User login
Powerful breast-implant testimony constrained by limited evidence
What’s the role of anecdotal medical histories in the era of evidence-based medicine?
But the anecdotal histories fell short of producing a clear committee consensus on dramatic, immediate changes in FDA policy, such as joining a renewed ban on certain types of breast implants linked with a rare lymphoma, a step recently taken by 38 other countries, including 33 European countries acting in concert through the European Union.
The disconnect between gripping testimony and limited panel recommendations was most stark for a complication that’s been named Breast Implant Illness (BII) by patients on the Internet. Many breast implant recipients have reported life-changing symptoms that appeared after implant placement, most often fatigue, joint and muscle pain, brain fog, neurologic symptoms, immune dysfunction, skin manifestations, and autoimmune disease or symptoms. By my count, 22 people spoke about their harrowing experiences with BII symptoms out of the 77 who stepped to the panel’s public-comment mic during 4 hours of public testimony over 2-days of hearings, often saying that they had experienced dramatic improvements after their implants came out. The meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee also heard presentations from two experts who ran some of the first reported studies on BII, or a BII-like syndrome called Autoimmune Syndrome Induced by Adjuvants (ASIA) described by Jan W.C. Tervaert, MD, professor of medicine and director of rheumatology at the University of Alberta in Edmonton. Dr. Tervaert and his associates published their findings about ASIA in the rheumatology literature last year (Clin Rheumatol. 2018 Feb;37[2]:483-93), and during his talk before the FDA panel, he said that silicone breast implants and the surgical mesh often used with them could be ASIA triggers.
Panel members seemed to mostly believe that the evidence they heard about BII did no more than hint at a possible association between breast implants and BII symptoms that required additional study. Many agreed on the need to include mention of the most common BII-linked patient complaints in informed consent material, but some were reluctant about even taking that step.
“I do not mention BII to patients. It’s not a disease; it’s a constellation of symptoms,” said panel member and plastic surgeon Pierre M. Chevray, MD, from Houston Methodist Hospital. The evidence for BII “is extremely anecdotal,” he said in an interview at the end of the 2-day session. Descriptions of BII “have been mainly published on social media. One reason why I don’t tell patients [about BII as part of informed consent] is because right now the evidence of a link is weak. We don’t yet even have a definition of this as an illness. A first step is to define it,” said Dr. Chevray, who has a very active implant practice. Other plastic surgeons were more accepting of BII as a real complication, although they agreed it needs much more study. During the testimony period, St. Louis plastic surgeon Patricia A. McGuire, MD, highlighted the challenge of teasing apart whether real symptoms are truly related to implants or are simply common ailments that accumulate during middle-age in many women. Dr. McGuire and some of her associates published an assessment of the challenges and possible solutions to studying BII that appeared shortly before the hearing (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S),
Consensus recommendations from the panel to the FDA to address BII included having a single registry that would include all U.S. patients who receive breast implants (recently launched as the National Breast Implant Registry), inclusion of a control group, and collection of data at baseline and after regular follow-up intervals that includes a variety of measures relevant to autoimmune and rheumatologic disorders. Several panel members cited inadequate postmarketing safety surveillance by manufacturers in the years since breast implants returned to the U.S. market, and earlier in March, the FDA issued warning letters to two of the four companies that market U.S. breast implants over their inadequate long-term safety follow-up.
The panel’s decisions about the other major implant-associated health risk it considered, breast implant associated anaplastic large cell lymphoma (BIA-ALCL), faced a different sort of challenge. First described as linked to breast implants in 2011, today there is little doubt that BIA-ALCL is a consequence of breast implants, what several patients derisively called a “man-made cancer.” The key issue the committee grappled with was whether the calculated incidence of BIA-ALCL was at a frequency that warranted a ban on at least selected breast implant types. Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, told the panel that he calculated the Allergan Biocell group of implants, which have textured surfaces that allows for easier and more stable placement in patients, linked with an incidence of BIA-ALCL that was sevenfold to eightfold higher than that with smooth implants. That’s against a background of an overall incidence of about one case for every 20,000 U.S. implant recipients, Dr. Clemens said.
Many testifying patients, including several of the eight who described a personal history of BIA-ALCL, called for a ban on the sale of at least some breast implants because of their role in causing lymphoma. That sentiment was shared by Dr. Chevray, who endorsed a ban on “salt-loss” implants (the method that makes Biocell implants) during his closing comments to his fellow panel members. But earlier during panel discussions, others on the committee pushed back against implant bans, leaving the FDA’s eventual decision on this issue unclear. Evidence presented during the hearings suggests that implants cause ALCL by triggering a local “inflammatory milieu” and that different types of implants can have varying levels of potency for producing this milieu.
Perhaps the closest congruence between what patients called for and what the committee recommended was on informed consent. “No doubt, patients feel that informed consent failed them,” concluded panel member Karen E. Burke, MD, a New York dermatologist who was one of two panel discussants for the topic.
In addition to many suggestions on how to improve informed consent and public awareness lobbed at FDA staffers during the session by panel members, the final public comment of the 2 days came from Laurie A. Casas, MD, a Chicago plastic surgeon affiliated with the University of Chicago and a member of the board of directors of the American Society of Aesthetic Plastic Surgery (also know as the Aesthetic Society). During her testimony, Dr. Casas said “Over the past 2 days, we heard that patients need a structured educational checklist for informed consent. The Aesthetic Society hears you,” and promised that the website of the Society’s publication, the Aesthetic Surgery Journal, will soon feature a safety checklist for people receiving breast implants that will get updated as new information becomes available. She also highlighted the need for a comprehensive registry and long-term follow-up of implant recipients by the plastic surgeons who treated them.
In addition to better informed consent, patients who came to the hearing clearly also hoped to raise awareness in the general American public about the potential dangers from breast implants and the need to follow patients who receive implants. The 2 days of hearing accomplished that in part just by taking place. The New York Times and The Washington Post ran at least a couple of articles apiece on implant safety just before or during the hearings, while a more regional paper, the Philadelphia Inquirer, ran one article, as presumably did many other newspapers, broadcast outlets, and websites across America. Much of the coverage focused on compelling and moving personal stories from patients.
Women who have been having adverse effects from breast implants “have felt dismissed,” noted panel member Natalie C. Portis, PhD, a clinical psychologist from Oakland, Calif., and the patient representative on the advisory committee. “We need to listen to women that something real is happening.”
Dr. Tervaert, Dr. Chevray, Dr. McGuire, Dr. Clemens, Dr. Burke, Dr. Casas, and Dr. Portis had no relevant commercial disclosures.
What’s the role of anecdotal medical histories in the era of evidence-based medicine?
But the anecdotal histories fell short of producing a clear committee consensus on dramatic, immediate changes in FDA policy, such as joining a renewed ban on certain types of breast implants linked with a rare lymphoma, a step recently taken by 38 other countries, including 33 European countries acting in concert through the European Union.
The disconnect between gripping testimony and limited panel recommendations was most stark for a complication that’s been named Breast Implant Illness (BII) by patients on the Internet. Many breast implant recipients have reported life-changing symptoms that appeared after implant placement, most often fatigue, joint and muscle pain, brain fog, neurologic symptoms, immune dysfunction, skin manifestations, and autoimmune disease or symptoms. By my count, 22 people spoke about their harrowing experiences with BII symptoms out of the 77 who stepped to the panel’s public-comment mic during 4 hours of public testimony over 2-days of hearings, often saying that they had experienced dramatic improvements after their implants came out. The meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee also heard presentations from two experts who ran some of the first reported studies on BII, or a BII-like syndrome called Autoimmune Syndrome Induced by Adjuvants (ASIA) described by Jan W.C. Tervaert, MD, professor of medicine and director of rheumatology at the University of Alberta in Edmonton. Dr. Tervaert and his associates published their findings about ASIA in the rheumatology literature last year (Clin Rheumatol. 2018 Feb;37[2]:483-93), and during his talk before the FDA panel, he said that silicone breast implants and the surgical mesh often used with them could be ASIA triggers.
Panel members seemed to mostly believe that the evidence they heard about BII did no more than hint at a possible association between breast implants and BII symptoms that required additional study. Many agreed on the need to include mention of the most common BII-linked patient complaints in informed consent material, but some were reluctant about even taking that step.
“I do not mention BII to patients. It’s not a disease; it’s a constellation of symptoms,” said panel member and plastic surgeon Pierre M. Chevray, MD, from Houston Methodist Hospital. The evidence for BII “is extremely anecdotal,” he said in an interview at the end of the 2-day session. Descriptions of BII “have been mainly published on social media. One reason why I don’t tell patients [about BII as part of informed consent] is because right now the evidence of a link is weak. We don’t yet even have a definition of this as an illness. A first step is to define it,” said Dr. Chevray, who has a very active implant practice. Other plastic surgeons were more accepting of BII as a real complication, although they agreed it needs much more study. During the testimony period, St. Louis plastic surgeon Patricia A. McGuire, MD, highlighted the challenge of teasing apart whether real symptoms are truly related to implants or are simply common ailments that accumulate during middle-age in many women. Dr. McGuire and some of her associates published an assessment of the challenges and possible solutions to studying BII that appeared shortly before the hearing (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S),
Consensus recommendations from the panel to the FDA to address BII included having a single registry that would include all U.S. patients who receive breast implants (recently launched as the National Breast Implant Registry), inclusion of a control group, and collection of data at baseline and after regular follow-up intervals that includes a variety of measures relevant to autoimmune and rheumatologic disorders. Several panel members cited inadequate postmarketing safety surveillance by manufacturers in the years since breast implants returned to the U.S. market, and earlier in March, the FDA issued warning letters to two of the four companies that market U.S. breast implants over their inadequate long-term safety follow-up.
The panel’s decisions about the other major implant-associated health risk it considered, breast implant associated anaplastic large cell lymphoma (BIA-ALCL), faced a different sort of challenge. First described as linked to breast implants in 2011, today there is little doubt that BIA-ALCL is a consequence of breast implants, what several patients derisively called a “man-made cancer.” The key issue the committee grappled with was whether the calculated incidence of BIA-ALCL was at a frequency that warranted a ban on at least selected breast implant types. Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, told the panel that he calculated the Allergan Biocell group of implants, which have textured surfaces that allows for easier and more stable placement in patients, linked with an incidence of BIA-ALCL that was sevenfold to eightfold higher than that with smooth implants. That’s against a background of an overall incidence of about one case for every 20,000 U.S. implant recipients, Dr. Clemens said.
Many testifying patients, including several of the eight who described a personal history of BIA-ALCL, called for a ban on the sale of at least some breast implants because of their role in causing lymphoma. That sentiment was shared by Dr. Chevray, who endorsed a ban on “salt-loss” implants (the method that makes Biocell implants) during his closing comments to his fellow panel members. But earlier during panel discussions, others on the committee pushed back against implant bans, leaving the FDA’s eventual decision on this issue unclear. Evidence presented during the hearings suggests that implants cause ALCL by triggering a local “inflammatory milieu” and that different types of implants can have varying levels of potency for producing this milieu.
Perhaps the closest congruence between what patients called for and what the committee recommended was on informed consent. “No doubt, patients feel that informed consent failed them,” concluded panel member Karen E. Burke, MD, a New York dermatologist who was one of two panel discussants for the topic.
In addition to many suggestions on how to improve informed consent and public awareness lobbed at FDA staffers during the session by panel members, the final public comment of the 2 days came from Laurie A. Casas, MD, a Chicago plastic surgeon affiliated with the University of Chicago and a member of the board of directors of the American Society of Aesthetic Plastic Surgery (also know as the Aesthetic Society). During her testimony, Dr. Casas said “Over the past 2 days, we heard that patients need a structured educational checklist for informed consent. The Aesthetic Society hears you,” and promised that the website of the Society’s publication, the Aesthetic Surgery Journal, will soon feature a safety checklist for people receiving breast implants that will get updated as new information becomes available. She also highlighted the need for a comprehensive registry and long-term follow-up of implant recipients by the plastic surgeons who treated them.
In addition to better informed consent, patients who came to the hearing clearly also hoped to raise awareness in the general American public about the potential dangers from breast implants and the need to follow patients who receive implants. The 2 days of hearing accomplished that in part just by taking place. The New York Times and The Washington Post ran at least a couple of articles apiece on implant safety just before or during the hearings, while a more regional paper, the Philadelphia Inquirer, ran one article, as presumably did many other newspapers, broadcast outlets, and websites across America. Much of the coverage focused on compelling and moving personal stories from patients.
Women who have been having adverse effects from breast implants “have felt dismissed,” noted panel member Natalie C. Portis, PhD, a clinical psychologist from Oakland, Calif., and the patient representative on the advisory committee. “We need to listen to women that something real is happening.”
Dr. Tervaert, Dr. Chevray, Dr. McGuire, Dr. Clemens, Dr. Burke, Dr. Casas, and Dr. Portis had no relevant commercial disclosures.
What’s the role of anecdotal medical histories in the era of evidence-based medicine?
But the anecdotal histories fell short of producing a clear committee consensus on dramatic, immediate changes in FDA policy, such as joining a renewed ban on certain types of breast implants linked with a rare lymphoma, a step recently taken by 38 other countries, including 33 European countries acting in concert through the European Union.
The disconnect between gripping testimony and limited panel recommendations was most stark for a complication that’s been named Breast Implant Illness (BII) by patients on the Internet. Many breast implant recipients have reported life-changing symptoms that appeared after implant placement, most often fatigue, joint and muscle pain, brain fog, neurologic symptoms, immune dysfunction, skin manifestations, and autoimmune disease or symptoms. By my count, 22 people spoke about their harrowing experiences with BII symptoms out of the 77 who stepped to the panel’s public-comment mic during 4 hours of public testimony over 2-days of hearings, often saying that they had experienced dramatic improvements after their implants came out. The meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee also heard presentations from two experts who ran some of the first reported studies on BII, or a BII-like syndrome called Autoimmune Syndrome Induced by Adjuvants (ASIA) described by Jan W.C. Tervaert, MD, professor of medicine and director of rheumatology at the University of Alberta in Edmonton. Dr. Tervaert and his associates published their findings about ASIA in the rheumatology literature last year (Clin Rheumatol. 2018 Feb;37[2]:483-93), and during his talk before the FDA panel, he said that silicone breast implants and the surgical mesh often used with them could be ASIA triggers.
Panel members seemed to mostly believe that the evidence they heard about BII did no more than hint at a possible association between breast implants and BII symptoms that required additional study. Many agreed on the need to include mention of the most common BII-linked patient complaints in informed consent material, but some were reluctant about even taking that step.
“I do not mention BII to patients. It’s not a disease; it’s a constellation of symptoms,” said panel member and plastic surgeon Pierre M. Chevray, MD, from Houston Methodist Hospital. The evidence for BII “is extremely anecdotal,” he said in an interview at the end of the 2-day session. Descriptions of BII “have been mainly published on social media. One reason why I don’t tell patients [about BII as part of informed consent] is because right now the evidence of a link is weak. We don’t yet even have a definition of this as an illness. A first step is to define it,” said Dr. Chevray, who has a very active implant practice. Other plastic surgeons were more accepting of BII as a real complication, although they agreed it needs much more study. During the testimony period, St. Louis plastic surgeon Patricia A. McGuire, MD, highlighted the challenge of teasing apart whether real symptoms are truly related to implants or are simply common ailments that accumulate during middle-age in many women. Dr. McGuire and some of her associates published an assessment of the challenges and possible solutions to studying BII that appeared shortly before the hearing (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S),
Consensus recommendations from the panel to the FDA to address BII included having a single registry that would include all U.S. patients who receive breast implants (recently launched as the National Breast Implant Registry), inclusion of a control group, and collection of data at baseline and after regular follow-up intervals that includes a variety of measures relevant to autoimmune and rheumatologic disorders. Several panel members cited inadequate postmarketing safety surveillance by manufacturers in the years since breast implants returned to the U.S. market, and earlier in March, the FDA issued warning letters to two of the four companies that market U.S. breast implants over their inadequate long-term safety follow-up.
The panel’s decisions about the other major implant-associated health risk it considered, breast implant associated anaplastic large cell lymphoma (BIA-ALCL), faced a different sort of challenge. First described as linked to breast implants in 2011, today there is little doubt that BIA-ALCL is a consequence of breast implants, what several patients derisively called a “man-made cancer.” The key issue the committee grappled with was whether the calculated incidence of BIA-ALCL was at a frequency that warranted a ban on at least selected breast implant types. Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, told the panel that he calculated the Allergan Biocell group of implants, which have textured surfaces that allows for easier and more stable placement in patients, linked with an incidence of BIA-ALCL that was sevenfold to eightfold higher than that with smooth implants. That’s against a background of an overall incidence of about one case for every 20,000 U.S. implant recipients, Dr. Clemens said.
Many testifying patients, including several of the eight who described a personal history of BIA-ALCL, called for a ban on the sale of at least some breast implants because of their role in causing lymphoma. That sentiment was shared by Dr. Chevray, who endorsed a ban on “salt-loss” implants (the method that makes Biocell implants) during his closing comments to his fellow panel members. But earlier during panel discussions, others on the committee pushed back against implant bans, leaving the FDA’s eventual decision on this issue unclear. Evidence presented during the hearings suggests that implants cause ALCL by triggering a local “inflammatory milieu” and that different types of implants can have varying levels of potency for producing this milieu.
Perhaps the closest congruence between what patients called for and what the committee recommended was on informed consent. “No doubt, patients feel that informed consent failed them,” concluded panel member Karen E. Burke, MD, a New York dermatologist who was one of two panel discussants for the topic.
In addition to many suggestions on how to improve informed consent and public awareness lobbed at FDA staffers during the session by panel members, the final public comment of the 2 days came from Laurie A. Casas, MD, a Chicago plastic surgeon affiliated with the University of Chicago and a member of the board of directors of the American Society of Aesthetic Plastic Surgery (also know as the Aesthetic Society). During her testimony, Dr. Casas said “Over the past 2 days, we heard that patients need a structured educational checklist for informed consent. The Aesthetic Society hears you,” and promised that the website of the Society’s publication, the Aesthetic Surgery Journal, will soon feature a safety checklist for people receiving breast implants that will get updated as new information becomes available. She also highlighted the need for a comprehensive registry and long-term follow-up of implant recipients by the plastic surgeons who treated them.
In addition to better informed consent, patients who came to the hearing clearly also hoped to raise awareness in the general American public about the potential dangers from breast implants and the need to follow patients who receive implants. The 2 days of hearing accomplished that in part just by taking place. The New York Times and The Washington Post ran at least a couple of articles apiece on implant safety just before or during the hearings, while a more regional paper, the Philadelphia Inquirer, ran one article, as presumably did many other newspapers, broadcast outlets, and websites across America. Much of the coverage focused on compelling and moving personal stories from patients.
Women who have been having adverse effects from breast implants “have felt dismissed,” noted panel member Natalie C. Portis, PhD, a clinical psychologist from Oakland, Calif., and the patient representative on the advisory committee. “We need to listen to women that something real is happening.”
Dr. Tervaert, Dr. Chevray, Dr. McGuire, Dr. Clemens, Dr. Burke, Dr. Casas, and Dr. Portis had no relevant commercial disclosures.
UNITY-NHL: Interim findings show activity, tolerability of umbralisib for R/R MZL
ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.
The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.
The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.
The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.
Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.
“Most patients who have responded continue on drug,” he said in a video interview.
Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.
“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”
ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.
The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.
The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.
The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.
Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.
“Most patients who have responded continue on drug,” he said in a video interview.
Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.
“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”
ATLANTA – The phosphoinositide 3-kinase (PI3K) delta inhibitor umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, according to findings from the ongoing phase 2 UNITY-NHL study.
The best overall response rate (ORR) among 42 study participants with at least 9 months of follow-up was 52% by both independent review committee (IRC) and investigator assessment, and the complete response rate was 19%, Nathan H. Fowler, MD, reported at the annual meeting of the American Association for Cancer Research.
The ORR by IRC assessment for those with extranodal, nodal, and splenic disease was 57%, 42%, and 43%, respectively, and for those with prior chemo-immunotherapy and those refractory to their last line of therapy, the ORR was 53% and 38%, respectively, said Dr. Fowler of MD Anderson Cancer Center, Houston.
The clinical benefit rate was 88%, and the median duration of response and progression-free survival (PFS) have not been reached; 12-month PFS is estimated at 66%, he added.
Patients in the marginal zone lymphoma cohort of the multicohort trial, which is evaluating umbralisib both as monotherapy and as part of various combinations in patients with previously treated non-Hodgkin’s lymphoma, received single agent umbralisib at a dose of 800 mg daily until disease progression or unacceptable toxicity.
“Most patients who have responded continue on drug,” he said in a video interview.
Dr. Fowler also further discussed the findings to date with respect to response, adverse events, and future directions in the wake of the breakthrough therapy designation recently granted by the Food and Drug Administration for umbralisib based on these findings.
“Despite the fact that a lot of things work in the front line, when patients relapse, especially when they become refractory to rituximab, there are limited options available,” he said, noting that currently used treatments are associated with significant adverse event and short remission times. “We still need better options.”
REPORTING FROM AACR 2019
FDA panel calls for changes to breast implant rupture screening
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
AT AN FDA ADVISORY PANEL MEETING
FDA panel leans toward more robust breast implant surveillance
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
Therapeutic dosing of busulfan helps reduce relapse in ASCT
HOUSTON – Compared with weight-based dosing, pharmacokinetic-directed therapeutic dose monitoring of busulfan used in combination with cyclophosphamide and etoposide reduced relapse risk in non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT), according to a review of 336 cases.
This was particularly true in patients with less than a complete response at the time of transplant, Brian T. Hill, MD, PhD, reported at the Transplantation & Cellular Therapy Meetings.
The relapse rate at 24 months after ASCT was 19% in 78 adult NHL patients who underwent ASCT with pharmacokinetic-guided therapeutic dose monitoring (PK-TDM), compared with 38% in 258 patients who received weight-based-dosing (WBD) of busulfan with cyclophosphamide and etoposide.
Progression-free survival (PFS) improved with PK-TDM vs. WBD (69% vs. 55%) but overall survival (OS) did not differ between the groups, most likely because of subsequent therapy given at the time of relapse, said Dr. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio.
The findings are from a retrospective comparison of outcomes in patients treated between 2014 and 2017 when PK-TDM was the standard practice, and patients treated between 2007 and 2013 when fixed weight-based dosing was standard, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“In 2013 we began a program of therapeutic dose monitoring at our site,” Dr. Hill said, explaining that with TDM the goal is to eliminate the low and high levels seen with weight-based dosing, and “to get the maximum number of patients into the therapeutic zone.”
TDM became the preferred approach for busulfan dosing because of the drug’s “unpredictable and widely variable pharmacokinetics,” and ASBMT guidelines now call for consideration of TDM with first-line busulfan to minimize the potential complications, he noted.
“But it’s noteworthy that ... there are really no data to show that TDM can reduce the rates of relapse,” he added.
For this study, WBD busulfan dosing was 2.8 mg/kg every 24 hours on day –9 to –6 of ASCT. For PK-TDM, plasma busulfan concentration was serially determined using a previously described and externally validated in-house liquid chromatography–tandem mass spectrometry assay, he said, explaining that busulfan area under the curve (AUC) after first dose was calculated for each patient and used to adjust subsequent doses to target a daily AUC of 4,500 micromol/min.
To account for baseline differences in the two groups, including a higher number of prior chemotherapy regimens in the WBD group and a higher proportion of aggressive B-cell and T-cell lymphoma in the TDM group, two propensity-matched cohorts of 47 patients each were derived via logistic regression analysis.
“In the propensity-matched cohorts we saw a similar pattern, with therapeutic dose monitoring patients having lower relapse and improved progression-free survival, but no change in the nonrelapse mortality or the overall survival,” Dr. Hill said.
Notably, PFS did not differ between the groups when the researchers looked only at those in complete remission at transplant, but a significant improvement in PFS was seen in the TDM vs. WBD cohorts when they looked only at patients with partial remission, stable disease, or progressive disease (collectively considered as those in less than CR at transplant), he said (P = .79 vs. .08, respectively).
On multivariate analysis, less than CR status was associated with an increased risk of relapse after ASCT (hazard ratio, 2.0), and TDM vs. WBD was associated with a decreased risk of relapse (HR, 0.5).
No differences were seen between the groups with respect to changes in pulmonary or liver function from baseline, or in treatment-related mortality rates, Dr. Hill noted.
The findings support the use of PK-TDM for NHL patients undergoing ASCT with busulfan, but further study is needed, he concluded.
Dr. Hill reported having no relevant financial disclosures.
SOURCE: Hill B et al. TCT 2019, Abstract 39.
HOUSTON – Compared with weight-based dosing, pharmacokinetic-directed therapeutic dose monitoring of busulfan used in combination with cyclophosphamide and etoposide reduced relapse risk in non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT), according to a review of 336 cases.
This was particularly true in patients with less than a complete response at the time of transplant, Brian T. Hill, MD, PhD, reported at the Transplantation & Cellular Therapy Meetings.
The relapse rate at 24 months after ASCT was 19% in 78 adult NHL patients who underwent ASCT with pharmacokinetic-guided therapeutic dose monitoring (PK-TDM), compared with 38% in 258 patients who received weight-based-dosing (WBD) of busulfan with cyclophosphamide and etoposide.
Progression-free survival (PFS) improved with PK-TDM vs. WBD (69% vs. 55%) but overall survival (OS) did not differ between the groups, most likely because of subsequent therapy given at the time of relapse, said Dr. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio.
The findings are from a retrospective comparison of outcomes in patients treated between 2014 and 2017 when PK-TDM was the standard practice, and patients treated between 2007 and 2013 when fixed weight-based dosing was standard, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“In 2013 we began a program of therapeutic dose monitoring at our site,” Dr. Hill said, explaining that with TDM the goal is to eliminate the low and high levels seen with weight-based dosing, and “to get the maximum number of patients into the therapeutic zone.”
TDM became the preferred approach for busulfan dosing because of the drug’s “unpredictable and widely variable pharmacokinetics,” and ASBMT guidelines now call for consideration of TDM with first-line busulfan to minimize the potential complications, he noted.
“But it’s noteworthy that ... there are really no data to show that TDM can reduce the rates of relapse,” he added.
For this study, WBD busulfan dosing was 2.8 mg/kg every 24 hours on day –9 to –6 of ASCT. For PK-TDM, plasma busulfan concentration was serially determined using a previously described and externally validated in-house liquid chromatography–tandem mass spectrometry assay, he said, explaining that busulfan area under the curve (AUC) after first dose was calculated for each patient and used to adjust subsequent doses to target a daily AUC of 4,500 micromol/min.
To account for baseline differences in the two groups, including a higher number of prior chemotherapy regimens in the WBD group and a higher proportion of aggressive B-cell and T-cell lymphoma in the TDM group, two propensity-matched cohorts of 47 patients each were derived via logistic regression analysis.
“In the propensity-matched cohorts we saw a similar pattern, with therapeutic dose monitoring patients having lower relapse and improved progression-free survival, but no change in the nonrelapse mortality or the overall survival,” Dr. Hill said.
Notably, PFS did not differ between the groups when the researchers looked only at those in complete remission at transplant, but a significant improvement in PFS was seen in the TDM vs. WBD cohorts when they looked only at patients with partial remission, stable disease, or progressive disease (collectively considered as those in less than CR at transplant), he said (P = .79 vs. .08, respectively).
On multivariate analysis, less than CR status was associated with an increased risk of relapse after ASCT (hazard ratio, 2.0), and TDM vs. WBD was associated with a decreased risk of relapse (HR, 0.5).
No differences were seen between the groups with respect to changes in pulmonary or liver function from baseline, or in treatment-related mortality rates, Dr. Hill noted.
The findings support the use of PK-TDM for NHL patients undergoing ASCT with busulfan, but further study is needed, he concluded.
Dr. Hill reported having no relevant financial disclosures.
SOURCE: Hill B et al. TCT 2019, Abstract 39.
HOUSTON – Compared with weight-based dosing, pharmacokinetic-directed therapeutic dose monitoring of busulfan used in combination with cyclophosphamide and etoposide reduced relapse risk in non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT), according to a review of 336 cases.
This was particularly true in patients with less than a complete response at the time of transplant, Brian T. Hill, MD, PhD, reported at the Transplantation & Cellular Therapy Meetings.
The relapse rate at 24 months after ASCT was 19% in 78 adult NHL patients who underwent ASCT with pharmacokinetic-guided therapeutic dose monitoring (PK-TDM), compared with 38% in 258 patients who received weight-based-dosing (WBD) of busulfan with cyclophosphamide and etoposide.
Progression-free survival (PFS) improved with PK-TDM vs. WBD (69% vs. 55%) but overall survival (OS) did not differ between the groups, most likely because of subsequent therapy given at the time of relapse, said Dr. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio.
The findings are from a retrospective comparison of outcomes in patients treated between 2014 and 2017 when PK-TDM was the standard practice, and patients treated between 2007 and 2013 when fixed weight-based dosing was standard, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“In 2013 we began a program of therapeutic dose monitoring at our site,” Dr. Hill said, explaining that with TDM the goal is to eliminate the low and high levels seen with weight-based dosing, and “to get the maximum number of patients into the therapeutic zone.”
TDM became the preferred approach for busulfan dosing because of the drug’s “unpredictable and widely variable pharmacokinetics,” and ASBMT guidelines now call for consideration of TDM with first-line busulfan to minimize the potential complications, he noted.
“But it’s noteworthy that ... there are really no data to show that TDM can reduce the rates of relapse,” he added.
For this study, WBD busulfan dosing was 2.8 mg/kg every 24 hours on day –9 to –6 of ASCT. For PK-TDM, plasma busulfan concentration was serially determined using a previously described and externally validated in-house liquid chromatography–tandem mass spectrometry assay, he said, explaining that busulfan area under the curve (AUC) after first dose was calculated for each patient and used to adjust subsequent doses to target a daily AUC of 4,500 micromol/min.
To account for baseline differences in the two groups, including a higher number of prior chemotherapy regimens in the WBD group and a higher proportion of aggressive B-cell and T-cell lymphoma in the TDM group, two propensity-matched cohorts of 47 patients each were derived via logistic regression analysis.
“In the propensity-matched cohorts we saw a similar pattern, with therapeutic dose monitoring patients having lower relapse and improved progression-free survival, but no change in the nonrelapse mortality or the overall survival,” Dr. Hill said.
Notably, PFS did not differ between the groups when the researchers looked only at those in complete remission at transplant, but a significant improvement in PFS was seen in the TDM vs. WBD cohorts when they looked only at patients with partial remission, stable disease, or progressive disease (collectively considered as those in less than CR at transplant), he said (P = .79 vs. .08, respectively).
On multivariate analysis, less than CR status was associated with an increased risk of relapse after ASCT (hazard ratio, 2.0), and TDM vs. WBD was associated with a decreased risk of relapse (HR, 0.5).
No differences were seen between the groups with respect to changes in pulmonary or liver function from baseline, or in treatment-related mortality rates, Dr. Hill noted.
The findings support the use of PK-TDM for NHL patients undergoing ASCT with busulfan, but further study is needed, he concluded.
Dr. Hill reported having no relevant financial disclosures.
SOURCE: Hill B et al. TCT 2019, Abstract 39.
REPORTING FROM TCT 2019
Priority review granted to lenalidomide for FL, MZL
The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).
Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).
The FDA plans to make a decision on the sNDA by June 27, 2019.
The FDA aims to take action on a priority review application within 6 months of receiving it rather than the standard 10 months. The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.
Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).
According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).
At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).
The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.
Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.
The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).
Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).
The FDA plans to make a decision on the sNDA by June 27, 2019.
The FDA aims to take action on a priority review application within 6 months of receiving it rather than the standard 10 months. The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.
Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).
According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).
At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).
The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.
Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.
The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).
Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).
The FDA plans to make a decision on the sNDA by June 27, 2019.
The FDA aims to take action on a priority review application within 6 months of receiving it rather than the standard 10 months. The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.
Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).
According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).
At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).
The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.
Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.
Barriers to CAR T use in the spotlight at first European meeting
outcomes data suggest.
For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).
“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.
In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”
“Increasingly these are the big issues,” Mr. Schulthess said.
In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.
The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.
“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.
EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.
The latter is where Mr. Schulthess came in.
His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.
Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.
The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.
“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”
And that comes back to the fact that bone marrow units make money, he said.
CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.
In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.
“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”
Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).
“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.
Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.
Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.
“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”
Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”
Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.
Mr. Schulthess reported that his research was funded by the Dutch government.
outcomes data suggest.
For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).
“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.
In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”
“Increasingly these are the big issues,” Mr. Schulthess said.
In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.
The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.
“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.
EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.
The latter is where Mr. Schulthess came in.
His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.
Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.
The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.
“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”
And that comes back to the fact that bone marrow units make money, he said.
CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.
In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.
“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”
Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).
“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.
Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.
Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.
“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”
Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”
Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.
Mr. Schulthess reported that his research was funded by the Dutch government.
outcomes data suggest.
For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).
“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.
In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”
“Increasingly these are the big issues,” Mr. Schulthess said.
In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.
The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.
“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.
EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.
The latter is where Mr. Schulthess came in.
His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.
Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.
The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.
“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”
And that comes back to the fact that bone marrow units make money, he said.
CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.
In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.
“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”
Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).
“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.
Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.
Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.
“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”
Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”
Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.
Mr. Schulthess reported that his research was funded by the Dutch government.
Researchers characterize new subtype of high-grade DLBCL
(DLBCL)
Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.
When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.
Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.
Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).
Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.
The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.
Characteristics of MHG DLBCL
The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.
Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.
Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.
Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).
The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”
The researchers also found, however, that “MHG and BL share high expression of signatures that contain cell-cycle genes, ribosome biogenesis, MYC overexpression, and TCF3 targets, which suggests a shared proliferative phenotype.”
The team determined that MHG has “a highly proliferative phenotype and shares features with centroblasts of the germinal center dark zone.”
Another discovery was that MHG patients in the REMoDL-B trial had worse progression-free survival (PFS) than their peers.
Among patients who received R-CHOP, the estimated 3-year PFS was:
- 37% for MHG patients
- 78% for patients with GCB DLBCL
- 64% for patients with activated B-cell like (ABC) DLBCL
- 65% for patients with unclassified DLBCL.
Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).
Validation cohort
Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.
Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).
The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.
Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.
In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.
“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.
Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.
Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.
The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.
SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583
(DLBCL)
Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.
When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.
Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.
Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).
Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.
The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.
Characteristics of MHG DLBCL
The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.
Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.
Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.
Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).
The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”
The researchers also found, however, that “MHG and BL share high expression of signatures that contain cell-cycle genes, ribosome biogenesis, MYC overexpression, and TCF3 targets, which suggests a shared proliferative phenotype.”
The team determined that MHG has “a highly proliferative phenotype and shares features with centroblasts of the germinal center dark zone.”
Another discovery was that MHG patients in the REMoDL-B trial had worse progression-free survival (PFS) than their peers.
Among patients who received R-CHOP, the estimated 3-year PFS was:
- 37% for MHG patients
- 78% for patients with GCB DLBCL
- 64% for patients with activated B-cell like (ABC) DLBCL
- 65% for patients with unclassified DLBCL.
Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).
Validation cohort
Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.
Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).
The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.
Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.
In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.
“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.
Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.
Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.
The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.
SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583
(DLBCL)
Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.
When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.
Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.
Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).
Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.
The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.
Characteristics of MHG DLBCL
The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.
Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.
Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.
Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).
The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”
The researchers also found, however, that “MHG and BL share high expression of signatures that contain cell-cycle genes, ribosome biogenesis, MYC overexpression, and TCF3 targets, which suggests a shared proliferative phenotype.”
The team determined that MHG has “a highly proliferative phenotype and shares features with centroblasts of the germinal center dark zone.”
Another discovery was that MHG patients in the REMoDL-B trial had worse progression-free survival (PFS) than their peers.
Among patients who received R-CHOP, the estimated 3-year PFS was:
- 37% for MHG patients
- 78% for patients with GCB DLBCL
- 64% for patients with activated B-cell like (ABC) DLBCL
- 65% for patients with unclassified DLBCL.
Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).
Validation cohort
Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.
Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).
The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.
Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.
In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.
“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.
Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.
Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.
The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.
SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Few DLBCL patients benefit from nivolumab
Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.
Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.
Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.
Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.
Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.
The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.
HSCT failures
The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.
About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.
The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).
Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.
Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.
Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.
Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.
HSCT-ineligible group
The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.
About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.
The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.
The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.
None of the patients in this group were still taking nivolumab at the data cutoff.
Biomarkers of response
Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.
Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.
Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.
None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.
Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.
Safety
Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.
The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).
Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.
This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.
SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.
Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.
Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.
Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.
Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.
Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.
The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.
HSCT failures
The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.
About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.
The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).
Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.
Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.
Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.
Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.
HSCT-ineligible group
The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.
About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.
The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.
The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.
None of the patients in this group were still taking nivolumab at the data cutoff.
Biomarkers of response
Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.
Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.
Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.
None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.
Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.
Safety
Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.
The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).
Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.
This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.
SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.
Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.
Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.
Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.
Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.
Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.
The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.
HSCT failures
The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.
About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.
The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).
Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.
Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.
Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.
Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.
HSCT-ineligible group
The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.
About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.
The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.
The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.
None of the patients in this group were still taking nivolumab at the data cutoff.
Biomarkers of response
Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.
Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.
Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.
None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.
Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.
Safety
Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.
The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).
Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.
This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.
SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: Nivolumab produced a response in 10 of 121 patients, including three complete responses.
Study details: A phase 2 study of 121 patients with relapsed/refractory diffuse large B-cell lymphoma.
Disclosures: This research was supported by Bristol-Myers Squibb and other organizations. The study authors reported relationships with Bristol-Myers Squibb and other companies.
Source: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.
Anthracyclines, bendamustine are options for grade 3A follicular lymphoma
While optimal treatment for grade 3A follicular lymphoma remains in question, either anthracycline-based chemotherapy or bendamustine appear to be preferable to cyclophosphamide, vincristine, and prednisone (CVP), results of a recent analysis suggest.
Time to progression with anthracycline-based chemotherapy was superior to that of CVP in the retrospective, multicenter study.
At the same time, clinical outcomes were comparable between anthracycline-based chemotherapy and bendamustine, according to Nirav N. Shah, MD, of the Medical College of Wisconsin, Milwaukee, and his coinvestigators.
“Both remain appropriate frontline options for this patient population,” Dr. Shah and his colleagues wrote in Clinical Lymphoma, Myeloma & Leukemia.
Frontline therapy for follicular lymphoma has evolved, and recently shifted toward bendamustine-based chemotherapy regimens in light of two large randomized trials, according to the investigators. However, optimal therapy – specifically for grade 3A follicular lymphoma – has been debated for more than 20 years, they added.
“While some approach it as an aggressive malignancy, others treat it as an indolent lymphoma,” they wrote.
Accordingly, Dr. Shah and his colleagues sought to evaluate treatment outcomes with these regimens in 103 advanced stage 3/4 follicular lymphoma patients from six centers seen over a 10-year period.
Of those patients, 65 had received anthracycline-based chemotherapy, 30 received bendamustine, and 8 received CVP. All received either rituximab or ofatumumab in combination with the chemotherapy, and about one-third went on to receive maintenance treatment with one of those two anti-CD20 antibodies.
The proportion of patients not experiencing disease progression at 24 months from the initiation of treatment was significantly different between arms, at 72% for those receiving anthracyclines, 79% for bendamustine, and 50% for CVP (P = .01).
Patients who received CVP had a significantly poorer time-to-progression outcomes versus anthracycline-based chemotherapy, an adjusted analysis showed (hazard ratio, 3.22; 95% confidence interval, 1.26-8.25; P = .01), while by contrast, there was no significant difference between bendamustine and anthracyclines on this endpoint.
Progression-free survival was likewise worse for CVP compared with anthracycline-based chemotherapy, but there was no significant difference in overall survival for either CVP or bendamustine compared with anthracycline-based chemotherapy, the investigators said.
The 5-year overall survival was estimated to be 82% for anthracycline-based chemotherapy, 74% for bendamustine, and 58% for CVP (P = .23).
Optimal treatment of grade 3A follicular lymphoma remains controversial despite these findings, the investigators noted.
“Unfortunately, this specific histology was excluded from pivotal trials comparing anthracycline-based chemotherapy to bendamustine, leaving the question of optimal frontline treatment unanswered in this subset,” they wrote.
The situation could change with a subgroup analysis of GALLIUM, which might provide some prospective data for this histology. Beyond that, it would be helpful to have prospective, randomized studies specifically enrolling grade 3A disease, Dr. Shah and his coauthors wrote.
Dr. Shah reported disclosures related to Exelixis, Oncosec, Geron, Jazz, Kite, Juno, and Lentigen Technology. Coauthors provided disclosures related to Sanofi-Genzyme, Celgene, Takeda, Otsuka, Spectrum, Merck, and Astellas, among others.
SOURCE: Shah NN et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):95-102.
While optimal treatment for grade 3A follicular lymphoma remains in question, either anthracycline-based chemotherapy or bendamustine appear to be preferable to cyclophosphamide, vincristine, and prednisone (CVP), results of a recent analysis suggest.
Time to progression with anthracycline-based chemotherapy was superior to that of CVP in the retrospective, multicenter study.
At the same time, clinical outcomes were comparable between anthracycline-based chemotherapy and bendamustine, according to Nirav N. Shah, MD, of the Medical College of Wisconsin, Milwaukee, and his coinvestigators.
“Both remain appropriate frontline options for this patient population,” Dr. Shah and his colleagues wrote in Clinical Lymphoma, Myeloma & Leukemia.
Frontline therapy for follicular lymphoma has evolved, and recently shifted toward bendamustine-based chemotherapy regimens in light of two large randomized trials, according to the investigators. However, optimal therapy – specifically for grade 3A follicular lymphoma – has been debated for more than 20 years, they added.
“While some approach it as an aggressive malignancy, others treat it as an indolent lymphoma,” they wrote.
Accordingly, Dr. Shah and his colleagues sought to evaluate treatment outcomes with these regimens in 103 advanced stage 3/4 follicular lymphoma patients from six centers seen over a 10-year period.
Of those patients, 65 had received anthracycline-based chemotherapy, 30 received bendamustine, and 8 received CVP. All received either rituximab or ofatumumab in combination with the chemotherapy, and about one-third went on to receive maintenance treatment with one of those two anti-CD20 antibodies.
The proportion of patients not experiencing disease progression at 24 months from the initiation of treatment was significantly different between arms, at 72% for those receiving anthracyclines, 79% for bendamustine, and 50% for CVP (P = .01).
Patients who received CVP had a significantly poorer time-to-progression outcomes versus anthracycline-based chemotherapy, an adjusted analysis showed (hazard ratio, 3.22; 95% confidence interval, 1.26-8.25; P = .01), while by contrast, there was no significant difference between bendamustine and anthracyclines on this endpoint.
Progression-free survival was likewise worse for CVP compared with anthracycline-based chemotherapy, but there was no significant difference in overall survival for either CVP or bendamustine compared with anthracycline-based chemotherapy, the investigators said.
The 5-year overall survival was estimated to be 82% for anthracycline-based chemotherapy, 74% for bendamustine, and 58% for CVP (P = .23).
Optimal treatment of grade 3A follicular lymphoma remains controversial despite these findings, the investigators noted.
“Unfortunately, this specific histology was excluded from pivotal trials comparing anthracycline-based chemotherapy to bendamustine, leaving the question of optimal frontline treatment unanswered in this subset,” they wrote.
The situation could change with a subgroup analysis of GALLIUM, which might provide some prospective data for this histology. Beyond that, it would be helpful to have prospective, randomized studies specifically enrolling grade 3A disease, Dr. Shah and his coauthors wrote.
Dr. Shah reported disclosures related to Exelixis, Oncosec, Geron, Jazz, Kite, Juno, and Lentigen Technology. Coauthors provided disclosures related to Sanofi-Genzyme, Celgene, Takeda, Otsuka, Spectrum, Merck, and Astellas, among others.
SOURCE: Shah NN et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):95-102.
While optimal treatment for grade 3A follicular lymphoma remains in question, either anthracycline-based chemotherapy or bendamustine appear to be preferable to cyclophosphamide, vincristine, and prednisone (CVP), results of a recent analysis suggest.
Time to progression with anthracycline-based chemotherapy was superior to that of CVP in the retrospective, multicenter study.
At the same time, clinical outcomes were comparable between anthracycline-based chemotherapy and bendamustine, according to Nirav N. Shah, MD, of the Medical College of Wisconsin, Milwaukee, and his coinvestigators.
“Both remain appropriate frontline options for this patient population,” Dr. Shah and his colleagues wrote in Clinical Lymphoma, Myeloma & Leukemia.
Frontline therapy for follicular lymphoma has evolved, and recently shifted toward bendamustine-based chemotherapy regimens in light of two large randomized trials, according to the investigators. However, optimal therapy – specifically for grade 3A follicular lymphoma – has been debated for more than 20 years, they added.
“While some approach it as an aggressive malignancy, others treat it as an indolent lymphoma,” they wrote.
Accordingly, Dr. Shah and his colleagues sought to evaluate treatment outcomes with these regimens in 103 advanced stage 3/4 follicular lymphoma patients from six centers seen over a 10-year period.
Of those patients, 65 had received anthracycline-based chemotherapy, 30 received bendamustine, and 8 received CVP. All received either rituximab or ofatumumab in combination with the chemotherapy, and about one-third went on to receive maintenance treatment with one of those two anti-CD20 antibodies.
The proportion of patients not experiencing disease progression at 24 months from the initiation of treatment was significantly different between arms, at 72% for those receiving anthracyclines, 79% for bendamustine, and 50% for CVP (P = .01).
Patients who received CVP had a significantly poorer time-to-progression outcomes versus anthracycline-based chemotherapy, an adjusted analysis showed (hazard ratio, 3.22; 95% confidence interval, 1.26-8.25; P = .01), while by contrast, there was no significant difference between bendamustine and anthracyclines on this endpoint.
Progression-free survival was likewise worse for CVP compared with anthracycline-based chemotherapy, but there was no significant difference in overall survival for either CVP or bendamustine compared with anthracycline-based chemotherapy, the investigators said.
The 5-year overall survival was estimated to be 82% for anthracycline-based chemotherapy, 74% for bendamustine, and 58% for CVP (P = .23).
Optimal treatment of grade 3A follicular lymphoma remains controversial despite these findings, the investigators noted.
“Unfortunately, this specific histology was excluded from pivotal trials comparing anthracycline-based chemotherapy to bendamustine, leaving the question of optimal frontline treatment unanswered in this subset,” they wrote.
The situation could change with a subgroup analysis of GALLIUM, which might provide some prospective data for this histology. Beyond that, it would be helpful to have prospective, randomized studies specifically enrolling grade 3A disease, Dr. Shah and his coauthors wrote.
Dr. Shah reported disclosures related to Exelixis, Oncosec, Geron, Jazz, Kite, Juno, and Lentigen Technology. Coauthors provided disclosures related to Sanofi-Genzyme, Celgene, Takeda, Otsuka, Spectrum, Merck, and Astellas, among others.
SOURCE: Shah NN et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):95-102.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: Patients who received CVP had a significantly poorer time-to-progression outcome versus anthracycline-based chemotherapy (hazard ratio, 3.22; 95% CI, 1.26-8.25; P = .01), while there was no significant difference between bendamustine and anthracyclines.
Study details: A multicenter analysis including 103 patients with advanced stage grade 3A follicular lymphoma.
Disclosures: The authors reported disclosures related to Exelixis, OncoSec, Geron, Jazz, Kite, Juno, Lentigen Technology, Sanofi-Genzyme, Celgene, Takeda, Otsuka, Spectrum, Merck, and Astellas, among others.
Source: Shah NN et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):95-102.