 and 2, beta-2 microglobulin, JAK-STAT, and NF-kappaB mutations) that provide opportunities to study novel agents, according to data published in Blood in 2019.
By early 2021, the S1826 and ANHL1931 studies, which have no age restriction, will be available to AYA lymphoma patients with HL and PMBCL, respectively, Dr. Roth said.
Follicular lymphoma: Clinical features by age
Panelist Abner Louissaint Jr, MD, PhD, of Massachusetts General Hospital in Boston, discussed age-related differences in follicular lymphoma (FL).
He noted that FL typically presents at an advanced stage, with low- or high-grade histology. It is increasingly common in adults in their 50s and 60s, representing 20% of all lymphomas. FL is rare in children and AYAs.
Dr. Louissaint explained that the typical flow cytometric findings in FL are BCL2 translocations, occurring in up to 85%-90% of low-grade and 50% of high-grade cases. The t(14;18)(q32;q21) translocation juxtaposes BCL2 on 18q21 to regulatory sequences and enhances the expression of elements of the Ig heavy chain.
Malignant cells in FL patients express CD20, CD10, CD21, and BCL2 (in contrast to normal germinal centers) and overexpress BCL6 (in contrast to normal follicles), Dr. Louissaint noted. He said the Ki-67 proliferative index of the malignant cells is typically low.
Pediatric-type FL is rare, but case series show clinical, pathologic, and molecular features that are distinctive from adult FL, Dr. Louissaint explained.
He then discussed the features of pediatric-type FL in multiple domains. In the clinical domain, there is a male predilection, and stage tends to be low. There is frequent involvement of nodes of the head and neck region and rare involvement of internal lymph node chains.
Pathologically, the malignant cells appear high grade, with architectural effacement, expansile follicular pattern, large lymphocyte size, and an elevated proliferation index. In contrast to adult FL, malignant cells in pediatric-type FL lack aberrant BCL2 expression.
Most importantly, for pediatric-type FL, the prognosis is excellent with durable remissions after surgical excision, Dr. Louissaint said.
Follicular lymphoma: Molecular features by age
Because of the excellent prognosis in pediatric-type FL, it is important to assess whether young adults with FL have adult-type or pediatric-type lesions, Dr. Louissaint said.
He cited many studies showing differences in adult and pediatric-type FL. In adult FL, the mutational landscape is characterized by frequent chromatin-modifying mutations in genes such as CREBBP, KM22D, and EP300.
In contrast, in pediatric-type FL, there are frequent activating MAPK pathway mutations, including mutations in the negative regulatory domain of MAP2K1. These mutations are not seen in adult FL.
Dr. Louissaint noted that there may be mutations in epigenetic modifiers (CREBBP, TNFRSF14) in both adult and pediatric-type FL. However, CREBBP is very unusual in pediatric-type FL and common in adult FL. This suggests the alterations in pediatric-type FL do not simply represent an early stage of the same disease as adult FL.
Despite a high proliferating fraction and absence of BCL2/BCL6/IRF4 rearrangements in pediatric-type FL, the presence of these features was associated with dramatic difference in progression-free survival, according to research published in Blood in 2012.
A distinct entity
In 2016, the World Health Organization recognized pediatric-type FL as a distinct entity, with the following diagnostic criteria (published in Blood):
- At least partial effacement of nodal architecture, expansile follicles, intermediate-size blastoid cells, and no component of diffuse large B-cell lymphoma.
- Immunohistochemistry showing BCL6 positivity, BCL2 negativity or weak positivity, and a high proliferative fraction.
- Genomic studies showing no BCL2 amplification.
- Clinical features of nodal disease in the head and neck region, early clinical stage, age younger than 40 years, typically in a male with no internal nodes involved.
When FL occurs in AYAs, the diagnostic findings of pediatric-type FL suggest the patient will do well with conservative management (e.g., excision alone), Dr. Louissaint noted.
Two sizes do not fit all
The strategies that have improved cancer outcomes since the 1970s for children and older adults have been much less successful for AYAs with cancer.
As an oncologic community, we should not allow the AYA gap to persist. As always, the solutions are likely to involve focused clinical research, education, and communication. Effort will need to be targeted specifically to the AYA population.
Since health-related mortality is high even when cancer-specific outcomes improve, adopting and maintaining a healthy lifestyle must be a key part of the discussion with these young patients.
The biologic differences associated with AYA lymphomas demand participation in clinical trials.
Oncologists should vigorously support removing impediments to the participation of AYAs in prospective clinical trials, stratified (but unrestricted) by age, with careful analysis of patient-reported outcomes, late adverse effects, and biospecimen collection.
As Dr. Kelly noted in the question-and-answer period, the Children’s Oncology Group has an existing biobank of paraffin-embedded tumor samples, DNA from lymphoma specimens, plasma, and sera with clinically annotated data that can be given to investigators upon request and justification.
Going beyond eligibility for clinical trials
Unfortunately, we will likely find that broadening eligibility criteria is the “low-hanging fruit.” There are protocol-, patient-, and physician-related obstacles, according to a review published in Cancer in 2019.
Patient-related obstacles include fear of toxicity, uncertainty about placebos, a steep learning curve for health literacy, insurance-related impediments, and other access-related issues.
Discussions will need to be tailored to the AYA population. Frank, early conversations about fertility, sexuality, financial hardship, career advancement, work-life balance, and cognitive risks may not only facilitate treatment planning but also encourage the trust that is essential for patients to enroll in trials.
The investment in time, multidisciplinary staff and physician involvement, and potential delays in treatment initiation may be painful and inconvenient, but the benefits for long-term health outcomes and personal-professional relationships will be gratifying beyond measure.
Dr. Smith disclosed relationships with Genentech/Roche, Celgene, TGTX, Karyopharm, Janssen, and Bantem. Dr. Roth disclosed relationships with Janssen, ADC Therapeutics, and Celgene. Dr. Kelly and Dr. Louissaint had no financial relationships to disclose.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
In the 1970s, cancer survival was poor for young children and older adults in the United States, as shown by data published in the Journal of the National Cancer Institute.
Great progress has been made since the 1970s, but improvements in outcome have been less impressive for cancer patients aged 15-39 years, as shown by research published in Cancer.
Patients aged 15-39 years have been designated by the National Institutes of Health (NIH) as “adolescents and young adults (AYAs),” and the lag in survival benefit has been termed “the AYA gap.”
The AYA gap persists in lymphoma patients, and an expert panel recently outlined differences between lymphoma in AYAs and lymphoma in other age groups.
The experts spoke at a special session of the AACR Virtual Meeting: Advances in Malignant Lymphoma moderated by Somali M. Smith, MD, of the University of Chicago.
Factors that contribute to the AYA gap
About 89,000 AYAs are diagnosed with cancer each year in the United States, according to data from the National Cancer Institute (NCI). Lymphomas and thyroid cancer are the most common cancers among younger AYAs, aged 15-24 years.
In a report commissioned by the NIH in 2006, many factors contributing to the AYA gap were identified. Chief among them were:
- Limitations in access to care.
- Delayed diagnosis.
- Inconsistency in treatment and follow-up.
- Long-term toxicity (fertility, second malignancies, and cardiovascular disease).
These factors compromise health-related survival, even when cancer-specific survival is improved.
Panelist Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., noted that there are additional unique challenges for AYAs with cancer. These include:
- Pubertal changes.
- Developmental transition to independence.
- Societal impediments such as insurance coverage and disparities in access to specialized centers.
- Psychosocial factors such as health literacy and adherence to treatment and follow-up.
Focusing on lymphoma specifically, Dr. Kelly noted that lymphoma biology differs across the age spectrum and by race and ethnicity. Both tumor and host factors require further study, she said.
Clinical trial access for AYAs
Dr. Kelly emphasized that, unfortunately, clinical research participation is low among AYAs. A major impediment is that adult clinical trials historically required participants to be at least 18 years old.
In addition, there has not been a focused effort to educate AYAs about regulatory safeguards to ensure safety and the promise of enhanced benefit to them in NCI Cancer Trials Network (NCTN) trials. As a result, the refusal rate is high.
A multi-stakeholder workshop, convened in May 2016 by the American Society of Clinical Oncology and Friends of Cancer Research, outlined opportunities for expanding trial eligibility to include children younger than 18 years in first-in-human and other adult cancer clinical trials, enhancing their access to new agents, without compromising safety.
Recently, collaborative efforts between the adult and children’s NCTN research groups have included AYAs in studies addressing cancers that span the age spectrum, including lymphoma.
However, as Dr. Kelly noted, there are differences in AYA lymphoid malignancy types with a transition from more pediatric to more adult types.
Hodgkin lymphoma and primary mediastinal B-cell lymphoma
Panelist Lisa G. Roth, MD, of Weill Cornell Medicine, New York, reviewed the genomic landscape of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL).
Dr. Roth explained that both HL and PMBCL are derived from thymic B cells, predominantly affect the mediastinum, and are CD30-positive lymphomas. Both are characterized by upregulation of JAK/STAT and NF-kappaB as well as overexpression of PD-L1.
Dr. Roth noted that HL is challenging to sequence by standard methods because Reed Sternberg (HRS) cells represent less than 1% of the cellular infiltrate. Recurrently mutated genes in HL cluster by histologic subtype.
Whole-exome sequencing of HRS cells show loss of beta-2 microglobulin and MHC-1 expression, HLA-B, NF-kappaB signaling, and JAK-STAT signaling, according to data published in Blood Advances in 2019.
Dr. Roth’s lab performed immunohistochemistry on tissue microarrays in 145 cases of HL (unpublished data). Results showed that loss of beta-2 microglobulin is more common in younger HL patients. For other alterations, there were too few cases to know.
Dr. Roth’s lab is a member of a pediatric/AYA HL sequencing multi-institutional consortium that has been able to extract DNA and RNA from samples submitted for whole-exome sequencing. The consortium’s goal is to shed light on implications of other genomic alterations that may differ by age in HL patients.
Dr. Roth cited research showing that PMBCL shares molecular alterations similar to those of HL. Alterations in PMBCL suggest dysregulated cellular signaling and immune evasion mechanisms (e.g., deletions in MHC type 1 and 2, beta-2 microglobulin, JAK-STAT, and NF-kappaB mutations) that provide opportunities to study novel agents, according to data published in Blood in 2019.
By early 2021, the S1826 and ANHL1931 studies, which have no age restriction, will be available to AYA lymphoma patients with HL and PMBCL, respectively, Dr. Roth said.
Follicular lymphoma: Clinical features by age
Panelist Abner Louissaint Jr, MD, PhD, of Massachusetts General Hospital in Boston, discussed age-related differences in follicular lymphoma (FL).
He noted that FL typically presents at an advanced stage, with low- or high-grade histology. It is increasingly common in adults in their 50s and 60s, representing 20% of all lymphomas. FL is rare in children and AYAs.
Dr. Louissaint explained that the typical flow cytometric findings in FL are BCL2 translocations, occurring in up to 85%-90% of low-grade and 50% of high-grade cases. The t(14;18)(q32;q21) translocation juxtaposes BCL2 on 18q21 to regulatory sequences and enhances the expression of elements of the Ig heavy chain.
Malignant cells in FL patients express CD20, CD10, CD21, and BCL2 (in contrast to normal germinal centers) and overexpress BCL6 (in contrast to normal follicles), Dr. Louissaint noted. He said the Ki-67 proliferative index of the malignant cells is typically low.
Pediatric-type FL is rare, but case series show clinical, pathologic, and molecular features that are distinctive from adult FL, Dr. Louissaint explained.
He then discussed the features of pediatric-type FL in multiple domains. In the clinical domain, there is a male predilection, and stage tends to be low. There is frequent involvement of nodes of the head and neck region and rare involvement of internal lymph node chains.
Pathologically, the malignant cells appear high grade, with architectural effacement, expansile follicular pattern, large lymphocyte size, and an elevated proliferation index. In contrast to adult FL, malignant cells in pediatric-type FL lack aberrant BCL2 expression.
Most importantly, for pediatric-type FL, the prognosis is excellent with durable remissions after surgical excision, Dr. Louissaint said.
Follicular lymphoma: Molecular features by age
Because of the excellent prognosis in pediatric-type FL, it is important to assess whether young adults with FL have adult-type or pediatric-type lesions, Dr. Louissaint said.
He cited many studies showing differences in adult and pediatric-type FL. In adult FL, the mutational landscape is characterized by frequent chromatin-modifying mutations in genes such as CREBBP, KM22D, and EP300.
In contrast, in pediatric-type FL, there are frequent activating MAPK pathway mutations, including mutations in the negative regulatory domain of MAP2K1. These mutations are not seen in adult FL.
Dr. Louissaint noted that there may be mutations in epigenetic modifiers (CREBBP, TNFRSF14) in both adult and pediatric-type FL. However, CREBBP is very unusual in pediatric-type FL and common in adult FL. This suggests the alterations in pediatric-type FL do not simply represent an early stage of the same disease as adult FL.
Despite a high proliferating fraction and absence of BCL2/BCL6/IRF4 rearrangements in pediatric-type FL, the presence of these features was associated with dramatic difference in progression-free survival, according to research published in Blood in 2012.
A distinct entity
In 2016, the World Health Organization recognized pediatric-type FL as a distinct entity, with the following diagnostic criteria (published in Blood):
- At least partial effacement of nodal architecture, expansile follicles, intermediate-size blastoid cells, and no component of diffuse large B-cell lymphoma.
- Immunohistochemistry showing BCL6 positivity, BCL2 negativity or weak positivity, and a high proliferative fraction.
- Genomic studies showing no BCL2 amplification.
- Clinical features of nodal disease in the head and neck region, early clinical stage, age younger than 40 years, typically in a male with no internal nodes involved.
When FL occurs in AYAs, the diagnostic findings of pediatric-type FL suggest the patient will do well with conservative management (e.g., excision alone), Dr. Louissaint noted.
Two sizes do not fit all
The strategies that have improved cancer outcomes since the 1970s for children and older adults have been much less successful for AYAs with cancer.
As an oncologic community, we should not allow the AYA gap to persist. As always, the solutions are likely to involve focused clinical research, education, and communication. Effort will need to be targeted specifically to the AYA population.
Since health-related mortality is high even when cancer-specific outcomes improve, adopting and maintaining a healthy lifestyle must be a key part of the discussion with these young patients.
The biologic differences associated with AYA lymphomas demand participation in clinical trials.
Oncologists should vigorously support removing impediments to the participation of AYAs in prospective clinical trials, stratified (but unrestricted) by age, with careful analysis of patient-reported outcomes, late adverse effects, and biospecimen collection.
As Dr. Kelly noted in the question-and-answer period, the Children’s Oncology Group has an existing biobank of paraffin-embedded tumor samples, DNA from lymphoma specimens, plasma, and sera with clinically annotated data that can be given to investigators upon request and justification.
Going beyond eligibility for clinical trials
Unfortunately, we will likely find that broadening eligibility criteria is the “low-hanging fruit.” There are protocol-, patient-, and physician-related obstacles, according to a review published in Cancer in 2019.
Patient-related obstacles include fear of toxicity, uncertainty about placebos, a steep learning curve for health literacy, insurance-related impediments, and other access-related issues.
Discussions will need to be tailored to the AYA population. Frank, early conversations about fertility, sexuality, financial hardship, career advancement, work-life balance, and cognitive risks may not only facilitate treatment planning but also encourage the trust that is essential for patients to enroll in trials.
The investment in time, multidisciplinary staff and physician involvement, and potential delays in treatment initiation may be painful and inconvenient, but the benefits for long-term health outcomes and personal-professional relationships will be gratifying beyond measure.
Dr. Smith disclosed relationships with Genentech/Roche, Celgene, TGTX, Karyopharm, Janssen, and Bantem. Dr. Roth disclosed relationships with Janssen, ADC Therapeutics, and Celgene. Dr. Kelly and Dr. Louissaint had no financial relationships to disclose.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
FROM AACR ADVANCES IN MALIGNANT LYMPHOMA 2020
HIT-6 may help track meaningful change in chronic migraine
, recent research suggests.
Using data from the phase 3 PROMISE-2 study, which evaluated intravenous eptinezumab in doses of 100 mg or 300 mg, or placebo every 12 weeks in 1,072 participants for the prevention of chronic migraine, Carrie R. Houts, PhD, director of psychometrics at the Vector Psychometric Group, in Chapel Hill, N.C., and colleagues determined that their finding of 6-point improvement of HIT-6 total score was consistent with other studies. However, they pointed out that little research has been done in evaluating how item-specific scores of HIT-6 impact individuals with chronic migraine. HIT-6 item scores examine whether individuals with headaches experience severe pain, limit their daily activities, have a desire to lie down, feel too tired to do daily activities, felt “fed up or irritated” because of headaches, and feel their headaches limit concentration on work or daily activities.
“The item-specific responder definitions give clinicians and researchers the ability to evaluate and track the impact of headache on specific item-level areas of patients’ lives. These responder definitions provide practical and easily interpreted results that can be used to evaluate treatment benefits over time and to improve clinician-patients communication focus on improvements in key aspects of functioning in individuals with chronic migraine,” Dr. Houts and colleagues wrote in their study, published in the October issue of Headache.
The 6-point value and the 1-2 category improvement values in item-specific scores, they suggested, could be used as a benchmark to help other clinicians and researchers detect meaningful change in individual patients with chronic migraine. Although the user guide for HIT-6 highlights a 5-point change in the total score as clinically meaningful, the authors of the guide do not provide evidence for why the 5-point value signifies clinically meaningful change, they said.
Determining thresholds of clinically meaningful change
In their study, Dr. Houts and colleagues used distribution-based methods to gauge responder values for the HIT-6 total score, while item-specific HIT-6 analyses were measured with Patients’ Global Impression of Change (PGIC), reduction in migraine frequency through monthly migraine days (MMDs), and EuroQol 5 dimensions 5 levels visual analog scale (EQ-5D-5L VAS). The researchers also used HIT-6 values from a literature review and from analyses in PROMISE-2 to calculate “a final chronic migraine-specific responder definition value” between baseline and 12 weeks. Participants in the PROMISE-2 study were mostly women (88.2%) and white (91.0%) with a mean age of 40.5 years.
The literature search revealed responder thresholds for the HIT-6 total score in a range between a decrease of 3 points and 8 points. Within PROMISE-2, the HIT-6 total score responder threshold was found to be between –2.6 and –2.2, which the researchers rounded down to a decrease of 3 points. When taking both sets of responder thresholds into account, the researchers calculated the median responder value as –5.5, which was rounded down to a decrease in 6 points in the HIT-6 total score. “[The estimate] appears most appropriate for discriminating between individuals with chronic migraine who have experienced meaningful change over time and those who have not,” Dr. Houts and colleagues said.
For item-specific HIT-6 scores, the mean score changes were –1 points for categories involving severe pain, limiting activities, lying down, and –2 points for categories involving feeling tired, being fed up or irritated, and limiting concentration.
“Taken together, the current chronic migraine-specific results are consistent with values derived from general headache/migraine samples and suggest that a decrease of 6 points or more on the HIT-6 total score would be considered meaningful to chronic migraine patients,” Dr. Houts and colleagues said. “This would translate to approximately a 4-category change on a single item, change on 2 items of approximately 2 and 3 categories, or a 1-category change on 3 or 4 of the 6 items, depending on the initial category.”
The researchers cautioned that the values outlined in the study “should not be used to determine clinically meaningful difference between treatment groups” and that “future work, similar to that reported here, will identify a chronic migraine-specific clinically meaningful difference between treatment groups value.”
A better measure of chronic migraine?
In an interview, J. D. Bartleson Jr., MD, a retired neurologist with the Mayo Clinic in Rochester, Minn., questioned why HIT-6 criteria was used in the initial PROMISE-2 study. “There is not a lot of difference between the significant and insignificant categories. Chronic migraine may be better measured with pain severity and number of headache days per month,” he said.
,“It may be appropriate to use just 1 or 2 symptoms for evaluating a given patient’s headache burden,” in terms of clinical application of the study for neurologists, Dr. Bartleson said. He emphasized that more research is needed.
This study was funded by H. Lundbeck A/S, which also provided funding of medical writing and editorial support for the manuscript. Three authors report being employees of Vector Psychometric Group at the time of the study, and the company received funding from H. Lundbeck A/S for their time conducting study-related research. Three other authors report relationships with pharmaceutical companies, medical societies, government agencies, and industry related to the study in the form of consultancies, advisory board memberships, honoraria, research support, stock or stock options, and employment. Dr. Bartleson reports no relevant conflicts of interest.
, recent research suggests.
Using data from the phase 3 PROMISE-2 study, which evaluated intravenous eptinezumab in doses of 100 mg or 300 mg, or placebo every 12 weeks in 1,072 participants for the prevention of chronic migraine, Carrie R. Houts, PhD, director of psychometrics at the Vector Psychometric Group, in Chapel Hill, N.C., and colleagues determined that their finding of 6-point improvement of HIT-6 total score was consistent with other studies. However, they pointed out that little research has been done in evaluating how item-specific scores of HIT-6 impact individuals with chronic migraine. HIT-6 item scores examine whether individuals with headaches experience severe pain, limit their daily activities, have a desire to lie down, feel too tired to do daily activities, felt “fed up or irritated” because of headaches, and feel their headaches limit concentration on work or daily activities.
“The item-specific responder definitions give clinicians and researchers the ability to evaluate and track the impact of headache on specific item-level areas of patients’ lives. These responder definitions provide practical and easily interpreted results that can be used to evaluate treatment benefits over time and to improve clinician-patients communication focus on improvements in key aspects of functioning in individuals with chronic migraine,” Dr. Houts and colleagues wrote in their study, published in the October issue of Headache.
The 6-point value and the 1-2 category improvement values in item-specific scores, they suggested, could be used as a benchmark to help other clinicians and researchers detect meaningful change in individual patients with chronic migraine. Although the user guide for HIT-6 highlights a 5-point change in the total score as clinically meaningful, the authors of the guide do not provide evidence for why the 5-point value signifies clinically meaningful change, they said.
Determining thresholds of clinically meaningful change
In their study, Dr. Houts and colleagues used distribution-based methods to gauge responder values for the HIT-6 total score, while item-specific HIT-6 analyses were measured with Patients’ Global Impression of Change (PGIC), reduction in migraine frequency through monthly migraine days (MMDs), and EuroQol 5 dimensions 5 levels visual analog scale (EQ-5D-5L VAS). The researchers also used HIT-6 values from a literature review and from analyses in PROMISE-2 to calculate “a final chronic migraine-specific responder definition value” between baseline and 12 weeks. Participants in the PROMISE-2 study were mostly women (88.2%) and white (91.0%) with a mean age of 40.5 years.
The literature search revealed responder thresholds for the HIT-6 total score in a range between a decrease of 3 points and 8 points. Within PROMISE-2, the HIT-6 total score responder threshold was found to be between –2.6 and –2.2, which the researchers rounded down to a decrease of 3 points. When taking both sets of responder thresholds into account, the researchers calculated the median responder value as –5.5, which was rounded down to a decrease in 6 points in the HIT-6 total score. “[The estimate] appears most appropriate for discriminating between individuals with chronic migraine who have experienced meaningful change over time and those who have not,” Dr. Houts and colleagues said.
For item-specific HIT-6 scores, the mean score changes were –1 points for categories involving severe pain, limiting activities, lying down, and –2 points for categories involving feeling tired, being fed up or irritated, and limiting concentration.
“Taken together, the current chronic migraine-specific results are consistent with values derived from general headache/migraine samples and suggest that a decrease of 6 points or more on the HIT-6 total score would be considered meaningful to chronic migraine patients,” Dr. Houts and colleagues said. “This would translate to approximately a 4-category change on a single item, change on 2 items of approximately 2 and 3 categories, or a 1-category change on 3 or 4 of the 6 items, depending on the initial category.”
The researchers cautioned that the values outlined in the study “should not be used to determine clinically meaningful difference between treatment groups” and that “future work, similar to that reported here, will identify a chronic migraine-specific clinically meaningful difference between treatment groups value.”
A better measure of chronic migraine?
In an interview, J. D. Bartleson Jr., MD, a retired neurologist with the Mayo Clinic in Rochester, Minn., questioned why HIT-6 criteria was used in the initial PROMISE-2 study. “There is not a lot of difference between the significant and insignificant categories. Chronic migraine may be better measured with pain severity and number of headache days per month,” he said.
,“It may be appropriate to use just 1 or 2 symptoms for evaluating a given patient’s headache burden,” in terms of clinical application of the study for neurologists, Dr. Bartleson said. He emphasized that more research is needed.
This study was funded by H. Lundbeck A/S, which also provided funding of medical writing and editorial support for the manuscript. Three authors report being employees of Vector Psychometric Group at the time of the study, and the company received funding from H. Lundbeck A/S for their time conducting study-related research. Three other authors report relationships with pharmaceutical companies, medical societies, government agencies, and industry related to the study in the form of consultancies, advisory board memberships, honoraria, research support, stock or stock options, and employment. Dr. Bartleson reports no relevant conflicts of interest.
, recent research suggests.
Using data from the phase 3 PROMISE-2 study, which evaluated intravenous eptinezumab in doses of 100 mg or 300 mg, or placebo every 12 weeks in 1,072 participants for the prevention of chronic migraine, Carrie R. Houts, PhD, director of psychometrics at the Vector Psychometric Group, in Chapel Hill, N.C., and colleagues determined that their finding of 6-point improvement of HIT-6 total score was consistent with other studies. However, they pointed out that little research has been done in evaluating how item-specific scores of HIT-6 impact individuals with chronic migraine. HIT-6 item scores examine whether individuals with headaches experience severe pain, limit their daily activities, have a desire to lie down, feel too tired to do daily activities, felt “fed up or irritated” because of headaches, and feel their headaches limit concentration on work or daily activities.
“The item-specific responder definitions give clinicians and researchers the ability to evaluate and track the impact of headache on specific item-level areas of patients’ lives. These responder definitions provide practical and easily interpreted results that can be used to evaluate treatment benefits over time and to improve clinician-patients communication focus on improvements in key aspects of functioning in individuals with chronic migraine,” Dr. Houts and colleagues wrote in their study, published in the October issue of Headache.
The 6-point value and the 1-2 category improvement values in item-specific scores, they suggested, could be used as a benchmark to help other clinicians and researchers detect meaningful change in individual patients with chronic migraine. Although the user guide for HIT-6 highlights a 5-point change in the total score as clinically meaningful, the authors of the guide do not provide evidence for why the 5-point value signifies clinically meaningful change, they said.
Determining thresholds of clinically meaningful change
In their study, Dr. Houts and colleagues used distribution-based methods to gauge responder values for the HIT-6 total score, while item-specific HIT-6 analyses were measured with Patients’ Global Impression of Change (PGIC), reduction in migraine frequency through monthly migraine days (MMDs), and EuroQol 5 dimensions 5 levels visual analog scale (EQ-5D-5L VAS). The researchers also used HIT-6 values from a literature review and from analyses in PROMISE-2 to calculate “a final chronic migraine-specific responder definition value” between baseline and 12 weeks. Participants in the PROMISE-2 study were mostly women (88.2%) and white (91.0%) with a mean age of 40.5 years.
The literature search revealed responder thresholds for the HIT-6 total score in a range between a decrease of 3 points and 8 points. Within PROMISE-2, the HIT-6 total score responder threshold was found to be between –2.6 and –2.2, which the researchers rounded down to a decrease of 3 points. When taking both sets of responder thresholds into account, the researchers calculated the median responder value as –5.5, which was rounded down to a decrease in 6 points in the HIT-6 total score. “[The estimate] appears most appropriate for discriminating between individuals with chronic migraine who have experienced meaningful change over time and those who have not,” Dr. Houts and colleagues said.
For item-specific HIT-6 scores, the mean score changes were –1 points for categories involving severe pain, limiting activities, lying down, and –2 points for categories involving feeling tired, being fed up or irritated, and limiting concentration.
“Taken together, the current chronic migraine-specific results are consistent with values derived from general headache/migraine samples and suggest that a decrease of 6 points or more on the HIT-6 total score would be considered meaningful to chronic migraine patients,” Dr. Houts and colleagues said. “This would translate to approximately a 4-category change on a single item, change on 2 items of approximately 2 and 3 categories, or a 1-category change on 3 or 4 of the 6 items, depending on the initial category.”
The researchers cautioned that the values outlined in the study “should not be used to determine clinically meaningful difference between treatment groups” and that “future work, similar to that reported here, will identify a chronic migraine-specific clinically meaningful difference between treatment groups value.”
A better measure of chronic migraine?
In an interview, J. D. Bartleson Jr., MD, a retired neurologist with the Mayo Clinic in Rochester, Minn., questioned why HIT-6 criteria was used in the initial PROMISE-2 study. “There is not a lot of difference between the significant and insignificant categories. Chronic migraine may be better measured with pain severity and number of headache days per month,” he said.
,“It may be appropriate to use just 1 or 2 symptoms for evaluating a given patient’s headache burden,” in terms of clinical application of the study for neurologists, Dr. Bartleson said. He emphasized that more research is needed.
This study was funded by H. Lundbeck A/S, which also provided funding of medical writing and editorial support for the manuscript. Three authors report being employees of Vector Psychometric Group at the time of the study, and the company received funding from H. Lundbeck A/S for their time conducting study-related research. Three other authors report relationships with pharmaceutical companies, medical societies, government agencies, and industry related to the study in the form of consultancies, advisory board memberships, honoraria, research support, stock or stock options, and employment. Dr. Bartleson reports no relevant conflicts of interest.
FROM HEADACHE
Migraine nerve stimulation device now available over the counter
The Food and Drug Administration has cleared Cefaly Dual (Cefaly Technology) which was previously available only by prescription.
Most migraines involve the trigeminal nerve, which can be accessed through the skin on the forehead. Cefaly Dual stimulates the trigeminal nerve using a reusable self-adhesive electrode placed on the forehead.
The device has two settings, ACUTE and PREVENT. In the ACUTE setting, the individual wears the device for 60 minutes at headache onset or during a migraine attack. In the PREVENT setting, the individual wears the device for 20 minutes daily to help prevent future episodes.
At the start of a session, the wearer may feel a slight tingling sensation, which gradually increases and spreads throughout the forehead and the front part of the head. After about 14 minutes, the intensity stabilizes and remains constant until the treatment session is over, according to the company. The device automatically shuts off at the end of each session. It can be used as a stand-alone option or with existing treatment, the company noted.
“For millions of people across the U.S., living with migraine pain and coping with debilitating symptoms are daily realities. It is our mission to provide consumers with increased access to an effective and safe dual modality migraine treatment that is scientifically proven to reduce the number of monthly migraine days by almost half,” Jennifer Trainor McDermott, CEO of Cefaly Technology, said in a news release.
The FDA’s over-the-counter clearance of Cefaly Dual was based on several randomized, controlled clinical trials supporting the efficacy and safety of the device, the company said.
An earlier version of the Cefaly device was approved in the United States in March 2014 to help prevent migraine headache in adults aged 18 or older. The next-generation Cefaly Dual device is “small and sleek in comparison to its older model, which uses bands along the sides to create room for batteries. The newest device is palm-sized, more portable, and uses a battery that is rechargeable via USB,” the company said.
Last spring, the company announced a buyback program where customers in the United States may return their original device and receive a discount of the purchase of the Cefaly Dual device.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has cleared Cefaly Dual (Cefaly Technology) which was previously available only by prescription.
Most migraines involve the trigeminal nerve, which can be accessed through the skin on the forehead. Cefaly Dual stimulates the trigeminal nerve using a reusable self-adhesive electrode placed on the forehead.
The device has two settings, ACUTE and PREVENT. In the ACUTE setting, the individual wears the device for 60 minutes at headache onset or during a migraine attack. In the PREVENT setting, the individual wears the device for 20 minutes daily to help prevent future episodes.
At the start of a session, the wearer may feel a slight tingling sensation, which gradually increases and spreads throughout the forehead and the front part of the head. After about 14 minutes, the intensity stabilizes and remains constant until the treatment session is over, according to the company. The device automatically shuts off at the end of each session. It can be used as a stand-alone option or with existing treatment, the company noted.
“For millions of people across the U.S., living with migraine pain and coping with debilitating symptoms are daily realities. It is our mission to provide consumers with increased access to an effective and safe dual modality migraine treatment that is scientifically proven to reduce the number of monthly migraine days by almost half,” Jennifer Trainor McDermott, CEO of Cefaly Technology, said in a news release.
The FDA’s over-the-counter clearance of Cefaly Dual was based on several randomized, controlled clinical trials supporting the efficacy and safety of the device, the company said.
An earlier version of the Cefaly device was approved in the United States in March 2014 to help prevent migraine headache in adults aged 18 or older. The next-generation Cefaly Dual device is “small and sleek in comparison to its older model, which uses bands along the sides to create room for batteries. The newest device is palm-sized, more portable, and uses a battery that is rechargeable via USB,” the company said.
Last spring, the company announced a buyback program where customers in the United States may return their original device and receive a discount of the purchase of the Cefaly Dual device.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration has cleared Cefaly Dual (Cefaly Technology) which was previously available only by prescription.
Most migraines involve the trigeminal nerve, which can be accessed through the skin on the forehead. Cefaly Dual stimulates the trigeminal nerve using a reusable self-adhesive electrode placed on the forehead.
The device has two settings, ACUTE and PREVENT. In the ACUTE setting, the individual wears the device for 60 minutes at headache onset or during a migraine attack. In the PREVENT setting, the individual wears the device for 20 minutes daily to help prevent future episodes.
At the start of a session, the wearer may feel a slight tingling sensation, which gradually increases and spreads throughout the forehead and the front part of the head. After about 14 minutes, the intensity stabilizes and remains constant until the treatment session is over, according to the company. The device automatically shuts off at the end of each session. It can be used as a stand-alone option or with existing treatment, the company noted.
“For millions of people across the U.S., living with migraine pain and coping with debilitating symptoms are daily realities. It is our mission to provide consumers with increased access to an effective and safe dual modality migraine treatment that is scientifically proven to reduce the number of monthly migraine days by almost half,” Jennifer Trainor McDermott, CEO of Cefaly Technology, said in a news release.
The FDA’s over-the-counter clearance of Cefaly Dual was based on several randomized, controlled clinical trials supporting the efficacy and safety of the device, the company said.
An earlier version of the Cefaly device was approved in the United States in March 2014 to help prevent migraine headache in adults aged 18 or older. The next-generation Cefaly Dual device is “small and sleek in comparison to its older model, which uses bands along the sides to create room for batteries. The newest device is palm-sized, more portable, and uses a battery that is rechargeable via USB,” the company said.
Last spring, the company announced a buyback program where customers in the United States may return their original device and receive a discount of the purchase of the Cefaly Dual device.
A version of this article originally appeared on Medscape.com.
Seven things to know about new lymphoma drug tafasitamab
The Food and Drug Administration recently approved tafasitamab-cxix (Monjuvi) in combination with lenalidomide for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT).
In an interview, Ann S. LaCasce, MD, a lymphoma specialist, associate professor of medicine at Harvard Medical School, and director of the Dana-Farber/Massachusetts General Brigham fellowship in hematology/oncology, discussed the drug and its approval:
Question: How common is relapsed or refractory DLBCL? Have there been any changes in the rates of this disease in recent years?
Dr. LaCasce: Approximately 40% of patients with DLBCL will have relapsed or refractory disease. The rates of lymphoma have been rising over the past several decades for unclear reasons. As this is a disease predominantly of older adults, increasing life expectancy likely plays a role. Environmental factors may also be contributing.
Q: How long do patients with relapsed or refractory DLBCL who are not eligible for stem cell transplant usually survive?
Dr. LaCasce: This is highly variable, though it’s estimated to be approximately 1 year. Some patients will be cured with autologous transplantation or CAR-T cells. The pace of the disease can be highly variable, with some patients responding to multiple lines of therapy whereas others may have rapidly progressive refractory disease.
Q: What makes patients with relapsed or refractory DLBCL ineligible for ASCT?
Dr. LaCasce: To be eligible, patients need to be younger than 70-75 years or so without significant comorbidities and must have chemotherapy-responsive disease. More than half of patients will not fit these criteria.
Q: Can you briefly describe the L-MIND study that led to the approval of tafasitamab-cxix?
Dr. LaCasce: This was a single-arm, phase 2 study of tafasitamab plus lenalidomide in patients with relapsed/refractory DLBCL status after one to three prior regimens who were not candidates for ASCT. Patients received tafasitamab until progression and up to 1 year of lenalidomide. The median age was 72 years, and 50% of patients had received only one prior line of therapy.
The overall and complete response rates in 80 patients treated were 60% and 43%, respectively. The median progression-free survival was approximately 1 year. Nearly half of patients required dose reduction of lenalidomide, and about a quarter discontinued the drug. Twenty-five percent of patients discontinued therapy for adverse events.
Q: What’s the toxicity profile of tafasitamab-cxix?
Dr. LaCasce: The most common adverse events were infusion reactions and myelosuppression, which are managed with standard approaches to incident rate ratios with steroids, antihistamines, etc. Myelosuppression can occur, but in this combination is mostly driven by lenalidomide, which is dose reduced or discontinued.
Q: Where does tafasitamab-cxix fit in the treatment paradigm for relapsed or refractory DLBCL? How does it compare with other available options?
Dr. LaCasce: This is an option for patients who are not candidates for potentially curative approaches, including ASCT and CAR T-cell therapy. There are patients not eligible for ASCT who may be appropriate for CAR-T.
Tafasitamab plus lenalidomide requires frequent visits, particularly during the first 3 months, and then every other week until progression. The dose of lenalidomide will not be tolerable for many of these patients.
Other options in this population include polatuzumab plus bendamustine/rituximab or possibly selinexor. The former has similar activity and is time limited, though many patients will not tolerate the full dose of bendamustine. In the study leading to approval, selinexor had a much lower response rate of approximately 30%, and the patient population was much more favorable, given that eligibility required 60-98 days after last therapy before enrolling.
The only approval specific for nontransplant patients is tafasitamab/lenalidomide.
Q: From a cost standpoint, how does tafasitamab compare with other options in this patient population?
Dr. LaCasce: I don’t have exact figures, but all options are very expensive. CAR-T is the most expensive. Given the ongoing therapy of tafasitamab until progression, the cumulative cost could be very high. Polatuzumab plus bendamustine/rituximab and selinexor are also very costly.
Q: What other drugs are in development for relapsed or refractory DLBCL?
Dr. LaCasce: Novel CAR T-cell therapies, including lisocabtagene maraleucel that is at the FDA, are in development. Bispecific antibodies (REGN1979 and mosunetuzumab), combinations with CD47 antibodies, and loncastuximab tesirine are all in phase 2 trials.
Dr. LaCasce has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration recently approved tafasitamab-cxix (Monjuvi) in combination with lenalidomide for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT).
In an interview, Ann S. LaCasce, MD, a lymphoma specialist, associate professor of medicine at Harvard Medical School, and director of the Dana-Farber/Massachusetts General Brigham fellowship in hematology/oncology, discussed the drug and its approval:
Question: How common is relapsed or refractory DLBCL? Have there been any changes in the rates of this disease in recent years?
Dr. LaCasce: Approximately 40% of patients with DLBCL will have relapsed or refractory disease. The rates of lymphoma have been rising over the past several decades for unclear reasons. As this is a disease predominantly of older adults, increasing life expectancy likely plays a role. Environmental factors may also be contributing.
Q: How long do patients with relapsed or refractory DLBCL who are not eligible for stem cell transplant usually survive?
Dr. LaCasce: This is highly variable, though it’s estimated to be approximately 1 year. Some patients will be cured with autologous transplantation or CAR-T cells. The pace of the disease can be highly variable, with some patients responding to multiple lines of therapy whereas others may have rapidly progressive refractory disease.
Q: What makes patients with relapsed or refractory DLBCL ineligible for ASCT?
Dr. LaCasce: To be eligible, patients need to be younger than 70-75 years or so without significant comorbidities and must have chemotherapy-responsive disease. More than half of patients will not fit these criteria.
Q: Can you briefly describe the L-MIND study that led to the approval of tafasitamab-cxix?
Dr. LaCasce: This was a single-arm, phase 2 study of tafasitamab plus lenalidomide in patients with relapsed/refractory DLBCL status after one to three prior regimens who were not candidates for ASCT. Patients received tafasitamab until progression and up to 1 year of lenalidomide. The median age was 72 years, and 50% of patients had received only one prior line of therapy.
The overall and complete response rates in 80 patients treated were 60% and 43%, respectively. The median progression-free survival was approximately 1 year. Nearly half of patients required dose reduction of lenalidomide, and about a quarter discontinued the drug. Twenty-five percent of patients discontinued therapy for adverse events.
Q: What’s the toxicity profile of tafasitamab-cxix?
Dr. LaCasce: The most common adverse events were infusion reactions and myelosuppression, which are managed with standard approaches to incident rate ratios with steroids, antihistamines, etc. Myelosuppression can occur, but in this combination is mostly driven by lenalidomide, which is dose reduced or discontinued.
Q: Where does tafasitamab-cxix fit in the treatment paradigm for relapsed or refractory DLBCL? How does it compare with other available options?
Dr. LaCasce: This is an option for patients who are not candidates for potentially curative approaches, including ASCT and CAR T-cell therapy. There are patients not eligible for ASCT who may be appropriate for CAR-T.
Tafasitamab plus lenalidomide requires frequent visits, particularly during the first 3 months, and then every other week until progression. The dose of lenalidomide will not be tolerable for many of these patients.
Other options in this population include polatuzumab plus bendamustine/rituximab or possibly selinexor. The former has similar activity and is time limited, though many patients will not tolerate the full dose of bendamustine. In the study leading to approval, selinexor had a much lower response rate of approximately 30%, and the patient population was much more favorable, given that eligibility required 60-98 days after last therapy before enrolling.
The only approval specific for nontransplant patients is tafasitamab/lenalidomide.
Q: From a cost standpoint, how does tafasitamab compare with other options in this patient population?
Dr. LaCasce: I don’t have exact figures, but all options are very expensive. CAR-T is the most expensive. Given the ongoing therapy of tafasitamab until progression, the cumulative cost could be very high. Polatuzumab plus bendamustine/rituximab and selinexor are also very costly.
Q: What other drugs are in development for relapsed or refractory DLBCL?
Dr. LaCasce: Novel CAR T-cell therapies, including lisocabtagene maraleucel that is at the FDA, are in development. Bispecific antibodies (REGN1979 and mosunetuzumab), combinations with CD47 antibodies, and loncastuximab tesirine are all in phase 2 trials.
Dr. LaCasce has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The Food and Drug Administration recently approved tafasitamab-cxix (Monjuvi) in combination with lenalidomide for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT).
In an interview, Ann S. LaCasce, MD, a lymphoma specialist, associate professor of medicine at Harvard Medical School, and director of the Dana-Farber/Massachusetts General Brigham fellowship in hematology/oncology, discussed the drug and its approval:
Question: How common is relapsed or refractory DLBCL? Have there been any changes in the rates of this disease in recent years?
Dr. LaCasce: Approximately 40% of patients with DLBCL will have relapsed or refractory disease. The rates of lymphoma have been rising over the past several decades for unclear reasons. As this is a disease predominantly of older adults, increasing life expectancy likely plays a role. Environmental factors may also be contributing.
Q: How long do patients with relapsed or refractory DLBCL who are not eligible for stem cell transplant usually survive?
Dr. LaCasce: This is highly variable, though it’s estimated to be approximately 1 year. Some patients will be cured with autologous transplantation or CAR-T cells. The pace of the disease can be highly variable, with some patients responding to multiple lines of therapy whereas others may have rapidly progressive refractory disease.
Q: What makes patients with relapsed or refractory DLBCL ineligible for ASCT?
Dr. LaCasce: To be eligible, patients need to be younger than 70-75 years or so without significant comorbidities and must have chemotherapy-responsive disease. More than half of patients will not fit these criteria.
Q: Can you briefly describe the L-MIND study that led to the approval of tafasitamab-cxix?
Dr. LaCasce: This was a single-arm, phase 2 study of tafasitamab plus lenalidomide in patients with relapsed/refractory DLBCL status after one to three prior regimens who were not candidates for ASCT. Patients received tafasitamab until progression and up to 1 year of lenalidomide. The median age was 72 years, and 50% of patients had received only one prior line of therapy.
The overall and complete response rates in 80 patients treated were 60% and 43%, respectively. The median progression-free survival was approximately 1 year. Nearly half of patients required dose reduction of lenalidomide, and about a quarter discontinued the drug. Twenty-five percent of patients discontinued therapy for adverse events.
Q: What’s the toxicity profile of tafasitamab-cxix?
Dr. LaCasce: The most common adverse events were infusion reactions and myelosuppression, which are managed with standard approaches to incident rate ratios with steroids, antihistamines, etc. Myelosuppression can occur, but in this combination is mostly driven by lenalidomide, which is dose reduced or discontinued.
Q: Where does tafasitamab-cxix fit in the treatment paradigm for relapsed or refractory DLBCL? How does it compare with other available options?
Dr. LaCasce: This is an option for patients who are not candidates for potentially curative approaches, including ASCT and CAR T-cell therapy. There are patients not eligible for ASCT who may be appropriate for CAR-T.
Tafasitamab plus lenalidomide requires frequent visits, particularly during the first 3 months, and then every other week until progression. The dose of lenalidomide will not be tolerable for many of these patients.
Other options in this population include polatuzumab plus bendamustine/rituximab or possibly selinexor. The former has similar activity and is time limited, though many patients will not tolerate the full dose of bendamustine. In the study leading to approval, selinexor had a much lower response rate of approximately 30%, and the patient population was much more favorable, given that eligibility required 60-98 days after last therapy before enrolling.
The only approval specific for nontransplant patients is tafasitamab/lenalidomide.
Q: From a cost standpoint, how does tafasitamab compare with other options in this patient population?
Dr. LaCasce: I don’t have exact figures, but all options are very expensive. CAR-T is the most expensive. Given the ongoing therapy of tafasitamab until progression, the cumulative cost could be very high. Polatuzumab plus bendamustine/rituximab and selinexor are also very costly.
Q: What other drugs are in development for relapsed or refractory DLBCL?
Dr. LaCasce: Novel CAR T-cell therapies, including lisocabtagene maraleucel that is at the FDA, are in development. Bispecific antibodies (REGN1979 and mosunetuzumab), combinations with CD47 antibodies, and loncastuximab tesirine are all in phase 2 trials.
Dr. LaCasce has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Biomarker in the eye may flag neurodegeneration risk
, opening the door to a potential new method of predicting neurodegenerative disease, new research suggests.
In a study of 77 patients undergoing eye surgery for various conditions, more than 70% had more than 20 pg/mL of NfL in their vitreous humor. Higher levels of NfL were associated with higher levels of other biomarkers known to be associated with Alzheimer’s disease, including amyloid-beta and tau proteins.
“The study had three primary findings,” said lead author Manju L. Subramanian, MD, associate professor of ophthalmology at Boston University.
First, the investigators were able to detect levels of NfL in eye fluid; and second, those levels were not in any way correlated to the patient’s clinical eye condition, Dr. Subramanian said. “The third finding was that we were able to correlate those neurofilament light levels with other markers that have been known to be associated with conditions such as Alzheimer’s disease,” she noted.
For Dr. Subramanian, these findings add to the hypothesis that the eye is an extension of the brain. “This is further evidence that the eye might potentially be a proxy for neurodegenerative diseases,” she said. “So finding neurofilament light chain in the eye demonstrates that the eye is not an isolated organ, and things that happen in the body can affect the eye and vice versa.”
The findings were published online Sept. 17 in Alzheimer’s Research & Therapy.
Verge of clinical applicability?
Early diagnosis of neurodegenerative diseases remains a challenge, the investigators noted. As such, there is a palpable need for reliable biomarkers that can help with early diagnosis, prognostic assessment, and measurable response to treatment for Alzheimer’s disease and other neurologic disorders
Recent research has identified NfL as a potential screening tool and some researchers believe it to be on the verge of clinical applicability. In addition, increased levels of the biomarker have been observed in both the cerebrospinal fluid (CSF) and blood of individuals with neurodegeneration and neurological diseases, including Alzheimer’s disease. In previous studies, for example, elevated levels of NfL in CSF and blood have been shown to reliably distinguish between patients with Alzheimer’s disease and healthy volunteers.
Because certain eye diseases have been associated with Alzheimer’s disease in epidemiological studies, they may share common risk factors and pathological mechanisms at the molecular level, the researchers noted. In an earlier study, the current investigators found that cognitive function among patients with eye disease was significantly associated with amyloid-beta and total tau protein levels in the vitreous humor.
Given these connections, the researchers hypothesized that NfL could be identified in the vitreous humor and may be associated with other relevant biomarkers of neuronal origin. “Neurofilament light chain is detectable in the cerebrospinal fluid, but it’s never been tested for detection in the eye,” Dr. Subramanian noted.
In total, vitreous humor samples were collected from 77 unique participants (mean age, 56.2 years; 63% men) as part of the single-center, prospective, cross-sectional cohort study. The researchers aspirated 0.5 to 1.0 ml of undiluted vitreous fluid during vitrectomy, while whole blood was drawn for APOE genotyping.
Immunoassay was used to quantitatively measure for NfL, amyloid-beta, total tau, phosphorylated tau 181 (p-tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous humor. The trial’s primary outcome measures were the detection of NfL levels in the vitreous humor, as well as its associations with other proteins.
Significant correlations
Results showed that 55 of the 77 participants (71.4%) had at least 20 pg/ml of NfL protein present in the vitreous humor. The median level was 68.65 pg/ml. Statistically significant associations were found between NfL levels in the vitreous humor and Abeta40, Abeta42, and total tau; higher NfL levels were associated with higher levels of all three biomarkers. On the other hand, NfL levels were not positively associated with increased vitreous levels of p-tau181.
Vitreous NfL concentration was significantly associated with inflammatory cytokines, including interleukin-15, interleukin-16, and monocyte chemoattractant protein-1, as well as vascular proteins such as vascular endothelial growth factor receptor-1, VEGF-C, vascular cell adhesion molecule-1, Tie-2, and intracellular adhesion molecular-1.
Despite these findings, NfL in the vitreous humor was not associated with patients’ clinical ophthalmic conditions or systemic diseases such as hypertension, diabetes, and hyperlipidemia. Similarly, NfL was not significantly associated with APOE genotype E2 and E4, the alleles most commonly associated with Alzheimer’s disease.
Finally, no statistically significant associations were found between NfL and Mini-Mental State Examination (MMSE) scores.
A “first step”
Most research currently examining the role of the eye in neurodegenerative disease is focused on retinal biomarkers imaged by optical coherence tomography, the investigators noted. Although promising, data obtained this way have yielded conflicting results.
Similarly, while the diagnostic potential of the core CSF biomarkers for AD (Abeta40, Abeta42, p-tau, and total tau) is well established, the practical utility of testing CSF for neurodegenerative diseases is limited, wrote the researchers.
As such, an additional biomarker source such as NfL–which is quantifiable and protein-based within eye fluid – has the potential to play an important role in predicting neurodegenerative disease in the clinical setting, they added.
“The holy grail of neurodegenerative-disease diagnosis is early diagnosis. Because if you can implement treatment early, you can slow down and potentially halt the progression of these diseases,” Dr. Subramanian said.
“This study is the first step toward determining if the eye could play a potential role in early diagnosis of conditions such as Alzheimer’s disease,” she added.
That said, Dr. Subramanian was quick to recognize the findings’ preliminary nature and that they do not offer reliable evidence that vitreous NfL levels definitively represent neurodegeneration. As such, the investigators called for more research to validate the association between this type of biomarker with other established biomarkers of neurodegeneration, such as those found in CSF fluid or on MRI and PET scans.
“At this point, we can’t look at eye fluid and say that people have neurodegenerative diseases,” she noted. “The other thing to consider is that vitreous humor is at the back of the eye, so it’s actually a fairly invasive procedure.
“I think the next step is to look at other types of eye fluids such as the aqueous fluid in the front of the eye, or even tear secretions, potentially,” Dr. Subramanian said.
Other study limitations include the lack of an association between NfL levels and MMSE scores and that none of the study participants were actually diagnosed with Alzheimer’s disease. Validation studies are needed to compare vitreous levels of NfL in patients with mild cognitive impairment/AD to normal controls, the investigators noted.
Fascinating but impractical?
Commenting on the findings, Sharon Fekrat, MD, professor of ophthalmology, Duke University, Durham, N.C., agreed that there’s potential importance of the eye in diagnosing neurodegeneration. However, she suggested that vitreous humor may not be the most expedient medium to use.
“I commend the authors for this fascinating work. But practically speaking, if we ultimately want to use intraocular fluid to diagnose Alzheimer’s and perhaps other neurodegeneration, I think aqueous humor might be more practical than the vitreous humor,” said Dr. Fekrat, who was not involved with the research. “What might be even better is to have a device that can be held against the eyeball that measures the levels of various substances inside the eyeball without having to enter the eye,” added Justin Ma, a Duke University medical student working under Dr. Fekrat’s guidance. “It could be similar technology to what’s currently used to measure blood glucose levels,” Mr. Ma added.
The study was supported in part by the National Institute of Aging. Dr. Subramanian, Dr. Fekrat, and Mr. Ma have disclosed no relevant financial relationships. Disclosures for other study authors are listed in the original article.
A version of this article originally appeared on Medscape.com.
, opening the door to a potential new method of predicting neurodegenerative disease, new research suggests.
In a study of 77 patients undergoing eye surgery for various conditions, more than 70% had more than 20 pg/mL of NfL in their vitreous humor. Higher levels of NfL were associated with higher levels of other biomarkers known to be associated with Alzheimer’s disease, including amyloid-beta and tau proteins.
“The study had three primary findings,” said lead author Manju L. Subramanian, MD, associate professor of ophthalmology at Boston University.
First, the investigators were able to detect levels of NfL in eye fluid; and second, those levels were not in any way correlated to the patient’s clinical eye condition, Dr. Subramanian said. “The third finding was that we were able to correlate those neurofilament light levels with other markers that have been known to be associated with conditions such as Alzheimer’s disease,” she noted.
For Dr. Subramanian, these findings add to the hypothesis that the eye is an extension of the brain. “This is further evidence that the eye might potentially be a proxy for neurodegenerative diseases,” she said. “So finding neurofilament light chain in the eye demonstrates that the eye is not an isolated organ, and things that happen in the body can affect the eye and vice versa.”
The findings were published online Sept. 17 in Alzheimer’s Research & Therapy.
Verge of clinical applicability?
Early diagnosis of neurodegenerative diseases remains a challenge, the investigators noted. As such, there is a palpable need for reliable biomarkers that can help with early diagnosis, prognostic assessment, and measurable response to treatment for Alzheimer’s disease and other neurologic disorders
Recent research has identified NfL as a potential screening tool and some researchers believe it to be on the verge of clinical applicability. In addition, increased levels of the biomarker have been observed in both the cerebrospinal fluid (CSF) and blood of individuals with neurodegeneration and neurological diseases, including Alzheimer’s disease. In previous studies, for example, elevated levels of NfL in CSF and blood have been shown to reliably distinguish between patients with Alzheimer’s disease and healthy volunteers.
Because certain eye diseases have been associated with Alzheimer’s disease in epidemiological studies, they may share common risk factors and pathological mechanisms at the molecular level, the researchers noted. In an earlier study, the current investigators found that cognitive function among patients with eye disease was significantly associated with amyloid-beta and total tau protein levels in the vitreous humor.
Given these connections, the researchers hypothesized that NfL could be identified in the vitreous humor and may be associated with other relevant biomarkers of neuronal origin. “Neurofilament light chain is detectable in the cerebrospinal fluid, but it’s never been tested for detection in the eye,” Dr. Subramanian noted.
In total, vitreous humor samples were collected from 77 unique participants (mean age, 56.2 years; 63% men) as part of the single-center, prospective, cross-sectional cohort study. The researchers aspirated 0.5 to 1.0 ml of undiluted vitreous fluid during vitrectomy, while whole blood was drawn for APOE genotyping.
Immunoassay was used to quantitatively measure for NfL, amyloid-beta, total tau, phosphorylated tau 181 (p-tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous humor. The trial’s primary outcome measures were the detection of NfL levels in the vitreous humor, as well as its associations with other proteins.
Significant correlations
Results showed that 55 of the 77 participants (71.4%) had at least 20 pg/ml of NfL protein present in the vitreous humor. The median level was 68.65 pg/ml. Statistically significant associations were found between NfL levels in the vitreous humor and Abeta40, Abeta42, and total tau; higher NfL levels were associated with higher levels of all three biomarkers. On the other hand, NfL levels were not positively associated with increased vitreous levels of p-tau181.
Vitreous NfL concentration was significantly associated with inflammatory cytokines, including interleukin-15, interleukin-16, and monocyte chemoattractant protein-1, as well as vascular proteins such as vascular endothelial growth factor receptor-1, VEGF-C, vascular cell adhesion molecule-1, Tie-2, and intracellular adhesion molecular-1.
Despite these findings, NfL in the vitreous humor was not associated with patients’ clinical ophthalmic conditions or systemic diseases such as hypertension, diabetes, and hyperlipidemia. Similarly, NfL was not significantly associated with APOE genotype E2 and E4, the alleles most commonly associated with Alzheimer’s disease.
Finally, no statistically significant associations were found between NfL and Mini-Mental State Examination (MMSE) scores.
A “first step”
Most research currently examining the role of the eye in neurodegenerative disease is focused on retinal biomarkers imaged by optical coherence tomography, the investigators noted. Although promising, data obtained this way have yielded conflicting results.
Similarly, while the diagnostic potential of the core CSF biomarkers for AD (Abeta40, Abeta42, p-tau, and total tau) is well established, the practical utility of testing CSF for neurodegenerative diseases is limited, wrote the researchers.
As such, an additional biomarker source such as NfL–which is quantifiable and protein-based within eye fluid – has the potential to play an important role in predicting neurodegenerative disease in the clinical setting, they added.
“The holy grail of neurodegenerative-disease diagnosis is early diagnosis. Because if you can implement treatment early, you can slow down and potentially halt the progression of these diseases,” Dr. Subramanian said.
“This study is the first step toward determining if the eye could play a potential role in early diagnosis of conditions such as Alzheimer’s disease,” she added.
That said, Dr. Subramanian was quick to recognize the findings’ preliminary nature and that they do not offer reliable evidence that vitreous NfL levels definitively represent neurodegeneration. As such, the investigators called for more research to validate the association between this type of biomarker with other established biomarkers of neurodegeneration, such as those found in CSF fluid or on MRI and PET scans.
“At this point, we can’t look at eye fluid and say that people have neurodegenerative diseases,” she noted. “The other thing to consider is that vitreous humor is at the back of the eye, so it’s actually a fairly invasive procedure.
“I think the next step is to look at other types of eye fluids such as the aqueous fluid in the front of the eye, or even tear secretions, potentially,” Dr. Subramanian said.
Other study limitations include the lack of an association between NfL levels and MMSE scores and that none of the study participants were actually diagnosed with Alzheimer’s disease. Validation studies are needed to compare vitreous levels of NfL in patients with mild cognitive impairment/AD to normal controls, the investigators noted.
Fascinating but impractical?
Commenting on the findings, Sharon Fekrat, MD, professor of ophthalmology, Duke University, Durham, N.C., agreed that there’s potential importance of the eye in diagnosing neurodegeneration. However, she suggested that vitreous humor may not be the most expedient medium to use.
“I commend the authors for this fascinating work. But practically speaking, if we ultimately want to use intraocular fluid to diagnose Alzheimer’s and perhaps other neurodegeneration, I think aqueous humor might be more practical than the vitreous humor,” said Dr. Fekrat, who was not involved with the research. “What might be even better is to have a device that can be held against the eyeball that measures the levels of various substances inside the eyeball without having to enter the eye,” added Justin Ma, a Duke University medical student working under Dr. Fekrat’s guidance. “It could be similar technology to what’s currently used to measure blood glucose levels,” Mr. Ma added.
The study was supported in part by the National Institute of Aging. Dr. Subramanian, Dr. Fekrat, and Mr. Ma have disclosed no relevant financial relationships. Disclosures for other study authors are listed in the original article.
A version of this article originally appeared on Medscape.com.
, opening the door to a potential new method of predicting neurodegenerative disease, new research suggests.
In a study of 77 patients undergoing eye surgery for various conditions, more than 70% had more than 20 pg/mL of NfL in their vitreous humor. Higher levels of NfL were associated with higher levels of other biomarkers known to be associated with Alzheimer’s disease, including amyloid-beta and tau proteins.
“The study had three primary findings,” said lead author Manju L. Subramanian, MD, associate professor of ophthalmology at Boston University.
First, the investigators were able to detect levels of NfL in eye fluid; and second, those levels were not in any way correlated to the patient’s clinical eye condition, Dr. Subramanian said. “The third finding was that we were able to correlate those neurofilament light levels with other markers that have been known to be associated with conditions such as Alzheimer’s disease,” she noted.
For Dr. Subramanian, these findings add to the hypothesis that the eye is an extension of the brain. “This is further evidence that the eye might potentially be a proxy for neurodegenerative diseases,” she said. “So finding neurofilament light chain in the eye demonstrates that the eye is not an isolated organ, and things that happen in the body can affect the eye and vice versa.”
The findings were published online Sept. 17 in Alzheimer’s Research & Therapy.
Verge of clinical applicability?
Early diagnosis of neurodegenerative diseases remains a challenge, the investigators noted. As such, there is a palpable need for reliable biomarkers that can help with early diagnosis, prognostic assessment, and measurable response to treatment for Alzheimer’s disease and other neurologic disorders
Recent research has identified NfL as a potential screening tool and some researchers believe it to be on the verge of clinical applicability. In addition, increased levels of the biomarker have been observed in both the cerebrospinal fluid (CSF) and blood of individuals with neurodegeneration and neurological diseases, including Alzheimer’s disease. In previous studies, for example, elevated levels of NfL in CSF and blood have been shown to reliably distinguish between patients with Alzheimer’s disease and healthy volunteers.
Because certain eye diseases have been associated with Alzheimer’s disease in epidemiological studies, they may share common risk factors and pathological mechanisms at the molecular level, the researchers noted. In an earlier study, the current investigators found that cognitive function among patients with eye disease was significantly associated with amyloid-beta and total tau protein levels in the vitreous humor.
Given these connections, the researchers hypothesized that NfL could be identified in the vitreous humor and may be associated with other relevant biomarkers of neuronal origin. “Neurofilament light chain is detectable in the cerebrospinal fluid, but it’s never been tested for detection in the eye,” Dr. Subramanian noted.
In total, vitreous humor samples were collected from 77 unique participants (mean age, 56.2 years; 63% men) as part of the single-center, prospective, cross-sectional cohort study. The researchers aspirated 0.5 to 1.0 ml of undiluted vitreous fluid during vitrectomy, while whole blood was drawn for APOE genotyping.
Immunoassay was used to quantitatively measure for NfL, amyloid-beta, total tau, phosphorylated tau 181 (p-tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous humor. The trial’s primary outcome measures were the detection of NfL levels in the vitreous humor, as well as its associations with other proteins.
Significant correlations
Results showed that 55 of the 77 participants (71.4%) had at least 20 pg/ml of NfL protein present in the vitreous humor. The median level was 68.65 pg/ml. Statistically significant associations were found between NfL levels in the vitreous humor and Abeta40, Abeta42, and total tau; higher NfL levels were associated with higher levels of all three biomarkers. On the other hand, NfL levels were not positively associated with increased vitreous levels of p-tau181.
Vitreous NfL concentration was significantly associated with inflammatory cytokines, including interleukin-15, interleukin-16, and monocyte chemoattractant protein-1, as well as vascular proteins such as vascular endothelial growth factor receptor-1, VEGF-C, vascular cell adhesion molecule-1, Tie-2, and intracellular adhesion molecular-1.
Despite these findings, NfL in the vitreous humor was not associated with patients’ clinical ophthalmic conditions or systemic diseases such as hypertension, diabetes, and hyperlipidemia. Similarly, NfL was not significantly associated with APOE genotype E2 and E4, the alleles most commonly associated with Alzheimer’s disease.
Finally, no statistically significant associations were found between NfL and Mini-Mental State Examination (MMSE) scores.
A “first step”
Most research currently examining the role of the eye in neurodegenerative disease is focused on retinal biomarkers imaged by optical coherence tomography, the investigators noted. Although promising, data obtained this way have yielded conflicting results.
Similarly, while the diagnostic potential of the core CSF biomarkers for AD (Abeta40, Abeta42, p-tau, and total tau) is well established, the practical utility of testing CSF for neurodegenerative diseases is limited, wrote the researchers.
As such, an additional biomarker source such as NfL–which is quantifiable and protein-based within eye fluid – has the potential to play an important role in predicting neurodegenerative disease in the clinical setting, they added.
“The holy grail of neurodegenerative-disease diagnosis is early diagnosis. Because if you can implement treatment early, you can slow down and potentially halt the progression of these diseases,” Dr. Subramanian said.
“This study is the first step toward determining if the eye could play a potential role in early diagnosis of conditions such as Alzheimer’s disease,” she added.
That said, Dr. Subramanian was quick to recognize the findings’ preliminary nature and that they do not offer reliable evidence that vitreous NfL levels definitively represent neurodegeneration. As such, the investigators called for more research to validate the association between this type of biomarker with other established biomarkers of neurodegeneration, such as those found in CSF fluid or on MRI and PET scans.
“At this point, we can’t look at eye fluid and say that people have neurodegenerative diseases,” she noted. “The other thing to consider is that vitreous humor is at the back of the eye, so it’s actually a fairly invasive procedure.
“I think the next step is to look at other types of eye fluids such as the aqueous fluid in the front of the eye, or even tear secretions, potentially,” Dr. Subramanian said.
Other study limitations include the lack of an association between NfL levels and MMSE scores and that none of the study participants were actually diagnosed with Alzheimer’s disease. Validation studies are needed to compare vitreous levels of NfL in patients with mild cognitive impairment/AD to normal controls, the investigators noted.
Fascinating but impractical?
Commenting on the findings, Sharon Fekrat, MD, professor of ophthalmology, Duke University, Durham, N.C., agreed that there’s potential importance of the eye in diagnosing neurodegeneration. However, she suggested that vitreous humor may not be the most expedient medium to use.
“I commend the authors for this fascinating work. But practically speaking, if we ultimately want to use intraocular fluid to diagnose Alzheimer’s and perhaps other neurodegeneration, I think aqueous humor might be more practical than the vitreous humor,” said Dr. Fekrat, who was not involved with the research. “What might be even better is to have a device that can be held against the eyeball that measures the levels of various substances inside the eyeball without having to enter the eye,” added Justin Ma, a Duke University medical student working under Dr. Fekrat’s guidance. “It could be similar technology to what’s currently used to measure blood glucose levels,” Mr. Ma added.
The study was supported in part by the National Institute of Aging. Dr. Subramanian, Dr. Fekrat, and Mr. Ma have disclosed no relevant financial relationships. Disclosures for other study authors are listed in the original article.
A version of this article originally appeared on Medscape.com.
FROM ALZHEIMER’S RESEARCH & THERAPY
Meta-analysis: Acalabrutinib showed better PFS and OS than other frontline CLL therapies
Acalabrutinib, given alone or in combination with obinutuzumab, showed favorable progression-free survival (PFS) and overall survival (OS), compared with other frontline therapies for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, according to the results of a meta-analysis comparing clinical trial results.
Researchers conducted a systematic literature review for applicable CLL studies that examined frontline treatments in order to compare the results with data on acalabrutinib (monotherapy and in combination with obinutuzumab) from patients in the ELEVATE-TN study (NCT02475681), according to a report published in Clinical Therapeutics.
Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston, and colleagues performed a network meta-analysis (NMA) comparing acalabrutinib versus other standard frontline therapies for CLL in patients for whom fludarabine-based treatment is not appropriate.
“In the absence of head-to-head trial data, NMAs allow for simultaneous comparisons of a number of interventions with multiple comparators, by synthesizing direct and indirect evidence,” the authors stated.
Eight randomized controlled trials (RCTs) met the criteria for comparison.
The researchers constructed two evidence networks: Network A comprised solely RCTs that met the inclusion criteria, and Network B comprised seven RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil plus obinutuzumab from iLLUMINATE. PFS and OS results were reported by using hazard ratios and 95% credible intervals.
Overall benefit
Both networks showed a significant improvement in PFS for acalabrutinib plus obinutuzumab over all comparators, according to the researchers. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B.
Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax plus obinutuzumab in Network B but not Network A.
Overall survival hazard ratios ranged from 0.18 to 0.65 in favor of acalabrutinib-based treatment, but not all were significant. Acalabrutinib plus obinutuzumab ranked highest in terms of PFS and OS improvement, followed by acalabrutinib monotherapy.
“Although our NMAs provide useful insights into the relative efficacy of acalabrutinib, compared with other frontline treatments of CLL, the results cannot be considered confirmatory, and head-to-head randomized trials are needed, especially to compare the efficacy of acalabrutinib versus other targeted agents,” the researchers concluded.
AstraZeneca sponsored the study. The authors reported funding from AstraZeneca and numerous other pharmaceutical companies.
SOURCE: Davids MS et al. Clin Ther. 2020 Oct 5. doi: 10.1016/j.clinthera.2020.08.017.
Acalabrutinib, given alone or in combination with obinutuzumab, showed favorable progression-free survival (PFS) and overall survival (OS), compared with other frontline therapies for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, according to the results of a meta-analysis comparing clinical trial results.
Researchers conducted a systematic literature review for applicable CLL studies that examined frontline treatments in order to compare the results with data on acalabrutinib (monotherapy and in combination with obinutuzumab) from patients in the ELEVATE-TN study (NCT02475681), according to a report published in Clinical Therapeutics.
Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston, and colleagues performed a network meta-analysis (NMA) comparing acalabrutinib versus other standard frontline therapies for CLL in patients for whom fludarabine-based treatment is not appropriate.
“In the absence of head-to-head trial data, NMAs allow for simultaneous comparisons of a number of interventions with multiple comparators, by synthesizing direct and indirect evidence,” the authors stated.
Eight randomized controlled trials (RCTs) met the criteria for comparison.
The researchers constructed two evidence networks: Network A comprised solely RCTs that met the inclusion criteria, and Network B comprised seven RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil plus obinutuzumab from iLLUMINATE. PFS and OS results were reported by using hazard ratios and 95% credible intervals.
Overall benefit
Both networks showed a significant improvement in PFS for acalabrutinib plus obinutuzumab over all comparators, according to the researchers. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B.
Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax plus obinutuzumab in Network B but not Network A.
Overall survival hazard ratios ranged from 0.18 to 0.65 in favor of acalabrutinib-based treatment, but not all were significant. Acalabrutinib plus obinutuzumab ranked highest in terms of PFS and OS improvement, followed by acalabrutinib monotherapy.
“Although our NMAs provide useful insights into the relative efficacy of acalabrutinib, compared with other frontline treatments of CLL, the results cannot be considered confirmatory, and head-to-head randomized trials are needed, especially to compare the efficacy of acalabrutinib versus other targeted agents,” the researchers concluded.
AstraZeneca sponsored the study. The authors reported funding from AstraZeneca and numerous other pharmaceutical companies.
SOURCE: Davids MS et al. Clin Ther. 2020 Oct 5. doi: 10.1016/j.clinthera.2020.08.017.
Acalabrutinib, given alone or in combination with obinutuzumab, showed favorable progression-free survival (PFS) and overall survival (OS), compared with other frontline therapies for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, according to the results of a meta-analysis comparing clinical trial results.
Researchers conducted a systematic literature review for applicable CLL studies that examined frontline treatments in order to compare the results with data on acalabrutinib (monotherapy and in combination with obinutuzumab) from patients in the ELEVATE-TN study (NCT02475681), according to a report published in Clinical Therapeutics.
Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston, and colleagues performed a network meta-analysis (NMA) comparing acalabrutinib versus other standard frontline therapies for CLL in patients for whom fludarabine-based treatment is not appropriate.
“In the absence of head-to-head trial data, NMAs allow for simultaneous comparisons of a number of interventions with multiple comparators, by synthesizing direct and indirect evidence,” the authors stated.
Eight randomized controlled trials (RCTs) met the criteria for comparison.
The researchers constructed two evidence networks: Network A comprised solely RCTs that met the inclusion criteria, and Network B comprised seven RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil plus obinutuzumab from iLLUMINATE. PFS and OS results were reported by using hazard ratios and 95% credible intervals.
Overall benefit
Both networks showed a significant improvement in PFS for acalabrutinib plus obinutuzumab over all comparators, according to the researchers. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B.
Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax plus obinutuzumab in Network B but not Network A.
Overall survival hazard ratios ranged from 0.18 to 0.65 in favor of acalabrutinib-based treatment, but not all were significant. Acalabrutinib plus obinutuzumab ranked highest in terms of PFS and OS improvement, followed by acalabrutinib monotherapy.
“Although our NMAs provide useful insights into the relative efficacy of acalabrutinib, compared with other frontline treatments of CLL, the results cannot be considered confirmatory, and head-to-head randomized trials are needed, especially to compare the efficacy of acalabrutinib versus other targeted agents,” the researchers concluded.
AstraZeneca sponsored the study. The authors reported funding from AstraZeneca and numerous other pharmaceutical companies.
SOURCE: Davids MS et al. Clin Ther. 2020 Oct 5. doi: 10.1016/j.clinthera.2020.08.017.
FROM CLINICAL THERAPEUTICS
Stroke may be the first symptom of COVID-19 in younger patients
new research suggests. Investigators carried out a meta-analysis of data, including 160 patients with COVID-19 and stroke, and found that nearly half of patients under the age of 50 were asymptomatic at the time of stroke onset.
Although younger patients had the highest risk of stroke, the highest risk of death was in patients who were older, had other chronic conditions, and had more severe COVID-19–associated respiratory symptoms.
“One of the most eye-opening findings of this study is that, for patients under 50 years old, many were totally asymptomatic when they had a stroke related to COVID-19, [which] means that, for these patients, the stroke was their first symptom of the disease,” lead author Luciano Sposato, MD, MBA, associate professor and chair in stroke research at Western University, London, Ont.
The study was published online Sept. 15 in Neurology.
Anecdotal reports
“In early April of 2020, we realized that COVID-19 was a highly thrombogenic disease,” said Dr. Sposato. “Almost in parallel, I started to see anecdotal reports in social media of strokes occurring in patients with COVID-19, and there were also very few case reports.”
The investigators “thought it would be a good idea to put all the data together in one paper,” he said, and began by conducting a systematic review of 10 published studies of COVID-19 and stroke (n = 125 patients), which were then pooled with 35 unpublished cases from Canada, the United States, and Iran for a total of 160 cases.
The analysis examined in-hospital mortality rates of patients with stroke and COVID-19.
In addition, the researchers conducted a second review of 150 papers, encompassing a final cohort of 3,306 COVID-19 patients with stroke of any type and 5,322 with ischemic stroke.
“Some studies reported data for only ischemic stroke, and some reported data for all strokes considered together, which resulted in a different number of patients on each meta-analysis, with a lower number of ‘any stroke’ cases,” Dr. Sposato explained. “This review looked at the number of patients who developed a stroke during admission and included thousands of patients.”
Dr. Sposato noted that the first review was conducted on single case reports and small case series “to understand the clinical characteristics of strokes in patients with COVID-19 on an individual patient level,” since “large studies, including hundreds of thousands of patients, usually do not provide the level of detail for a descriptive analysis of the clinical characteristics of a disease.”
Cluster analyses were used to “identify specific clinical phenotypes and their relationship with death.” Patients were stratified into three age groups: <50, 50-70, and >70 years (“young,” “middle aged,” and “older,” respectively). The median age was 65 years and 43% were female.
Mortality ‘remarkably high’
The review showed that 1.8% (95% confidence interval, 0.9%-3.7%) of patients experienced a new stroke, while 1.5% (95% CI, 0.8%-2.8%) of these experienced an ischemic stroke. “These numbers are higher than historical data for other infectious diseases – for example, 0.75% in SARS-CoV-1, 0.78% in sepsis, and 0.2% in influenza,” Dr. Sposato commented.
Moreover, “this number may be an underestimate, given that many patients die without a confirmed diagnosis and that some patients did not come to the emergency department when experiencing mild symptoms during the first months of the pandemic,” he added.
Focusing on the review of 160 patients, the researchers described in-hospital mortality for strokes of all types and for ischemic strokes alone as “remarkably high” (34.4% [95% CI, 27.2%-42.4%] and 35.7% [95% CI, 27.5%-44.8%], respectively), with most deaths occurring among ischemic stroke patients.
“This high mortality rate is higher than the [roughly] 15% to 30% reported for stroke patients without COVID-19 admitted to intensive care units,” Dr. Sposato said.
High-risk phenotype
Many “young” COVID-19 patients (under age 50) who had a stroke (42.9%) had no previous risk factors or comorbidities. Moreover, in almost half of these patients (48.3%), stroke was more likely to occur before the onset of any COVID-19 respiratory symptoms.
Additionally, younger patients showed the highest frequency of elevated cardiac troponin compared with middle-aged and older patients (71.4% vs. 48.4% and 27.8%, respectively). On the other hand, mortality was 67% lower in younger versus older patients (odds ratio, 0.33; 95% CI, 0.12-0.94; P = .039).
Dr. Sposato noted that the proportion of ischemic stroke patients with large-vessel occlusion was “higher than previously reported” for patients with stroke without COVID-19 (47% compared with 29%, respectively).
“We should consider COVID-19 as a new cause or risk factor for stroke. At least, patients with stroke should probably be tested for SARS-CoV-2 infection if they are young and present with a large-vessel occlusion, even in the absence of typical COVID-19 respiratory symptoms,” he suggested.
The researchers identified a “high-risk phenotype” for death for all types of stroke considered together: older age, a higher burden of comorbidities, and severe COVID-19 respiratory symptoms. Patients with all three characteristics had the highest in-hospital mortality rate (58.6%) and a threefold risk of death, compared with the rest of the cohort (OR, 3.52; 95% CI, 1.53-8.09; P = .003).
“Several potential mechanisms can explain the increased risk of stroke among COVID-19 patients, but perhaps the most important one is increased thrombogenesis secondary to an exaggerated inflammatory response,” Dr. Sposato said.
Not just elders
Commenting on the study, Jodi Edwards, PhD, director of the Brain and Heart Nexus Research Program at the University of Ottawa Heart Institute, said the findings are “consistent with and underscore public health messaging emphasizing that COVID-19 does not only affect the elderly and those with underlying health conditions, but can have serious and even fatal consequences at any age.”
Dr. Edwards, who was not involved with the study, emphasized that “adherence to public health recommendations is critical to begin to reduce the rising incidence in younger adults.”
Dr. Sposato acknowledged that the study was small and that there “can be problems associated with a systematic review of case reports, such as publication bias, lack of completeness of data, etc, so more research is needed.”
Dr. Sposato is supported by the Kathleen & Dr. Henry Barnett Research Chair in Stroke Research at Western University, the Edward and Alma Saraydar Neurosciences Fund of the London Health Sciences Foundation, and the Opportunities Fund of the Academic Health Sciences Centre Alternative Funding Plan of the Academic Medical Organization of Southwestern Ontario. Dr. Sposato reported speaker honoraria from Boehringer Ingelheim, Pfizer, Gore, and Bayer and research/quality improvement grants from Boehringer Ingelheim and Bayer. The other authors’ disclosures are listed on the original article. Dr. Edwards has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. Investigators carried out a meta-analysis of data, including 160 patients with COVID-19 and stroke, and found that nearly half of patients under the age of 50 were asymptomatic at the time of stroke onset.
Although younger patients had the highest risk of stroke, the highest risk of death was in patients who were older, had other chronic conditions, and had more severe COVID-19–associated respiratory symptoms.
“One of the most eye-opening findings of this study is that, for patients under 50 years old, many were totally asymptomatic when they had a stroke related to COVID-19, [which] means that, for these patients, the stroke was their first symptom of the disease,” lead author Luciano Sposato, MD, MBA, associate professor and chair in stroke research at Western University, London, Ont.
The study was published online Sept. 15 in Neurology.
Anecdotal reports
“In early April of 2020, we realized that COVID-19 was a highly thrombogenic disease,” said Dr. Sposato. “Almost in parallel, I started to see anecdotal reports in social media of strokes occurring in patients with COVID-19, and there were also very few case reports.”
The investigators “thought it would be a good idea to put all the data together in one paper,” he said, and began by conducting a systematic review of 10 published studies of COVID-19 and stroke (n = 125 patients), which were then pooled with 35 unpublished cases from Canada, the United States, and Iran for a total of 160 cases.
The analysis examined in-hospital mortality rates of patients with stroke and COVID-19.
In addition, the researchers conducted a second review of 150 papers, encompassing a final cohort of 3,306 COVID-19 patients with stroke of any type and 5,322 with ischemic stroke.
“Some studies reported data for only ischemic stroke, and some reported data for all strokes considered together, which resulted in a different number of patients on each meta-analysis, with a lower number of ‘any stroke’ cases,” Dr. Sposato explained. “This review looked at the number of patients who developed a stroke during admission and included thousands of patients.”
Dr. Sposato noted that the first review was conducted on single case reports and small case series “to understand the clinical characteristics of strokes in patients with COVID-19 on an individual patient level,” since “large studies, including hundreds of thousands of patients, usually do not provide the level of detail for a descriptive analysis of the clinical characteristics of a disease.”
Cluster analyses were used to “identify specific clinical phenotypes and their relationship with death.” Patients were stratified into three age groups: <50, 50-70, and >70 years (“young,” “middle aged,” and “older,” respectively). The median age was 65 years and 43% were female.
Mortality ‘remarkably high’
The review showed that 1.8% (95% confidence interval, 0.9%-3.7%) of patients experienced a new stroke, while 1.5% (95% CI, 0.8%-2.8%) of these experienced an ischemic stroke. “These numbers are higher than historical data for other infectious diseases – for example, 0.75% in SARS-CoV-1, 0.78% in sepsis, and 0.2% in influenza,” Dr. Sposato commented.
Moreover, “this number may be an underestimate, given that many patients die without a confirmed diagnosis and that some patients did not come to the emergency department when experiencing mild symptoms during the first months of the pandemic,” he added.
Focusing on the review of 160 patients, the researchers described in-hospital mortality for strokes of all types and for ischemic strokes alone as “remarkably high” (34.4% [95% CI, 27.2%-42.4%] and 35.7% [95% CI, 27.5%-44.8%], respectively), with most deaths occurring among ischemic stroke patients.
“This high mortality rate is higher than the [roughly] 15% to 30% reported for stroke patients without COVID-19 admitted to intensive care units,” Dr. Sposato said.
High-risk phenotype
Many “young” COVID-19 patients (under age 50) who had a stroke (42.9%) had no previous risk factors or comorbidities. Moreover, in almost half of these patients (48.3%), stroke was more likely to occur before the onset of any COVID-19 respiratory symptoms.
Additionally, younger patients showed the highest frequency of elevated cardiac troponin compared with middle-aged and older patients (71.4% vs. 48.4% and 27.8%, respectively). On the other hand, mortality was 67% lower in younger versus older patients (odds ratio, 0.33; 95% CI, 0.12-0.94; P = .039).
Dr. Sposato noted that the proportion of ischemic stroke patients with large-vessel occlusion was “higher than previously reported” for patients with stroke without COVID-19 (47% compared with 29%, respectively).
“We should consider COVID-19 as a new cause or risk factor for stroke. At least, patients with stroke should probably be tested for SARS-CoV-2 infection if they are young and present with a large-vessel occlusion, even in the absence of typical COVID-19 respiratory symptoms,” he suggested.
The researchers identified a “high-risk phenotype” for death for all types of stroke considered together: older age, a higher burden of comorbidities, and severe COVID-19 respiratory symptoms. Patients with all three characteristics had the highest in-hospital mortality rate (58.6%) and a threefold risk of death, compared with the rest of the cohort (OR, 3.52; 95% CI, 1.53-8.09; P = .003).
“Several potential mechanisms can explain the increased risk of stroke among COVID-19 patients, but perhaps the most important one is increased thrombogenesis secondary to an exaggerated inflammatory response,” Dr. Sposato said.
Not just elders
Commenting on the study, Jodi Edwards, PhD, director of the Brain and Heart Nexus Research Program at the University of Ottawa Heart Institute, said the findings are “consistent with and underscore public health messaging emphasizing that COVID-19 does not only affect the elderly and those with underlying health conditions, but can have serious and even fatal consequences at any age.”
Dr. Edwards, who was not involved with the study, emphasized that “adherence to public health recommendations is critical to begin to reduce the rising incidence in younger adults.”
Dr. Sposato acknowledged that the study was small and that there “can be problems associated with a systematic review of case reports, such as publication bias, lack of completeness of data, etc, so more research is needed.”
Dr. Sposato is supported by the Kathleen & Dr. Henry Barnett Research Chair in Stroke Research at Western University, the Edward and Alma Saraydar Neurosciences Fund of the London Health Sciences Foundation, and the Opportunities Fund of the Academic Health Sciences Centre Alternative Funding Plan of the Academic Medical Organization of Southwestern Ontario. Dr. Sposato reported speaker honoraria from Boehringer Ingelheim, Pfizer, Gore, and Bayer and research/quality improvement grants from Boehringer Ingelheim and Bayer. The other authors’ disclosures are listed on the original article. Dr. Edwards has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. Investigators carried out a meta-analysis of data, including 160 patients with COVID-19 and stroke, and found that nearly half of patients under the age of 50 were asymptomatic at the time of stroke onset.
Although younger patients had the highest risk of stroke, the highest risk of death was in patients who were older, had other chronic conditions, and had more severe COVID-19–associated respiratory symptoms.
“One of the most eye-opening findings of this study is that, for patients under 50 years old, many were totally asymptomatic when they had a stroke related to COVID-19, [which] means that, for these patients, the stroke was their first symptom of the disease,” lead author Luciano Sposato, MD, MBA, associate professor and chair in stroke research at Western University, London, Ont.
The study was published online Sept. 15 in Neurology.
Anecdotal reports
“In early April of 2020, we realized that COVID-19 was a highly thrombogenic disease,” said Dr. Sposato. “Almost in parallel, I started to see anecdotal reports in social media of strokes occurring in patients with COVID-19, and there were also very few case reports.”
The investigators “thought it would be a good idea to put all the data together in one paper,” he said, and began by conducting a systematic review of 10 published studies of COVID-19 and stroke (n = 125 patients), which were then pooled with 35 unpublished cases from Canada, the United States, and Iran for a total of 160 cases.
The analysis examined in-hospital mortality rates of patients with stroke and COVID-19.
In addition, the researchers conducted a second review of 150 papers, encompassing a final cohort of 3,306 COVID-19 patients with stroke of any type and 5,322 with ischemic stroke.
“Some studies reported data for only ischemic stroke, and some reported data for all strokes considered together, which resulted in a different number of patients on each meta-analysis, with a lower number of ‘any stroke’ cases,” Dr. Sposato explained. “This review looked at the number of patients who developed a stroke during admission and included thousands of patients.”
Dr. Sposato noted that the first review was conducted on single case reports and small case series “to understand the clinical characteristics of strokes in patients with COVID-19 on an individual patient level,” since “large studies, including hundreds of thousands of patients, usually do not provide the level of detail for a descriptive analysis of the clinical characteristics of a disease.”
Cluster analyses were used to “identify specific clinical phenotypes and their relationship with death.” Patients were stratified into three age groups: <50, 50-70, and >70 years (“young,” “middle aged,” and “older,” respectively). The median age was 65 years and 43% were female.
Mortality ‘remarkably high’
The review showed that 1.8% (95% confidence interval, 0.9%-3.7%) of patients experienced a new stroke, while 1.5% (95% CI, 0.8%-2.8%) of these experienced an ischemic stroke. “These numbers are higher than historical data for other infectious diseases – for example, 0.75% in SARS-CoV-1, 0.78% in sepsis, and 0.2% in influenza,” Dr. Sposato commented.
Moreover, “this number may be an underestimate, given that many patients die without a confirmed diagnosis and that some patients did not come to the emergency department when experiencing mild symptoms during the first months of the pandemic,” he added.
Focusing on the review of 160 patients, the researchers described in-hospital mortality for strokes of all types and for ischemic strokes alone as “remarkably high” (34.4% [95% CI, 27.2%-42.4%] and 35.7% [95% CI, 27.5%-44.8%], respectively), with most deaths occurring among ischemic stroke patients.
“This high mortality rate is higher than the [roughly] 15% to 30% reported for stroke patients without COVID-19 admitted to intensive care units,” Dr. Sposato said.
High-risk phenotype
Many “young” COVID-19 patients (under age 50) who had a stroke (42.9%) had no previous risk factors or comorbidities. Moreover, in almost half of these patients (48.3%), stroke was more likely to occur before the onset of any COVID-19 respiratory symptoms.
Additionally, younger patients showed the highest frequency of elevated cardiac troponin compared with middle-aged and older patients (71.4% vs. 48.4% and 27.8%, respectively). On the other hand, mortality was 67% lower in younger versus older patients (odds ratio, 0.33; 95% CI, 0.12-0.94; P = .039).
Dr. Sposato noted that the proportion of ischemic stroke patients with large-vessel occlusion was “higher than previously reported” for patients with stroke without COVID-19 (47% compared with 29%, respectively).
“We should consider COVID-19 as a new cause or risk factor for stroke. At least, patients with stroke should probably be tested for SARS-CoV-2 infection if they are young and present with a large-vessel occlusion, even in the absence of typical COVID-19 respiratory symptoms,” he suggested.
The researchers identified a “high-risk phenotype” for death for all types of stroke considered together: older age, a higher burden of comorbidities, and severe COVID-19 respiratory symptoms. Patients with all three characteristics had the highest in-hospital mortality rate (58.6%) and a threefold risk of death, compared with the rest of the cohort (OR, 3.52; 95% CI, 1.53-8.09; P = .003).
“Several potential mechanisms can explain the increased risk of stroke among COVID-19 patients, but perhaps the most important one is increased thrombogenesis secondary to an exaggerated inflammatory response,” Dr. Sposato said.
Not just elders
Commenting on the study, Jodi Edwards, PhD, director of the Brain and Heart Nexus Research Program at the University of Ottawa Heart Institute, said the findings are “consistent with and underscore public health messaging emphasizing that COVID-19 does not only affect the elderly and those with underlying health conditions, but can have serious and even fatal consequences at any age.”
Dr. Edwards, who was not involved with the study, emphasized that “adherence to public health recommendations is critical to begin to reduce the rising incidence in younger adults.”
Dr. Sposato acknowledged that the study was small and that there “can be problems associated with a systematic review of case reports, such as publication bias, lack of completeness of data, etc, so more research is needed.”
Dr. Sposato is supported by the Kathleen & Dr. Henry Barnett Research Chair in Stroke Research at Western University, the Edward and Alma Saraydar Neurosciences Fund of the London Health Sciences Foundation, and the Opportunities Fund of the Academic Health Sciences Centre Alternative Funding Plan of the Academic Medical Organization of Southwestern Ontario. Dr. Sposato reported speaker honoraria from Boehringer Ingelheim, Pfizer, Gore, and Bayer and research/quality improvement grants from Boehringer Ingelheim and Bayer. The other authors’ disclosures are listed on the original article. Dr. Edwards has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
From Neurology