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Researchers tout new CLL prognostic tool
Researchers report that they’ve confirmed the usefulness of a new tool to help physicians pinpoint prognoses for patients with chronic lymphocytic leukemia (CLL).
“Physicians may use this tool to support decisions regarding supportive care, manage the patient’s and physician’s expectations, and potentially tailor therapy,” study lead author and epidemiologist Emelie Rotbain, MD, PhD, of Rigshospitalet in Copenhagen, said in an interview.
The study appeared Jan. 10 in the journal Blood Advances.
According to Dr. Rotbain,
Researchers developed the questions based on an analysis of categories in the Cumulative Illness Rating Scale that are most linked to event-free survival (EFS) from time of treatment.
The tool looks at three organ systems – vascular, upper GI, and endocrine – and asks about conditions such as diabetes and chronic use of a proton pump inhibitor, study coauthor and hematologist/oncologist Alexey V. Danilov, MD, PhD, codirector of the Toni Stephenson Lymphoma Center at the City of Hope National Medical Center, Duarte, Calif., said in an interview. The tool then generates a score based on the variables.
For the new study, the researchers retrospectively applied the tool to 4,975 patients who appeared in the Danish National CLL Register from 2008 to 2018 (61% male, median age 70.7.). Of those, 1,513 received first-line treatment during follow-up (median = 4.39 years).
At diagnosis, nearly two-thirds (63%) of patients were considered to be low risk. None of these had endocrinological, upper gastrointestinal, or vascular disease. Another 30% were considered to be at intermediate risk. The remaining 7% were at high risk. They had high levels of endocrinological (55.6%), upper gastrointestinal (64.6%), and vascular disease (91.0%).
The high-risk patients had a median survival of 6.0 years. The intermediate-risk patients lived for a median of 8.5 years, while the low-risk patients didn’t reach a median survival level.
Fifty-six percent of high-risk patients were treated within 4 years, compared to 20%-30% of intermediate- and low-risk patients. Median event-free survival from time of treatment was 8.4, 4.4, and 2.2 years for the low-, intermediate-, and high-risk groups, respectively.
The authors cautioned that “differences in survival by type of treatment, particularly in patients treated with targeted therapies who were underrepresented in this study, could influence survival and limit the generalizability of these results.”
They added that “while prognostic factors should remain key for treatment decisions, clinical trial data from pivotal phase 3 trials with novel targeted agents versus chemoimmunotherapy should be reanalyzed with addition of CLL-CI to assess the optimal treatment for patients according to CLL-CI.”
The tool is not yet available online, Dr. Danilov said, “but that is something that we as a group could potentially work on.”
Joanna Rhodes, MD, assistant professor with Northwell Health Cancer Institute/Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the tool is easy to use and appropriate to apply at first consultation. It should be used in conjunction with the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI), she said.
“We often discuss frailty as a factor in types of and timing of treatment for patients with CLL, but often this is not directly measured in clinical practice,” she said. “The CLL-CI is associated with important outcomes, particularly overall survival, which is our most important metric in oncology. Additionally, it provides important information on time to first treatment and overall survival, which are useful when we are counseling patients.”
Like the study authors, Dr. Rhodes cautioned that the CLL-CI has not been validated specifically in patients treated with targeted therapies. “It may not be applicable in this setting, particularly in the front-line setting, as these treatments were underrepresented in this cohort. Further studies in this population are needed to answer this question.”
The study is funded in part by Novo Nordisk Foundation. Several study authors report various disclosures outside the scope of this study. Dr. Rhodes has no disclosures.
Researchers report that they’ve confirmed the usefulness of a new tool to help physicians pinpoint prognoses for patients with chronic lymphocytic leukemia (CLL).
“Physicians may use this tool to support decisions regarding supportive care, manage the patient’s and physician’s expectations, and potentially tailor therapy,” study lead author and epidemiologist Emelie Rotbain, MD, PhD, of Rigshospitalet in Copenhagen, said in an interview.
The study appeared Jan. 10 in the journal Blood Advances.
According to Dr. Rotbain,
Researchers developed the questions based on an analysis of categories in the Cumulative Illness Rating Scale that are most linked to event-free survival (EFS) from time of treatment.
The tool looks at three organ systems – vascular, upper GI, and endocrine – and asks about conditions such as diabetes and chronic use of a proton pump inhibitor, study coauthor and hematologist/oncologist Alexey V. Danilov, MD, PhD, codirector of the Toni Stephenson Lymphoma Center at the City of Hope National Medical Center, Duarte, Calif., said in an interview. The tool then generates a score based on the variables.
For the new study, the researchers retrospectively applied the tool to 4,975 patients who appeared in the Danish National CLL Register from 2008 to 2018 (61% male, median age 70.7.). Of those, 1,513 received first-line treatment during follow-up (median = 4.39 years).
At diagnosis, nearly two-thirds (63%) of patients were considered to be low risk. None of these had endocrinological, upper gastrointestinal, or vascular disease. Another 30% were considered to be at intermediate risk. The remaining 7% were at high risk. They had high levels of endocrinological (55.6%), upper gastrointestinal (64.6%), and vascular disease (91.0%).
The high-risk patients had a median survival of 6.0 years. The intermediate-risk patients lived for a median of 8.5 years, while the low-risk patients didn’t reach a median survival level.
Fifty-six percent of high-risk patients were treated within 4 years, compared to 20%-30% of intermediate- and low-risk patients. Median event-free survival from time of treatment was 8.4, 4.4, and 2.2 years for the low-, intermediate-, and high-risk groups, respectively.
The authors cautioned that “differences in survival by type of treatment, particularly in patients treated with targeted therapies who were underrepresented in this study, could influence survival and limit the generalizability of these results.”
They added that “while prognostic factors should remain key for treatment decisions, clinical trial data from pivotal phase 3 trials with novel targeted agents versus chemoimmunotherapy should be reanalyzed with addition of CLL-CI to assess the optimal treatment for patients according to CLL-CI.”
The tool is not yet available online, Dr. Danilov said, “but that is something that we as a group could potentially work on.”
Joanna Rhodes, MD, assistant professor with Northwell Health Cancer Institute/Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the tool is easy to use and appropriate to apply at first consultation. It should be used in conjunction with the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI), she said.
“We often discuss frailty as a factor in types of and timing of treatment for patients with CLL, but often this is not directly measured in clinical practice,” she said. “The CLL-CI is associated with important outcomes, particularly overall survival, which is our most important metric in oncology. Additionally, it provides important information on time to first treatment and overall survival, which are useful when we are counseling patients.”
Like the study authors, Dr. Rhodes cautioned that the CLL-CI has not been validated specifically in patients treated with targeted therapies. “It may not be applicable in this setting, particularly in the front-line setting, as these treatments were underrepresented in this cohort. Further studies in this population are needed to answer this question.”
The study is funded in part by Novo Nordisk Foundation. Several study authors report various disclosures outside the scope of this study. Dr. Rhodes has no disclosures.
Researchers report that they’ve confirmed the usefulness of a new tool to help physicians pinpoint prognoses for patients with chronic lymphocytic leukemia (CLL).
“Physicians may use this tool to support decisions regarding supportive care, manage the patient’s and physician’s expectations, and potentially tailor therapy,” study lead author and epidemiologist Emelie Rotbain, MD, PhD, of Rigshospitalet in Copenhagen, said in an interview.
The study appeared Jan. 10 in the journal Blood Advances.
According to Dr. Rotbain,
Researchers developed the questions based on an analysis of categories in the Cumulative Illness Rating Scale that are most linked to event-free survival (EFS) from time of treatment.
The tool looks at three organ systems – vascular, upper GI, and endocrine – and asks about conditions such as diabetes and chronic use of a proton pump inhibitor, study coauthor and hematologist/oncologist Alexey V. Danilov, MD, PhD, codirector of the Toni Stephenson Lymphoma Center at the City of Hope National Medical Center, Duarte, Calif., said in an interview. The tool then generates a score based on the variables.
For the new study, the researchers retrospectively applied the tool to 4,975 patients who appeared in the Danish National CLL Register from 2008 to 2018 (61% male, median age 70.7.). Of those, 1,513 received first-line treatment during follow-up (median = 4.39 years).
At diagnosis, nearly two-thirds (63%) of patients were considered to be low risk. None of these had endocrinological, upper gastrointestinal, or vascular disease. Another 30% were considered to be at intermediate risk. The remaining 7% were at high risk. They had high levels of endocrinological (55.6%), upper gastrointestinal (64.6%), and vascular disease (91.0%).
The high-risk patients had a median survival of 6.0 years. The intermediate-risk patients lived for a median of 8.5 years, while the low-risk patients didn’t reach a median survival level.
Fifty-six percent of high-risk patients were treated within 4 years, compared to 20%-30% of intermediate- and low-risk patients. Median event-free survival from time of treatment was 8.4, 4.4, and 2.2 years for the low-, intermediate-, and high-risk groups, respectively.
The authors cautioned that “differences in survival by type of treatment, particularly in patients treated with targeted therapies who were underrepresented in this study, could influence survival and limit the generalizability of these results.”
They added that “while prognostic factors should remain key for treatment decisions, clinical trial data from pivotal phase 3 trials with novel targeted agents versus chemoimmunotherapy should be reanalyzed with addition of CLL-CI to assess the optimal treatment for patients according to CLL-CI.”
The tool is not yet available online, Dr. Danilov said, “but that is something that we as a group could potentially work on.”
Joanna Rhodes, MD, assistant professor with Northwell Health Cancer Institute/Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y., said in an interview that the tool is easy to use and appropriate to apply at first consultation. It should be used in conjunction with the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI), she said.
“We often discuss frailty as a factor in types of and timing of treatment for patients with CLL, but often this is not directly measured in clinical practice,” she said. “The CLL-CI is associated with important outcomes, particularly overall survival, which is our most important metric in oncology. Additionally, it provides important information on time to first treatment and overall survival, which are useful when we are counseling patients.”
Like the study authors, Dr. Rhodes cautioned that the CLL-CI has not been validated specifically in patients treated with targeted therapies. “It may not be applicable in this setting, particularly in the front-line setting, as these treatments were underrepresented in this cohort. Further studies in this population are needed to answer this question.”
The study is funded in part by Novo Nordisk Foundation. Several study authors report various disclosures outside the scope of this study. Dr. Rhodes has no disclosures.
FROM BLOOD ADVANCES
Rituximab and COVID-19 vaccines: Studies begin to answer key questions
Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.
Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.
As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?
Humoral and cell-mediated responses following COVID-19 vaccination
First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.
“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.
For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.
“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.
One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.
One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.
The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.
While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.
“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
Does treatment timing impact COVID-19 vaccine response?
Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”
“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.
In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.
The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.
“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.
Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.
“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.
However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.
Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”
Should clinicians measure antibodies?
The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.
“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”
However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”
Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.
“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”
Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?
As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.
In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.
All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.
When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”
Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.
“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”
Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.
“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.
The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.
Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.
Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.
As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?
Humoral and cell-mediated responses following COVID-19 vaccination
First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.
“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.
For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.
“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.
One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.
One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.
The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.
While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.
“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
Does treatment timing impact COVID-19 vaccine response?
Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”
“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.
In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.
The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.
“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.
Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.
“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.
However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.
Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”
Should clinicians measure antibodies?
The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.
“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”
However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”
Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.
“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”
Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?
As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.
In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.
All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.
When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”
Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.
“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”
Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.
“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.
The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.
Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.
Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.
As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?
Humoral and cell-mediated responses following COVID-19 vaccination
First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.
“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.
For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.
“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.
One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.
One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.
The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.
While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.
“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
Does treatment timing impact COVID-19 vaccine response?
Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”
“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.
In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.
The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.
“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.
Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.
“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.
However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.
Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”
Should clinicians measure antibodies?
The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.
“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”
However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”
Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.
“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”
Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?
As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.
In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.
All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.
When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”
Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.
“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”
Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.
“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.
The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.
Convenience, not outcomes may drive robot-assisted surgeries
“The problem in minimally invasive surgery, especially in cancer surgery, is that the concept has been flip-flopped,” said Hooman Noorchashm, MD, PhD, a retired cardiothoracic surgeon turned patient advocate. “The main purpose of surgery should be removal of diseased tissue or repair of damaged tissue with adequate safety. The size of the incision on that triage scheme is secondary.”
In 2013, Dr. Noorchashm’s wife, Amy Reed, MD, an anesthesiologist, had a hysterectomy for treatment of severe uterine fibroids. The surgery was performed with a laparoscopic power morcellator, which led to the dissemination of cells from a previously undetected abdominal lesion. She was later diagnosed with stage 4 leiomyosarcoma and died in May 2017.
Dr. Noorchashm said the problem with robotic surgery isn’t the technology itself or how it’s used, but why it’s used in the first place. “Not only was there an extreme level of laxity with respect to the malignant potential of fibroids, but also that the size of the incision supersedes the safety of the procedure.”
The ultimate goal of oncologic surgery is to achieve an en bloc resection with clean surgical margins and removal of the tumor intact, Dr. Noorchashm said. The only scientific way of showing the benefits or therapeutic equivalence of new technology is through noninferiority comparison trials.
Robotic surgery inching toward $14 billion in revenue by 2028
Although robotic surgical technology has been in use since the 1990s, the technology is still considered to be its infancy. The first Food and Drug Administration–approved robotics platform, the da Vinci Surgical System (Intuitive Surgical) was approved by the FDA in 2000. And, now, with its patent expiring in 2022, competitors will be developing and launching new products for abdominal and colorectal surgery, partial knee replacements, cardiovascular procedures, head and neck surgery, and spinal procedures.
Robotic surgery is a rapidly expanding area with new product launches announced daily. In August 2021, the market research firm Grand View Research, reported the surgical robot marketplace is projected to reach $14 billion by 2028, up from $3.6 billion this year.
“This new era of robotic-assisted surgery attracts both surgeons and patients. Robotic surgery has reshaped our surgeries over the last 2 decades, and robots are now used in almost in every surgical field. Still, as surgeons, we continue to look – with great interest – to new robotic companies that may be able to provide better robots in a more cost-effective manner,” wrote urologists Ahmad Almujalhem and Koon Ho Rha in a review published in the journal BJUI Compass.
However, the authors wrote that, although the market is competitive, cost remains an issue, as are competing interests. In addition, many companies are creating replicas of existing technologies instead of focusing on new designs and new technology. “Although the da Vinci system propelled many robots to market, there has been no significant improvement in the console,” they added.
The technology is attractive to both surgeons and patients. “Surgeons are attracted to newer technologies, better vision, and easier learning curves. Patients are also attracted to robotic surgery, as this technology is considered state of the art and is associated with reduced pain and scar size,” the authors wrote.
Outcomes depend on many variables
In terms of outcomes, the literature is mixed. It largely depends on a number of variables from the site of surgery, the type of cancer, technology used, and the surgeon’s skill.
Jung Mogg Kim, MD, PhD, a microbiologist with Hanyang University, Seoul, South Korea, published a systemic review and meta-analysis of 27 clinical reports in PLoS ONE assessing clinical outcomes. They found that robot-assisted laparoscopic surgery did not result in statistically superior outcomes, compared with conventional laparoscopic surgery, except for lower estimated blood loss with robots. Operative time and total complications rates were “significantly more favorable” with conventional laparoscopic procedures.
Thomas E. Ahlering, MD, a robotic prostatectomy specialist at the University of California, Irvine, explained that the success or failure of robot-assisted surgery can be highly dependent on the body site and tumor type.
“The oncologic outcome, as long as the surgeon is up to speed, is not going to be better, but the goal is to be as good,” he said in an interview.
In most cases, Dr. Ahlering said, the goal of surgery is to remove a viable tumor with clean margins while leaving the organ intact. But in prostate surgery, the goal is to remove the entire organ while trying to preserve urinary continence and sexual function.
“One of the biggest benefits of the robot is that we’re able to use it in a laparoscopic environment meaning that we need a pneumoperitoneum [which] dramatically decreases bleeding. In prostate cancer, the area is so highly vascular that bleeding is a major issue,” he said.
The same benefits of reduced bleeding, improved visualization, and precision are also seen with robotic-assisted surgery for renal cancer, he noted.
He also emphasized that positive surgical margins, while less desirable than complete elimination of malignant cells, is not nearly as dire in prostate cancer as it is in surgery for other malignancies, such as soft-tissue sarcomas.
“The majority of cases are never going to recur, and if they do recur they essentially never lead to metastatic disease to bone, much less to prostate cancer–related death. The only thing they can do is slightly increase the PSA [prostate-specific antigen] recurrence,” he said.
Assuming that outcomes are comparable between an open procedure, conventional laparoscopic procedure, or robot-assisted approach, surgeons “will almost all go for the robot. It’s easier on the surgeon and it’s easier on the system,” Dr. Ahlering said.
In skilled hands for select patients, the use of a carefully researched and well-designed surgical assistive device can result in outcomes that are comparable with those seen in open surgical procedures, with robot-assisted surgery offering the possibility of less perioperative bleeding, lower postoperative morbidity, and faster recovery times.
“In our program we have been using robots to perform robotic radical prostatectomy and nephron-sparing surgery – partial nephrectomy and we’re also using them to perform intracorporeal bowel reconstruction and robotic radical cystectomy,” said Ashutosh Tewari, MD, of the Icahn School of Medicine at Mount Sinai, New York.
Robot-assisted surgery can be used “anywhere where you have to be selective, anywhere where you have to be reconstructive, anywhere where [assisted] vision can help, anywhere where the lack of bleeding will be of help to patients, and anywhere where a smaller incision can achieve the same goals,” Dr. Tewari said in an interview. Dr. Tewari’s Mount Sinai colleagues reported at the 2021 American Urological Association annual meeting, robotic-assisted salvage radical and partial nephrectomies were found to be safe and feasible procedures in patients with metachronous kidney tumors. For patients with early invasive cancer (stage pT1), oncologic outcomes with robotic-assisted partial nephrectomy were similar to those of patients who underwent radical surgery. The authors concluded that salvage robotic-assisted partial nephrectomy “can be considered in this group of patients due to the risk of future recurrences and need to preserve renal function.”
The National Comprehensive Cancer Network guideline for prostate cancer, updated in September 2021, states that “laparoscopic and robot-assisted radical prostatectomy are commonly used and are considered comparable to conventional approaches in experienced hands.”
In 2018, researchers in a multinational comparison trial reported that patients with cervical cancer who were randomly assigned to minimally invasive robot-assisted radical hysterectomy had significantly lower rates of both disease-free survival and overall survival than women randomized to open abdominal radical hysterectomy. The study results were published in the New England Journal of Medicine.
The use of robotically assisted surgical (RAS) devices could possibly create a “shielding layer” between the surgical team and patient reducing the risk of infection, according to Ajmal Zemmar, MD, PhD, FMH, a neurosurgeon with the University of Louisville (Ky.) Dr. Zemmar and colleagues recently published a perspective in Nature Machine Intelligence on trends in the use of surgical robots.
“In the operating theatre, robots can place intravascular lines, intubate the patient and manage the airway. The integration of a robot as a shielding layer, physically separating the health care worker and patient, is a powerful tool to combat the omnipresent fear of pathogen contamination and maintain surgical volumes,” Dr. Zemmar and colleagues wrote.
Surgical vs. clinical outcomes
In July 2021, this news organization reported that clinical trials of RAS for nipple-sparing mastectomy procedures were looking primarily at cosmetic or surgical outcomes and were not collecting cancer outcomes and if they were, it was secondary to cosmetic or surgical outcomes.
The FDA followed up by issuing a safety communication in August warning patients and providers that neither the safety nor efficacy of RAS for use in mastectomy procedures or treatment of breast cancer have been established.
“In addition, the FDA is aware of allegations that clinical studies are being conducted using RAS devices to perform mastectomies for the prevention or treatment of cancer without the FDA oversight required for such significant risk studies,” the communication stated.
Dr. Tewari disclosed relationships with various companies. Dr. Noorchashm had no relevant disclosures. Dr. Ahlering disclosed past funding or other considerations from Intuitive Robotics.
“The problem in minimally invasive surgery, especially in cancer surgery, is that the concept has been flip-flopped,” said Hooman Noorchashm, MD, PhD, a retired cardiothoracic surgeon turned patient advocate. “The main purpose of surgery should be removal of diseased tissue or repair of damaged tissue with adequate safety. The size of the incision on that triage scheme is secondary.”
In 2013, Dr. Noorchashm’s wife, Amy Reed, MD, an anesthesiologist, had a hysterectomy for treatment of severe uterine fibroids. The surgery was performed with a laparoscopic power morcellator, which led to the dissemination of cells from a previously undetected abdominal lesion. She was later diagnosed with stage 4 leiomyosarcoma and died in May 2017.
Dr. Noorchashm said the problem with robotic surgery isn’t the technology itself or how it’s used, but why it’s used in the first place. “Not only was there an extreme level of laxity with respect to the malignant potential of fibroids, but also that the size of the incision supersedes the safety of the procedure.”
The ultimate goal of oncologic surgery is to achieve an en bloc resection with clean surgical margins and removal of the tumor intact, Dr. Noorchashm said. The only scientific way of showing the benefits or therapeutic equivalence of new technology is through noninferiority comparison trials.
Robotic surgery inching toward $14 billion in revenue by 2028
Although robotic surgical technology has been in use since the 1990s, the technology is still considered to be its infancy. The first Food and Drug Administration–approved robotics platform, the da Vinci Surgical System (Intuitive Surgical) was approved by the FDA in 2000. And, now, with its patent expiring in 2022, competitors will be developing and launching new products for abdominal and colorectal surgery, partial knee replacements, cardiovascular procedures, head and neck surgery, and spinal procedures.
Robotic surgery is a rapidly expanding area with new product launches announced daily. In August 2021, the market research firm Grand View Research, reported the surgical robot marketplace is projected to reach $14 billion by 2028, up from $3.6 billion this year.
“This new era of robotic-assisted surgery attracts both surgeons and patients. Robotic surgery has reshaped our surgeries over the last 2 decades, and robots are now used in almost in every surgical field. Still, as surgeons, we continue to look – with great interest – to new robotic companies that may be able to provide better robots in a more cost-effective manner,” wrote urologists Ahmad Almujalhem and Koon Ho Rha in a review published in the journal BJUI Compass.
However, the authors wrote that, although the market is competitive, cost remains an issue, as are competing interests. In addition, many companies are creating replicas of existing technologies instead of focusing on new designs and new technology. “Although the da Vinci system propelled many robots to market, there has been no significant improvement in the console,” they added.
The technology is attractive to both surgeons and patients. “Surgeons are attracted to newer technologies, better vision, and easier learning curves. Patients are also attracted to robotic surgery, as this technology is considered state of the art and is associated with reduced pain and scar size,” the authors wrote.
Outcomes depend on many variables
In terms of outcomes, the literature is mixed. It largely depends on a number of variables from the site of surgery, the type of cancer, technology used, and the surgeon’s skill.
Jung Mogg Kim, MD, PhD, a microbiologist with Hanyang University, Seoul, South Korea, published a systemic review and meta-analysis of 27 clinical reports in PLoS ONE assessing clinical outcomes. They found that robot-assisted laparoscopic surgery did not result in statistically superior outcomes, compared with conventional laparoscopic surgery, except for lower estimated blood loss with robots. Operative time and total complications rates were “significantly more favorable” with conventional laparoscopic procedures.
Thomas E. Ahlering, MD, a robotic prostatectomy specialist at the University of California, Irvine, explained that the success or failure of robot-assisted surgery can be highly dependent on the body site and tumor type.
“The oncologic outcome, as long as the surgeon is up to speed, is not going to be better, but the goal is to be as good,” he said in an interview.
In most cases, Dr. Ahlering said, the goal of surgery is to remove a viable tumor with clean margins while leaving the organ intact. But in prostate surgery, the goal is to remove the entire organ while trying to preserve urinary continence and sexual function.
“One of the biggest benefits of the robot is that we’re able to use it in a laparoscopic environment meaning that we need a pneumoperitoneum [which] dramatically decreases bleeding. In prostate cancer, the area is so highly vascular that bleeding is a major issue,” he said.
The same benefits of reduced bleeding, improved visualization, and precision are also seen with robotic-assisted surgery for renal cancer, he noted.
He also emphasized that positive surgical margins, while less desirable than complete elimination of malignant cells, is not nearly as dire in prostate cancer as it is in surgery for other malignancies, such as soft-tissue sarcomas.
“The majority of cases are never going to recur, and if they do recur they essentially never lead to metastatic disease to bone, much less to prostate cancer–related death. The only thing they can do is slightly increase the PSA [prostate-specific antigen] recurrence,” he said.
Assuming that outcomes are comparable between an open procedure, conventional laparoscopic procedure, or robot-assisted approach, surgeons “will almost all go for the robot. It’s easier on the surgeon and it’s easier on the system,” Dr. Ahlering said.
In skilled hands for select patients, the use of a carefully researched and well-designed surgical assistive device can result in outcomes that are comparable with those seen in open surgical procedures, with robot-assisted surgery offering the possibility of less perioperative bleeding, lower postoperative morbidity, and faster recovery times.
“In our program we have been using robots to perform robotic radical prostatectomy and nephron-sparing surgery – partial nephrectomy and we’re also using them to perform intracorporeal bowel reconstruction and robotic radical cystectomy,” said Ashutosh Tewari, MD, of the Icahn School of Medicine at Mount Sinai, New York.
Robot-assisted surgery can be used “anywhere where you have to be selective, anywhere where you have to be reconstructive, anywhere where [assisted] vision can help, anywhere where the lack of bleeding will be of help to patients, and anywhere where a smaller incision can achieve the same goals,” Dr. Tewari said in an interview. Dr. Tewari’s Mount Sinai colleagues reported at the 2021 American Urological Association annual meeting, robotic-assisted salvage radical and partial nephrectomies were found to be safe and feasible procedures in patients with metachronous kidney tumors. For patients with early invasive cancer (stage pT1), oncologic outcomes with robotic-assisted partial nephrectomy were similar to those of patients who underwent radical surgery. The authors concluded that salvage robotic-assisted partial nephrectomy “can be considered in this group of patients due to the risk of future recurrences and need to preserve renal function.”
The National Comprehensive Cancer Network guideline for prostate cancer, updated in September 2021, states that “laparoscopic and robot-assisted radical prostatectomy are commonly used and are considered comparable to conventional approaches in experienced hands.”
In 2018, researchers in a multinational comparison trial reported that patients with cervical cancer who were randomly assigned to minimally invasive robot-assisted radical hysterectomy had significantly lower rates of both disease-free survival and overall survival than women randomized to open abdominal radical hysterectomy. The study results were published in the New England Journal of Medicine.
The use of robotically assisted surgical (RAS) devices could possibly create a “shielding layer” between the surgical team and patient reducing the risk of infection, according to Ajmal Zemmar, MD, PhD, FMH, a neurosurgeon with the University of Louisville (Ky.) Dr. Zemmar and colleagues recently published a perspective in Nature Machine Intelligence on trends in the use of surgical robots.
“In the operating theatre, robots can place intravascular lines, intubate the patient and manage the airway. The integration of a robot as a shielding layer, physically separating the health care worker and patient, is a powerful tool to combat the omnipresent fear of pathogen contamination and maintain surgical volumes,” Dr. Zemmar and colleagues wrote.
Surgical vs. clinical outcomes
In July 2021, this news organization reported that clinical trials of RAS for nipple-sparing mastectomy procedures were looking primarily at cosmetic or surgical outcomes and were not collecting cancer outcomes and if they were, it was secondary to cosmetic or surgical outcomes.
The FDA followed up by issuing a safety communication in August warning patients and providers that neither the safety nor efficacy of RAS for use in mastectomy procedures or treatment of breast cancer have been established.
“In addition, the FDA is aware of allegations that clinical studies are being conducted using RAS devices to perform mastectomies for the prevention or treatment of cancer without the FDA oversight required for such significant risk studies,” the communication stated.
Dr. Tewari disclosed relationships with various companies. Dr. Noorchashm had no relevant disclosures. Dr. Ahlering disclosed past funding or other considerations from Intuitive Robotics.
“The problem in minimally invasive surgery, especially in cancer surgery, is that the concept has been flip-flopped,” said Hooman Noorchashm, MD, PhD, a retired cardiothoracic surgeon turned patient advocate. “The main purpose of surgery should be removal of diseased tissue or repair of damaged tissue with adequate safety. The size of the incision on that triage scheme is secondary.”
In 2013, Dr. Noorchashm’s wife, Amy Reed, MD, an anesthesiologist, had a hysterectomy for treatment of severe uterine fibroids. The surgery was performed with a laparoscopic power morcellator, which led to the dissemination of cells from a previously undetected abdominal lesion. She was later diagnosed with stage 4 leiomyosarcoma and died in May 2017.
Dr. Noorchashm said the problem with robotic surgery isn’t the technology itself or how it’s used, but why it’s used in the first place. “Not only was there an extreme level of laxity with respect to the malignant potential of fibroids, but also that the size of the incision supersedes the safety of the procedure.”
The ultimate goal of oncologic surgery is to achieve an en bloc resection with clean surgical margins and removal of the tumor intact, Dr. Noorchashm said. The only scientific way of showing the benefits or therapeutic equivalence of new technology is through noninferiority comparison trials.
Robotic surgery inching toward $14 billion in revenue by 2028
Although robotic surgical technology has been in use since the 1990s, the technology is still considered to be its infancy. The first Food and Drug Administration–approved robotics platform, the da Vinci Surgical System (Intuitive Surgical) was approved by the FDA in 2000. And, now, with its patent expiring in 2022, competitors will be developing and launching new products for abdominal and colorectal surgery, partial knee replacements, cardiovascular procedures, head and neck surgery, and spinal procedures.
Robotic surgery is a rapidly expanding area with new product launches announced daily. In August 2021, the market research firm Grand View Research, reported the surgical robot marketplace is projected to reach $14 billion by 2028, up from $3.6 billion this year.
“This new era of robotic-assisted surgery attracts both surgeons and patients. Robotic surgery has reshaped our surgeries over the last 2 decades, and robots are now used in almost in every surgical field. Still, as surgeons, we continue to look – with great interest – to new robotic companies that may be able to provide better robots in a more cost-effective manner,” wrote urologists Ahmad Almujalhem and Koon Ho Rha in a review published in the journal BJUI Compass.
However, the authors wrote that, although the market is competitive, cost remains an issue, as are competing interests. In addition, many companies are creating replicas of existing technologies instead of focusing on new designs and new technology. “Although the da Vinci system propelled many robots to market, there has been no significant improvement in the console,” they added.
The technology is attractive to both surgeons and patients. “Surgeons are attracted to newer technologies, better vision, and easier learning curves. Patients are also attracted to robotic surgery, as this technology is considered state of the art and is associated with reduced pain and scar size,” the authors wrote.
Outcomes depend on many variables
In terms of outcomes, the literature is mixed. It largely depends on a number of variables from the site of surgery, the type of cancer, technology used, and the surgeon’s skill.
Jung Mogg Kim, MD, PhD, a microbiologist with Hanyang University, Seoul, South Korea, published a systemic review and meta-analysis of 27 clinical reports in PLoS ONE assessing clinical outcomes. They found that robot-assisted laparoscopic surgery did not result in statistically superior outcomes, compared with conventional laparoscopic surgery, except for lower estimated blood loss with robots. Operative time and total complications rates were “significantly more favorable” with conventional laparoscopic procedures.
Thomas E. Ahlering, MD, a robotic prostatectomy specialist at the University of California, Irvine, explained that the success or failure of robot-assisted surgery can be highly dependent on the body site and tumor type.
“The oncologic outcome, as long as the surgeon is up to speed, is not going to be better, but the goal is to be as good,” he said in an interview.
In most cases, Dr. Ahlering said, the goal of surgery is to remove a viable tumor with clean margins while leaving the organ intact. But in prostate surgery, the goal is to remove the entire organ while trying to preserve urinary continence and sexual function.
“One of the biggest benefits of the robot is that we’re able to use it in a laparoscopic environment meaning that we need a pneumoperitoneum [which] dramatically decreases bleeding. In prostate cancer, the area is so highly vascular that bleeding is a major issue,” he said.
The same benefits of reduced bleeding, improved visualization, and precision are also seen with robotic-assisted surgery for renal cancer, he noted.
He also emphasized that positive surgical margins, while less desirable than complete elimination of malignant cells, is not nearly as dire in prostate cancer as it is in surgery for other malignancies, such as soft-tissue sarcomas.
“The majority of cases are never going to recur, and if they do recur they essentially never lead to metastatic disease to bone, much less to prostate cancer–related death. The only thing they can do is slightly increase the PSA [prostate-specific antigen] recurrence,” he said.
Assuming that outcomes are comparable between an open procedure, conventional laparoscopic procedure, or robot-assisted approach, surgeons “will almost all go for the robot. It’s easier on the surgeon and it’s easier on the system,” Dr. Ahlering said.
In skilled hands for select patients, the use of a carefully researched and well-designed surgical assistive device can result in outcomes that are comparable with those seen in open surgical procedures, with robot-assisted surgery offering the possibility of less perioperative bleeding, lower postoperative morbidity, and faster recovery times.
“In our program we have been using robots to perform robotic radical prostatectomy and nephron-sparing surgery – partial nephrectomy and we’re also using them to perform intracorporeal bowel reconstruction and robotic radical cystectomy,” said Ashutosh Tewari, MD, of the Icahn School of Medicine at Mount Sinai, New York.
Robot-assisted surgery can be used “anywhere where you have to be selective, anywhere where you have to be reconstructive, anywhere where [assisted] vision can help, anywhere where the lack of bleeding will be of help to patients, and anywhere where a smaller incision can achieve the same goals,” Dr. Tewari said in an interview. Dr. Tewari’s Mount Sinai colleagues reported at the 2021 American Urological Association annual meeting, robotic-assisted salvage radical and partial nephrectomies were found to be safe and feasible procedures in patients with metachronous kidney tumors. For patients with early invasive cancer (stage pT1), oncologic outcomes with robotic-assisted partial nephrectomy were similar to those of patients who underwent radical surgery. The authors concluded that salvage robotic-assisted partial nephrectomy “can be considered in this group of patients due to the risk of future recurrences and need to preserve renal function.”
The National Comprehensive Cancer Network guideline for prostate cancer, updated in September 2021, states that “laparoscopic and robot-assisted radical prostatectomy are commonly used and are considered comparable to conventional approaches in experienced hands.”
In 2018, researchers in a multinational comparison trial reported that patients with cervical cancer who were randomly assigned to minimally invasive robot-assisted radical hysterectomy had significantly lower rates of both disease-free survival and overall survival than women randomized to open abdominal radical hysterectomy. The study results were published in the New England Journal of Medicine.
The use of robotically assisted surgical (RAS) devices could possibly create a “shielding layer” between the surgical team and patient reducing the risk of infection, according to Ajmal Zemmar, MD, PhD, FMH, a neurosurgeon with the University of Louisville (Ky.) Dr. Zemmar and colleagues recently published a perspective in Nature Machine Intelligence on trends in the use of surgical robots.
“In the operating theatre, robots can place intravascular lines, intubate the patient and manage the airway. The integration of a robot as a shielding layer, physically separating the health care worker and patient, is a powerful tool to combat the omnipresent fear of pathogen contamination and maintain surgical volumes,” Dr. Zemmar and colleagues wrote.
Surgical vs. clinical outcomes
In July 2021, this news organization reported that clinical trials of RAS for nipple-sparing mastectomy procedures were looking primarily at cosmetic or surgical outcomes and were not collecting cancer outcomes and if they were, it was secondary to cosmetic or surgical outcomes.
The FDA followed up by issuing a safety communication in August warning patients and providers that neither the safety nor efficacy of RAS for use in mastectomy procedures or treatment of breast cancer have been established.
“In addition, the FDA is aware of allegations that clinical studies are being conducted using RAS devices to perform mastectomies for the prevention or treatment of cancer without the FDA oversight required for such significant risk studies,” the communication stated.
Dr. Tewari disclosed relationships with various companies. Dr. Noorchashm had no relevant disclosures. Dr. Ahlering disclosed past funding or other considerations from Intuitive Robotics.
Many patients, doctors unaware of advancements in cancer care
This is the main finding from two studies presented at the 2021 European Society for Medical Oncology Congress.
The survey of patients found that most don’t understand how immunotherapy works, and the survey of doctors found that many working outside of the cancer field are using information on survival that is wildly out of date.
When a patient is first told they have cancer, counseling is usually done by a surgeon or general medical doctor and not an oncologist, said Conleth Murphy, MD, of Bon Secours Hospital Cork, Ireland, and coauthor of the second study.
Noncancer doctors often grossly underestimate patients’ chances of survival, Dr. Murphy’s study found. This suggests that doctors who practice outside of cancer care may be working with the same information they learned in medical school, he said.
“These patients must be spared the traumatic effects of being handed a death sentence that no longer reflects the current reality,” Dr. Murphy said.
After receiving a diagnosis of cancer, “patients often immediately have pressing questions about what it means for their future,” he noted. A common question is: “How long do I have left?”
Nononcologists should refrain from answering patients’ questions with numbers, Dr. Murphy said.
Family doctors are likely to be influenced by the experience they have had with specific cancer patients in their practice, said Cyril Bonin, MD, a general practitioner in Usson-du-Poitou, France, who has 900 patients in his practice.
He sees about 10 patients with a new diagnosis of cancer each year. In addition, about 50 of his patients are in active treatment for cancer or have finished treatment and are considered cancer survivors.
“It is not entirely realistic for us to expect practitioners who deal with hundreds of different diseases to keep up with every facet of a rapidly changing oncology landscape,” said Marco Donia, MD, an expert in immunotherapy from the University of Copenhagen.
That landscape has changed dramatically in recent years, particularly since immunotherapy was added to the arsenal. Immunotherapy is a way to fine-tune your immune system to fight cancer.
For example, in the past, patients with metastatic melanoma would have an average survival of about 1 year. But now, some patients who have responded to immunotherapy are still alive 10 years later.
Findings from the patient survey
It is important that patients stay well informed because immunotherapy is a “complex treatment that is too often mistaken for a miracle cure,” said Paris Kosmidis, MD, the co-author of the patient survey.
“The more patients know about it, the better the communication with their medical team and thus the better their outcomes are likely to be,” said Dr. Kosmidis, who is co-founder and chief medical officer of CareAcross, an online service that provides personalized education for cancer patients
The survey was of 5,589 patients with cancer who were recruited from CareAcross clients from the United Kingdom, France, Italy, Spain, and Germany.
The survey asked them about how immunotherapy works, what it costs, and its side effects.
Almost half responded “not sure/do not know,” but about a third correctly answered that immunotherapy “activates the immune system to kill cancer cells.”
Similarly, more than half thought that immunotherapy started working right away, while only 20% correctly answered that it takes several weeks to become effective.
“This is important because patients need to start their therapy with realistic expectations, for example to avoid disappointment when their symptoms take some time to disappear,” Dr. Kosmidis said.
A small group of 24 patients with lung cancer who had been treated with immunotherapy got many correct answers, but they overestimated the intensity of side effects, compared with other therapies.
“Well-informed patients who know what to expect can do 90% of the job of preventing side effects from becoming severe by having them treated early,” said Dr. Donia, of the University of Copenhagen.
Most cancer patients were also unaware of the cost of immunotherapy, which can exceed $100,000 a year, Dr. Kosmidis said.
Results of the doctor survey
The other survey presented at the meeting looked at how much doctors know about survival for 12 of the most common cancers.
Dr. Murphy and colleagues asked 301 noncancer doctors and 46 cancer specialists to estimate the percentage of patients who could be expected to live for 5 years after diagnosis (a measure known as the 5-year survival rate).
Answers from the two groups were compared and graded according to cancer survival statistics from the National Cancer Registry of Ireland.
Both groups of doctors had a hard time estimating the survival of common cancers.
Nononcologists accurately predicted 5-year survival for just two of the cancer types, while the cancer specialists got it right for four cancer types.
However, the noncancer doctors had a more pessimistic outlook on cancer survival generally and severely underestimated the chances of survival in specific cancers, particularly stage IV breast cancer. The survival for this cancer has “evolved considerably over time and now reaches 40% in Ireland,” Dr. Murphy pointed out.
“These results are in line with what we had expected because most physicians’ knowledge of oncology dates back to whatever education they received during their years of training, so their perceptions of cancer prognosis are likely to lag behind the major survival gains achieved in the recent past,” Dr. Murphy said.
A version of this article first appeared on Medscape.com.
This is the main finding from two studies presented at the 2021 European Society for Medical Oncology Congress.
The survey of patients found that most don’t understand how immunotherapy works, and the survey of doctors found that many working outside of the cancer field are using information on survival that is wildly out of date.
When a patient is first told they have cancer, counseling is usually done by a surgeon or general medical doctor and not an oncologist, said Conleth Murphy, MD, of Bon Secours Hospital Cork, Ireland, and coauthor of the second study.
Noncancer doctors often grossly underestimate patients’ chances of survival, Dr. Murphy’s study found. This suggests that doctors who practice outside of cancer care may be working with the same information they learned in medical school, he said.
“These patients must be spared the traumatic effects of being handed a death sentence that no longer reflects the current reality,” Dr. Murphy said.
After receiving a diagnosis of cancer, “patients often immediately have pressing questions about what it means for their future,” he noted. A common question is: “How long do I have left?”
Nononcologists should refrain from answering patients’ questions with numbers, Dr. Murphy said.
Family doctors are likely to be influenced by the experience they have had with specific cancer patients in their practice, said Cyril Bonin, MD, a general practitioner in Usson-du-Poitou, France, who has 900 patients in his practice.
He sees about 10 patients with a new diagnosis of cancer each year. In addition, about 50 of his patients are in active treatment for cancer or have finished treatment and are considered cancer survivors.
“It is not entirely realistic for us to expect practitioners who deal with hundreds of different diseases to keep up with every facet of a rapidly changing oncology landscape,” said Marco Donia, MD, an expert in immunotherapy from the University of Copenhagen.
That landscape has changed dramatically in recent years, particularly since immunotherapy was added to the arsenal. Immunotherapy is a way to fine-tune your immune system to fight cancer.
For example, in the past, patients with metastatic melanoma would have an average survival of about 1 year. But now, some patients who have responded to immunotherapy are still alive 10 years later.
Findings from the patient survey
It is important that patients stay well informed because immunotherapy is a “complex treatment that is too often mistaken for a miracle cure,” said Paris Kosmidis, MD, the co-author of the patient survey.
“The more patients know about it, the better the communication with their medical team and thus the better their outcomes are likely to be,” said Dr. Kosmidis, who is co-founder and chief medical officer of CareAcross, an online service that provides personalized education for cancer patients
The survey was of 5,589 patients with cancer who were recruited from CareAcross clients from the United Kingdom, France, Italy, Spain, and Germany.
The survey asked them about how immunotherapy works, what it costs, and its side effects.
Almost half responded “not sure/do not know,” but about a third correctly answered that immunotherapy “activates the immune system to kill cancer cells.”
Similarly, more than half thought that immunotherapy started working right away, while only 20% correctly answered that it takes several weeks to become effective.
“This is important because patients need to start their therapy with realistic expectations, for example to avoid disappointment when their symptoms take some time to disappear,” Dr. Kosmidis said.
A small group of 24 patients with lung cancer who had been treated with immunotherapy got many correct answers, but they overestimated the intensity of side effects, compared with other therapies.
“Well-informed patients who know what to expect can do 90% of the job of preventing side effects from becoming severe by having them treated early,” said Dr. Donia, of the University of Copenhagen.
Most cancer patients were also unaware of the cost of immunotherapy, which can exceed $100,000 a year, Dr. Kosmidis said.
Results of the doctor survey
The other survey presented at the meeting looked at how much doctors know about survival for 12 of the most common cancers.
Dr. Murphy and colleagues asked 301 noncancer doctors and 46 cancer specialists to estimate the percentage of patients who could be expected to live for 5 years after diagnosis (a measure known as the 5-year survival rate).
Answers from the two groups were compared and graded according to cancer survival statistics from the National Cancer Registry of Ireland.
Both groups of doctors had a hard time estimating the survival of common cancers.
Nononcologists accurately predicted 5-year survival for just two of the cancer types, while the cancer specialists got it right for four cancer types.
However, the noncancer doctors had a more pessimistic outlook on cancer survival generally and severely underestimated the chances of survival in specific cancers, particularly stage IV breast cancer. The survival for this cancer has “evolved considerably over time and now reaches 40% in Ireland,” Dr. Murphy pointed out.
“These results are in line with what we had expected because most physicians’ knowledge of oncology dates back to whatever education they received during their years of training, so their perceptions of cancer prognosis are likely to lag behind the major survival gains achieved in the recent past,” Dr. Murphy said.
A version of this article first appeared on Medscape.com.
This is the main finding from two studies presented at the 2021 European Society for Medical Oncology Congress.
The survey of patients found that most don’t understand how immunotherapy works, and the survey of doctors found that many working outside of the cancer field are using information on survival that is wildly out of date.
When a patient is first told they have cancer, counseling is usually done by a surgeon or general medical doctor and not an oncologist, said Conleth Murphy, MD, of Bon Secours Hospital Cork, Ireland, and coauthor of the second study.
Noncancer doctors often grossly underestimate patients’ chances of survival, Dr. Murphy’s study found. This suggests that doctors who practice outside of cancer care may be working with the same information they learned in medical school, he said.
“These patients must be spared the traumatic effects of being handed a death sentence that no longer reflects the current reality,” Dr. Murphy said.
After receiving a diagnosis of cancer, “patients often immediately have pressing questions about what it means for their future,” he noted. A common question is: “How long do I have left?”
Nononcologists should refrain from answering patients’ questions with numbers, Dr. Murphy said.
Family doctors are likely to be influenced by the experience they have had with specific cancer patients in their practice, said Cyril Bonin, MD, a general practitioner in Usson-du-Poitou, France, who has 900 patients in his practice.
He sees about 10 patients with a new diagnosis of cancer each year. In addition, about 50 of his patients are in active treatment for cancer or have finished treatment and are considered cancer survivors.
“It is not entirely realistic for us to expect practitioners who deal with hundreds of different diseases to keep up with every facet of a rapidly changing oncology landscape,” said Marco Donia, MD, an expert in immunotherapy from the University of Copenhagen.
That landscape has changed dramatically in recent years, particularly since immunotherapy was added to the arsenal. Immunotherapy is a way to fine-tune your immune system to fight cancer.
For example, in the past, patients with metastatic melanoma would have an average survival of about 1 year. But now, some patients who have responded to immunotherapy are still alive 10 years later.
Findings from the patient survey
It is important that patients stay well informed because immunotherapy is a “complex treatment that is too often mistaken for a miracle cure,” said Paris Kosmidis, MD, the co-author of the patient survey.
“The more patients know about it, the better the communication with their medical team and thus the better their outcomes are likely to be,” said Dr. Kosmidis, who is co-founder and chief medical officer of CareAcross, an online service that provides personalized education for cancer patients
The survey was of 5,589 patients with cancer who were recruited from CareAcross clients from the United Kingdom, France, Italy, Spain, and Germany.
The survey asked them about how immunotherapy works, what it costs, and its side effects.
Almost half responded “not sure/do not know,” but about a third correctly answered that immunotherapy “activates the immune system to kill cancer cells.”
Similarly, more than half thought that immunotherapy started working right away, while only 20% correctly answered that it takes several weeks to become effective.
“This is important because patients need to start their therapy with realistic expectations, for example to avoid disappointment when their symptoms take some time to disappear,” Dr. Kosmidis said.
A small group of 24 patients with lung cancer who had been treated with immunotherapy got many correct answers, but they overestimated the intensity of side effects, compared with other therapies.
“Well-informed patients who know what to expect can do 90% of the job of preventing side effects from becoming severe by having them treated early,” said Dr. Donia, of the University of Copenhagen.
Most cancer patients were also unaware of the cost of immunotherapy, which can exceed $100,000 a year, Dr. Kosmidis said.
Results of the doctor survey
The other survey presented at the meeting looked at how much doctors know about survival for 12 of the most common cancers.
Dr. Murphy and colleagues asked 301 noncancer doctors and 46 cancer specialists to estimate the percentage of patients who could be expected to live for 5 years after diagnosis (a measure known as the 5-year survival rate).
Answers from the two groups were compared and graded according to cancer survival statistics from the National Cancer Registry of Ireland.
Both groups of doctors had a hard time estimating the survival of common cancers.
Nononcologists accurately predicted 5-year survival for just two of the cancer types, while the cancer specialists got it right for four cancer types.
However, the noncancer doctors had a more pessimistic outlook on cancer survival generally and severely underestimated the chances of survival in specific cancers, particularly stage IV breast cancer. The survival for this cancer has “evolved considerably over time and now reaches 40% in Ireland,” Dr. Murphy pointed out.
“These results are in line with what we had expected because most physicians’ knowledge of oncology dates back to whatever education they received during their years of training, so their perceptions of cancer prognosis are likely to lag behind the major survival gains achieved in the recent past,” Dr. Murphy said.
A version of this article first appeared on Medscape.com.
Most community-based oncologists skip biomarker testing
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
REPORTING FROM WCLC 2020
FDA grants zanubrutinib an accelerated approval in marginal zone lymphoma
The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.
The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.
The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.
The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.
In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”
In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.
The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.
In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.
The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.
In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.
The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.
The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.
The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.
The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.
In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”
In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.
The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.
In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.
The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.
In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.
The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.
The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.
The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.
The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.
In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”
In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.
The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.
In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.
The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.
In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.
The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.
A version of this article first appeared on Medscape.com.
Can reversing T-cell exhaustion benefit in B-cell lymphoma relapse?
Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.
To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.
Success for some
Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.
In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
Looking forward
“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.
The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.
Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.
To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.
Success for some
Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.
In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
Looking forward
“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.
The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.
Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.
To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.
Success for some
Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.
In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
Looking forward
“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.
The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.
FROM BLOOD
Evans’ Syndrome in Undiagnosed Small Lymphocytic Lymphoma: Case Report and Literature Review
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
FDA approves zanubrutinib in Waldenström’s macroglobulinemia
The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.
The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.
The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.
The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.
The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.
The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.
In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.
The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.
The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.
An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).
The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).
In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.
The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.
The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.
The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.
The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.
The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.
In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.
The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.
The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.
An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).
The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).
In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.
The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.
The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.
The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.
The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.
The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.
In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.
The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.
The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.
An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).
The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).
In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
A version of this article first appeared on Medscape.com.
FDA warns of higher death risk with Pepaxto in multiple myeloma
participating in the ongoing OCEAN clinical trial.
The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.
Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.
The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.
Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”
The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
Accelerated approval data
Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.
Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
Confirmatory trial data
The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.
The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.
“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.
The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.
Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.
A version of this article first appeared on Medscape.com.
participating in the ongoing OCEAN clinical trial.
The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.
Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.
The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.
Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”
The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
Accelerated approval data
Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.
Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
Confirmatory trial data
The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.
The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.
“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.
The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.
Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.
A version of this article first appeared on Medscape.com.
participating in the ongoing OCEAN clinical trial.
The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.
Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.
The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.
Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”
The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
Accelerated approval data
Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.
Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.
Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
Confirmatory trial data
The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.
The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.
“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.
The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.
Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.
A version of this article first appeared on Medscape.com.