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Venetoclax shows promise for r/r hairy cell leukemia
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Inclusive reminder: LGBTQ community may donate stem cells
In fact, gay men have been able to donate stem cells in the United States since 2015. That’s when National Marrow Donor Program’s Be the Match registry lifted restrictions on men who have sex with men (MSM).
Physicians say advocacy is still necessary, because LGBTQ people may assume they can’t donate or be wary of clinicians. “The LGBTQIA+ population in general has experienced a lot of issues with the medical-industrial complex in terms of discrimination and inappropriate care,” said UT Southwestern Medical Center pathologist Brian Adkins, MD, who manages the blood bank at Children’s Health in Dallas, in an interview. “There’s a weariness there that may produce some hesitancy to interact with the donation process.”
An estimated 6.8 million people give blood in the United States each year, and an estimated 9 million people are registered as potential stem cell donors. A total of 22,013 hematopoietic cell transplantation procedures were performed in 2020, according to the U.S. Health Resources and Services Administration.
Expanding the number of LGBTQ donors, especially those born as biological males, could pay major dividends. As Dr. Adkins noted, the ideal stem cell donor is young – Be the Match says doctors generally prefer donors aged 18-35 – and male. According to a 2021 Gallup Poll, 21% of those born from 1997 to 2003 (Generation Z) say they’re LGBTQ, as do 11% of those born from 1981 to 1996 (Millennials).
In North America, the most extensive outreach to the LGBTQ community about stem cell donation has been launched in Canada. There, an organization called Stem Cell Club focuses on encouraging college students and other young people to register as potential stem cell donors.
Stem Cell Club has several campaigns aimed at ethnic minority groups, and its Saving Lives With Pride project focuses on MSM. The project’s web page includes testimonials from a woman whose life was saved by an unrelated gay male donor and from a gay male nurse who recovered from blood cancer thanks to a stem cell donation. The site also includes videos about stem cell donation featuring LGBTQ young people and Canadian hematologists.
“Our specialized collection center will treat donors with the highest levels of respect and courtesy, indeed as heroes of their unselfish gift that can truly save a life,” says Ottawa Hospital transplant hematologist David Allan, MD, in one of the videos.
Stem Cell Club was founded by transplant hematologist Warren Fingrut, MD, a research fellow at Memorial Sloan Kettering Cancer Center. In an interview, he said the organization’s LGBTQ project has promoted stem cell donation at several annual gay pride events and will continue the outreach this coming summer. In 2018 and 2019, advocates recruited 354 potential stem-cell donors (40% male, 42 non-White) at five pride events, Dr. Fingrut and colleagues reported last year in the journal Bone Marrow Transplantation.
For a new study, researchers interviewed 37 gay and bisexual men from five Canadian provinces about stem cell donation. Dr. Fingrut and colleagues reported the findings in February in an abstract at the Transplantation & Cellular Therapy Meetings.
Most participants didn’t know they “are eligible to donate stem cells, with many confusing stem cell versus blood donor eligibility criteria,” the researchers reported. According to Dr. Fingrut, some of the men “felt they were treated as second-class citizens, and that translated into frustration and decreased motivation to donate. There were concerns that they would be treated as though they shouldn’t be there.”
Canada has allowed gay men to donate stem cells for at least 10 years, Dr. Fingrut said. In 2022, Canadian officials said blood banks would no longer require MSM donors to have been abstinent from sex for 3 months, the BBC reported. However, donors will be asked about high-risk sexual behaviors.
The United States, where HIV spread through the blood supply during the early years of the AIDS pandemic and killed thousands of hemophiliacs, has much been slower to change its policies. For decades, starting in the 1980s, both blood banks and stem cell donation programs chose to lower the risk by turning away MSM donors.
Policies only began to change in recent years. Be the Match’s registry led the way by welcoming MSM in 2015. Stem cell donations go through more extensive testing than blood donations, Dr. Adkins said, so it’s more likely that HIV will be screened out. Also, he said, officials probably realized “it was necessary to widen the donor pool in order to best serve the patients” because it’s so hard to find matched stem-cell donors.
Be the Match has also stepped up its outreach to the LGBTQ community. “During Pride Month in 2022, Be The Match sponsored booths at events in 12 major markets from coast to coast,” said Jamie Margolis, senior vice president of Donor Services. “These efforts enabled us to increase awareness among more than 500,000 festival attendees and added more than 2,000 new members to the Be The Match Registry. We also produced a social media awareness campaign featuring one of our own employees, who is a cofounder of the Pride Employee Resource Group at Be The Match and a recent blood stem cell donor.”
In 2020 as blood banks became desperate for donations during the early days of the COVID-19 pandemic, the FDA changed its policy and required MSM to be abstinent for 3 months instead of 1 year before giving blood. (Prior to December 2014, any man who’d had sex with a man, even once, was indefinitely banned from giving blood.)
The 3-month policy instituted in 2020 drew fire from critics such as the American Medical Association, which noted the regulation treated men differently if they had unprotected sex with a single man versus with multiple women.
Now, the FDA is proposing that it once again change the policy about blood donations: It is recommending that there be no special polices regarding MSM. “All prospective donors who report having a new sexual partner or more than one sexual partner and had anal sex in the past 3 months would be deferred from donation.”
Under the proposal, anyone who’s ever had HIV will not be able to donate. (They can’t donate stem cells either.) And the FDA proposes restrictions on those who take pre-exposure prophylaxis or postexposure prophylaxis for HIV.
Margolis, of Be the Match, noted that some members of the LGBTQ community may not be able to donate to Be The Match BioTherapies, which works with cell and gene therapy developers worldwide to provide cellular starting material. “These therapies may have different requirements than those for blood stem-cell transplants. Men who have had sex with men in the past 5 years or women who have had sex with a man who has had sex with a man in the past 5 years may not be able to donate to Be The Match BioTherapies. While we understand this could be upsetting or frustrating for someone who desires to be a part of these therapies, we are committed to following medical guidelines and regulations, while also advocating for our donors and the LBGTQIA+ community as a whole.”
MSM aren’t the only target of outreach by proponents of stem cell donation. In 2019, UT Southwestern’s Dr. Adkins and colleagues wrote a commentary in Bone Marrow Transplantation that called for bone marrow donation centers to do more to be welcoming to transgender donors. “The largest age group identifying as transgender is 18-24 years of life, which overlaps considerably with the population of hematopoietic stem cell donors, which tend to be younger individuals,” the researchers wrote.
The transgender community was “simply overlooked,” Dr. Adkins said. Since then, as he pointed out, things have changed. Now, Be the Match’s website notes that “members of the LGBTQIA+ community CAN join the registry and donate.” The organization says that “for medical reasons, everyone is asked to provide their sex assigned at birth when they register. Should you be called as a match, pronouns and gender identity are respected throughout the process.”
In addition, the site says people on prescription hormone therapy are not excluded from joining the registry. Patients who have undergone surgery within the last 12 months, including sex-reassignment procedures, “will be asked about the current status of their recovery and whether they are still seeing a physician for follow-up in regards to the surgery.”
What’s next? Dr. Fingrut said he expects the lifting of strict rules about MSM and blood donation will boost stem cell donation in the community.
There seems to be plenty of room for more outreach. Cole Williams, founder of Pride & Plasma, which advocates for allowing gay men to give blood, suggested in an interview that advocates who want to increase stem cell donation in the LGBTQ community reach out to its community centers, health organizations, providers, and clinics.
So far, though, “I haven’t seen a big call for registration of any individuals unless they have a personal relation to bone marrow donation,” he said.
Dr. Fingrut and Dr. Adkins report no disclosures.
In fact, gay men have been able to donate stem cells in the United States since 2015. That’s when National Marrow Donor Program’s Be the Match registry lifted restrictions on men who have sex with men (MSM).
Physicians say advocacy is still necessary, because LGBTQ people may assume they can’t donate or be wary of clinicians. “The LGBTQIA+ population in general has experienced a lot of issues with the medical-industrial complex in terms of discrimination and inappropriate care,” said UT Southwestern Medical Center pathologist Brian Adkins, MD, who manages the blood bank at Children’s Health in Dallas, in an interview. “There’s a weariness there that may produce some hesitancy to interact with the donation process.”
An estimated 6.8 million people give blood in the United States each year, and an estimated 9 million people are registered as potential stem cell donors. A total of 22,013 hematopoietic cell transplantation procedures were performed in 2020, according to the U.S. Health Resources and Services Administration.
Expanding the number of LGBTQ donors, especially those born as biological males, could pay major dividends. As Dr. Adkins noted, the ideal stem cell donor is young – Be the Match says doctors generally prefer donors aged 18-35 – and male. According to a 2021 Gallup Poll, 21% of those born from 1997 to 2003 (Generation Z) say they’re LGBTQ, as do 11% of those born from 1981 to 1996 (Millennials).
In North America, the most extensive outreach to the LGBTQ community about stem cell donation has been launched in Canada. There, an organization called Stem Cell Club focuses on encouraging college students and other young people to register as potential stem cell donors.
Stem Cell Club has several campaigns aimed at ethnic minority groups, and its Saving Lives With Pride project focuses on MSM. The project’s web page includes testimonials from a woman whose life was saved by an unrelated gay male donor and from a gay male nurse who recovered from blood cancer thanks to a stem cell donation. The site also includes videos about stem cell donation featuring LGBTQ young people and Canadian hematologists.
“Our specialized collection center will treat donors with the highest levels of respect and courtesy, indeed as heroes of their unselfish gift that can truly save a life,” says Ottawa Hospital transplant hematologist David Allan, MD, in one of the videos.
Stem Cell Club was founded by transplant hematologist Warren Fingrut, MD, a research fellow at Memorial Sloan Kettering Cancer Center. In an interview, he said the organization’s LGBTQ project has promoted stem cell donation at several annual gay pride events and will continue the outreach this coming summer. In 2018 and 2019, advocates recruited 354 potential stem-cell donors (40% male, 42 non-White) at five pride events, Dr. Fingrut and colleagues reported last year in the journal Bone Marrow Transplantation.
For a new study, researchers interviewed 37 gay and bisexual men from five Canadian provinces about stem cell donation. Dr. Fingrut and colleagues reported the findings in February in an abstract at the Transplantation & Cellular Therapy Meetings.
Most participants didn’t know they “are eligible to donate stem cells, with many confusing stem cell versus blood donor eligibility criteria,” the researchers reported. According to Dr. Fingrut, some of the men “felt they were treated as second-class citizens, and that translated into frustration and decreased motivation to donate. There were concerns that they would be treated as though they shouldn’t be there.”
Canada has allowed gay men to donate stem cells for at least 10 years, Dr. Fingrut said. In 2022, Canadian officials said blood banks would no longer require MSM donors to have been abstinent from sex for 3 months, the BBC reported. However, donors will be asked about high-risk sexual behaviors.
The United States, where HIV spread through the blood supply during the early years of the AIDS pandemic and killed thousands of hemophiliacs, has much been slower to change its policies. For decades, starting in the 1980s, both blood banks and stem cell donation programs chose to lower the risk by turning away MSM donors.
Policies only began to change in recent years. Be the Match’s registry led the way by welcoming MSM in 2015. Stem cell donations go through more extensive testing than blood donations, Dr. Adkins said, so it’s more likely that HIV will be screened out. Also, he said, officials probably realized “it was necessary to widen the donor pool in order to best serve the patients” because it’s so hard to find matched stem-cell donors.
Be the Match has also stepped up its outreach to the LGBTQ community. “During Pride Month in 2022, Be The Match sponsored booths at events in 12 major markets from coast to coast,” said Jamie Margolis, senior vice president of Donor Services. “These efforts enabled us to increase awareness among more than 500,000 festival attendees and added more than 2,000 new members to the Be The Match Registry. We also produced a social media awareness campaign featuring one of our own employees, who is a cofounder of the Pride Employee Resource Group at Be The Match and a recent blood stem cell donor.”
In 2020 as blood banks became desperate for donations during the early days of the COVID-19 pandemic, the FDA changed its policy and required MSM to be abstinent for 3 months instead of 1 year before giving blood. (Prior to December 2014, any man who’d had sex with a man, even once, was indefinitely banned from giving blood.)
The 3-month policy instituted in 2020 drew fire from critics such as the American Medical Association, which noted the regulation treated men differently if they had unprotected sex with a single man versus with multiple women.
Now, the FDA is proposing that it once again change the policy about blood donations: It is recommending that there be no special polices regarding MSM. “All prospective donors who report having a new sexual partner or more than one sexual partner and had anal sex in the past 3 months would be deferred from donation.”
Under the proposal, anyone who’s ever had HIV will not be able to donate. (They can’t donate stem cells either.) And the FDA proposes restrictions on those who take pre-exposure prophylaxis or postexposure prophylaxis for HIV.
Margolis, of Be the Match, noted that some members of the LGBTQ community may not be able to donate to Be The Match BioTherapies, which works with cell and gene therapy developers worldwide to provide cellular starting material. “These therapies may have different requirements than those for blood stem-cell transplants. Men who have had sex with men in the past 5 years or women who have had sex with a man who has had sex with a man in the past 5 years may not be able to donate to Be The Match BioTherapies. While we understand this could be upsetting or frustrating for someone who desires to be a part of these therapies, we are committed to following medical guidelines and regulations, while also advocating for our donors and the LBGTQIA+ community as a whole.”
MSM aren’t the only target of outreach by proponents of stem cell donation. In 2019, UT Southwestern’s Dr. Adkins and colleagues wrote a commentary in Bone Marrow Transplantation that called for bone marrow donation centers to do more to be welcoming to transgender donors. “The largest age group identifying as transgender is 18-24 years of life, which overlaps considerably with the population of hematopoietic stem cell donors, which tend to be younger individuals,” the researchers wrote.
The transgender community was “simply overlooked,” Dr. Adkins said. Since then, as he pointed out, things have changed. Now, Be the Match’s website notes that “members of the LGBTQIA+ community CAN join the registry and donate.” The organization says that “for medical reasons, everyone is asked to provide their sex assigned at birth when they register. Should you be called as a match, pronouns and gender identity are respected throughout the process.”
In addition, the site says people on prescription hormone therapy are not excluded from joining the registry. Patients who have undergone surgery within the last 12 months, including sex-reassignment procedures, “will be asked about the current status of their recovery and whether they are still seeing a physician for follow-up in regards to the surgery.”
What’s next? Dr. Fingrut said he expects the lifting of strict rules about MSM and blood donation will boost stem cell donation in the community.
There seems to be plenty of room for more outreach. Cole Williams, founder of Pride & Plasma, which advocates for allowing gay men to give blood, suggested in an interview that advocates who want to increase stem cell donation in the LGBTQ community reach out to its community centers, health organizations, providers, and clinics.
So far, though, “I haven’t seen a big call for registration of any individuals unless they have a personal relation to bone marrow donation,” he said.
Dr. Fingrut and Dr. Adkins report no disclosures.
In fact, gay men have been able to donate stem cells in the United States since 2015. That’s when National Marrow Donor Program’s Be the Match registry lifted restrictions on men who have sex with men (MSM).
Physicians say advocacy is still necessary, because LGBTQ people may assume they can’t donate or be wary of clinicians. “The LGBTQIA+ population in general has experienced a lot of issues with the medical-industrial complex in terms of discrimination and inappropriate care,” said UT Southwestern Medical Center pathologist Brian Adkins, MD, who manages the blood bank at Children’s Health in Dallas, in an interview. “There’s a weariness there that may produce some hesitancy to interact with the donation process.”
An estimated 6.8 million people give blood in the United States each year, and an estimated 9 million people are registered as potential stem cell donors. A total of 22,013 hematopoietic cell transplantation procedures were performed in 2020, according to the U.S. Health Resources and Services Administration.
Expanding the number of LGBTQ donors, especially those born as biological males, could pay major dividends. As Dr. Adkins noted, the ideal stem cell donor is young – Be the Match says doctors generally prefer donors aged 18-35 – and male. According to a 2021 Gallup Poll, 21% of those born from 1997 to 2003 (Generation Z) say they’re LGBTQ, as do 11% of those born from 1981 to 1996 (Millennials).
In North America, the most extensive outreach to the LGBTQ community about stem cell donation has been launched in Canada. There, an organization called Stem Cell Club focuses on encouraging college students and other young people to register as potential stem cell donors.
Stem Cell Club has several campaigns aimed at ethnic minority groups, and its Saving Lives With Pride project focuses on MSM. The project’s web page includes testimonials from a woman whose life was saved by an unrelated gay male donor and from a gay male nurse who recovered from blood cancer thanks to a stem cell donation. The site also includes videos about stem cell donation featuring LGBTQ young people and Canadian hematologists.
“Our specialized collection center will treat donors with the highest levels of respect and courtesy, indeed as heroes of their unselfish gift that can truly save a life,” says Ottawa Hospital transplant hematologist David Allan, MD, in one of the videos.
Stem Cell Club was founded by transplant hematologist Warren Fingrut, MD, a research fellow at Memorial Sloan Kettering Cancer Center. In an interview, he said the organization’s LGBTQ project has promoted stem cell donation at several annual gay pride events and will continue the outreach this coming summer. In 2018 and 2019, advocates recruited 354 potential stem-cell donors (40% male, 42 non-White) at five pride events, Dr. Fingrut and colleagues reported last year in the journal Bone Marrow Transplantation.
For a new study, researchers interviewed 37 gay and bisexual men from five Canadian provinces about stem cell donation. Dr. Fingrut and colleagues reported the findings in February in an abstract at the Transplantation & Cellular Therapy Meetings.
Most participants didn’t know they “are eligible to donate stem cells, with many confusing stem cell versus blood donor eligibility criteria,” the researchers reported. According to Dr. Fingrut, some of the men “felt they were treated as second-class citizens, and that translated into frustration and decreased motivation to donate. There were concerns that they would be treated as though they shouldn’t be there.”
Canada has allowed gay men to donate stem cells for at least 10 years, Dr. Fingrut said. In 2022, Canadian officials said blood banks would no longer require MSM donors to have been abstinent from sex for 3 months, the BBC reported. However, donors will be asked about high-risk sexual behaviors.
The United States, where HIV spread through the blood supply during the early years of the AIDS pandemic and killed thousands of hemophiliacs, has much been slower to change its policies. For decades, starting in the 1980s, both blood banks and stem cell donation programs chose to lower the risk by turning away MSM donors.
Policies only began to change in recent years. Be the Match’s registry led the way by welcoming MSM in 2015. Stem cell donations go through more extensive testing than blood donations, Dr. Adkins said, so it’s more likely that HIV will be screened out. Also, he said, officials probably realized “it was necessary to widen the donor pool in order to best serve the patients” because it’s so hard to find matched stem-cell donors.
Be the Match has also stepped up its outreach to the LGBTQ community. “During Pride Month in 2022, Be The Match sponsored booths at events in 12 major markets from coast to coast,” said Jamie Margolis, senior vice president of Donor Services. “These efforts enabled us to increase awareness among more than 500,000 festival attendees and added more than 2,000 new members to the Be The Match Registry. We also produced a social media awareness campaign featuring one of our own employees, who is a cofounder of the Pride Employee Resource Group at Be The Match and a recent blood stem cell donor.”
In 2020 as blood banks became desperate for donations during the early days of the COVID-19 pandemic, the FDA changed its policy and required MSM to be abstinent for 3 months instead of 1 year before giving blood. (Prior to December 2014, any man who’d had sex with a man, even once, was indefinitely banned from giving blood.)
The 3-month policy instituted in 2020 drew fire from critics such as the American Medical Association, which noted the regulation treated men differently if they had unprotected sex with a single man versus with multiple women.
Now, the FDA is proposing that it once again change the policy about blood donations: It is recommending that there be no special polices regarding MSM. “All prospective donors who report having a new sexual partner or more than one sexual partner and had anal sex in the past 3 months would be deferred from donation.”
Under the proposal, anyone who’s ever had HIV will not be able to donate. (They can’t donate stem cells either.) And the FDA proposes restrictions on those who take pre-exposure prophylaxis or postexposure prophylaxis for HIV.
Margolis, of Be the Match, noted that some members of the LGBTQ community may not be able to donate to Be The Match BioTherapies, which works with cell and gene therapy developers worldwide to provide cellular starting material. “These therapies may have different requirements than those for blood stem-cell transplants. Men who have had sex with men in the past 5 years or women who have had sex with a man who has had sex with a man in the past 5 years may not be able to donate to Be The Match BioTherapies. While we understand this could be upsetting or frustrating for someone who desires to be a part of these therapies, we are committed to following medical guidelines and regulations, while also advocating for our donors and the LBGTQIA+ community as a whole.”
MSM aren’t the only target of outreach by proponents of stem cell donation. In 2019, UT Southwestern’s Dr. Adkins and colleagues wrote a commentary in Bone Marrow Transplantation that called for bone marrow donation centers to do more to be welcoming to transgender donors. “The largest age group identifying as transgender is 18-24 years of life, which overlaps considerably with the population of hematopoietic stem cell donors, which tend to be younger individuals,” the researchers wrote.
The transgender community was “simply overlooked,” Dr. Adkins said. Since then, as he pointed out, things have changed. Now, Be the Match’s website notes that “members of the LGBTQIA+ community CAN join the registry and donate.” The organization says that “for medical reasons, everyone is asked to provide their sex assigned at birth when they register. Should you be called as a match, pronouns and gender identity are respected throughout the process.”
In addition, the site says people on prescription hormone therapy are not excluded from joining the registry. Patients who have undergone surgery within the last 12 months, including sex-reassignment procedures, “will be asked about the current status of their recovery and whether they are still seeing a physician for follow-up in regards to the surgery.”
What’s next? Dr. Fingrut said he expects the lifting of strict rules about MSM and blood donation will boost stem cell donation in the community.
There seems to be plenty of room for more outreach. Cole Williams, founder of Pride & Plasma, which advocates for allowing gay men to give blood, suggested in an interview that advocates who want to increase stem cell donation in the LGBTQ community reach out to its community centers, health organizations, providers, and clinics.
So far, though, “I haven’t seen a big call for registration of any individuals unless they have a personal relation to bone marrow donation,” he said.
Dr. Fingrut and Dr. Adkins report no disclosures.
High cost and demand for old cancer drug sparks crisis
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
Gloom lifting as MCL treatments evolve
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
CAR T-cell therapy neurotoxicity linked to NfL elevations
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
FROM JAMA ONCOLOGY
Novel approach brings hospice-bound MM patient into remission
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
FROM THE JOURNAL OF HEMATOLOGY & ONCOLOGY
Many die waiting for `last-chance’ therapy
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
CAR T-cell therapy turns 10 and finally earns the word ‘cure’
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
‘Superior’ CLL regimen cuts chemo in half
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
FROM EHA 2022
FDA approves liso-cel as second-line therapy for LBCL
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.