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DKMS: Small nonprofit to world’s largest stem cell donor registry
When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.
“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.
In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.
“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.
Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).
In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”
From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.
Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
World’s largest registry
“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.
“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,
Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.
Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
Global partners
DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.
“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.
The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
Pandemic affects donations
But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.
Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.
“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.
However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.
“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
Workforce and clinical problems
Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.
“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.
“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.
Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.
“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.
In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.
“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.
To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.
The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
‘Every patient saved’
The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.
DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.
In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.
The last word goes to Mechtild Harf’s daughter Katharina.
“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”
“I have to believe that this dream will come true because otherwise, why dream, right?” she said.
Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.
When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.
“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.
In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.
“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.
Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).
In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”
From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.
Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
World’s largest registry
“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.
“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,
Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.
Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
Global partners
DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.
“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.
The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
Pandemic affects donations
But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.
Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.
“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.
However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.
“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
Workforce and clinical problems
Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.
“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.
“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.
Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.
“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.
In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.
“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.
To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.
The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
‘Every patient saved’
The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.
DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.
In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.
The last word goes to Mechtild Harf’s daughter Katharina.
“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”
“I have to believe that this dream will come true because otherwise, why dream, right?” she said.
Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.
When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.
“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.
In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.
“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.
Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).
In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”
From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.
Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
World’s largest registry
“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.
“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,
Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.
Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
Global partners
DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.
“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.
The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
Pandemic affects donations
But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.
Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.
“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.
However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.
“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
Workforce and clinical problems
Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.
“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.
“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.
Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.
“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.
In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.
“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.
To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.
The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
‘Every patient saved’
The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.
DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.
In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.
The last word goes to Mechtild Harf’s daughter Katharina.
“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”
“I have to believe that this dream will come true because otherwise, why dream, right?” she said.
Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.
TKI/BiTE combo extends survival of older patients with Ph+ALL
ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.
Now, results from an ongoing study suggest that the combination of the
The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).
Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.
At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.
“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.
“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
Early promise
A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.
“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.
“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.
“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.
Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.
“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
Study results
The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.
Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.
Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.
Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.
Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.
Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.
Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.
In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.
These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.
The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.
Now, results from an ongoing study suggest that the combination of the
The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).
Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.
At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.
“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.
“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
Early promise
A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.
“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.
“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.
“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.
Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.
“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
Study results
The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.
Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.
Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.
Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.
Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.
Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.
Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.
In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.
These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.
The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA – Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.
Now, results from an ongoing study suggest that the combination of the
The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).
Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic.
At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation at the annual meeting of the American Society of Hematology.
“I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab,” she said in an interview with this news organization.
“The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging,” she said.
Early promise
A leukemia specialist who was not involved in the study told this news organization that the results are promising, but added that it’s too early to make definitive judgments about the efficacy of the combination.
“People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don’t last,” said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Ark.
“The promise with this approach is that you’re getting a longer-lasting remission – maybe not a cure, but a longer-lasting remission – without having to use intensive chemotherapy,” he said.
“It’s still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it’s certainly very encouraging and very promising,” he added.
Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, said in an interview that “the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data,” he said.
“The caveat is that this is still early, and one needs to wait and see how it all pans out, but it’s very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant,” Dr. Hock added.
Study results
The new results come from a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.
Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.
Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would then undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.
Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.
Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.
Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD negative.
Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.
In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.
These adverse events were deemed acceptable by both U.S. Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Dr. Advani noted.
The study was funded by grants from the National Institutes of Health. Dr. Advani disclosed financial relationships with several companies. Dr. Emanuel and Dr. Hock have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASH 2021
Adaptive therapy borrows from nature to keep rhabdomyosarcoma in check
In 1859, Charles Darwin published “On the Origin of Species,” which outlined his world-shaking theory of evolution and its core principle of natural selection caused by environmental pressures that may determine whether an organism adapts and survives, or remains static, languishes, and eventually dies out.
The same forces that have influenced the size and shape of the beaks of finches in the Galapagos Islands, the length of giraffe necks in Africa, and the intestinal microbiomes of the nearly 8 billion human inhabitants of this planet also control whether malignant cells thrive and multiply, wither and die when assaulted by chemotherapy, or go into hiding, mutating and waiting for their next opportunity to erupt again and metastasize.
The ability of malignant cells to adapt to environmental pressures is “cancer’s most lethal and sophisticated property,” said Damon R. Reed, MD, program leader of the adolescent/young adult program at Moffitt Cancer Center in Tampa, Fla.
Dr. Reed and colleagues are developing methods to meet cancer on its own terms, applying evolutionary principles to the treatment of childhood fusion-positive rhabdomyosarcoma in an innovative, and some would say audacious, clinical trial.
Adaptive versus conventional therapy
The trial, now recruiting, is designed to evaluate each of four different strategies for chemotherapy schedules in patients with newly diagnosed metastatic fusion-positive rhabdomyosarcoma.
The trial contains four arms, three of which consist of either conventional chemotherapy based on published clinical trials, moving a second-line therapy to the first line, or adding maintenance therapy, all of which have the goal of inducing as many complete remissions as possible.
The remaining adaptive therapy arm, however, is entirely novel in approach, with therapy using a combination of chemotherapy drugs that will be started and interrupted based on tumor responses, with resumption of therapy on an adaptive schedule unique to each patient. The goal of treatment for patients enrolled in this arm will be prolongation of the time to disease progression, rather than complete remission.
Although some people might consider the adaptive therapy approach to be sacrificing the hope for a cure in exchange for palliation, the hard truth is that patients with fusion-positive rhabdomyosarcoma (in contrast to those with fusion-negative disease) have a dismal prognosis following relapse after up-front intensified therapy.
Instead, because a cure is exceedingly unlikely in patients with metastatic disease, the conventional idea of delivering the maximum tolerated dose of chemotherapy until disease progression could be replaced by an approach based on understanding of the evolution of cancer cells under selective pressures, Dr. Reed and colleagues contend.
“Although adaptive therapy would represent a major paradigm shift in pediatric oncology, this approach would exploit the chemotherapy-sensitive population to prevent the emergence of resistant populations, optimizing tumor control with less toxicity,” they wrote in a commentary published online in the journal Cancer.1
Poor survival with advanced disease
Childhood rhabdomyosarcoma (RMS) is a form of soft tissue sarcoma of mesenchymal origin. Approximately 25% of cases are parameningeal, arising from sites adjacent to the meninges of the nasopharynx, middle ear, paranasal sinuses, orbit, and other regions of the head and neck. Approximately 31% of cases arise in the genitourinary tract and 13% in the extremities, and other tumors occur less commonly in the trunk, chest wall, perineal/anal region, and abdomen.
The overall 5-year survival rate is approximately 71%.1
However, for patients with high-risk disease, a group that includes children 10 years of age or older with widespread disease with or without an activating PAX/FOX01 gene fusion, 5-year survival ranges from just 20% to 30% (Cancer Facts & Figures 2020).
“Among patients with metastatic disease, there is a clear difference in overall survival between those who have fusion-positive disease, where the 5-year overall survival is about 19%, and patients with fusion-negative disease,” said Douglas S. Hawkins, MD, chair of the children’s oncology group and professor of pediatrics at the University of Washington, Seattle, and associate chief in the division of hematology/oncology at Seattle Children’s Hospital.
Patients with fusion-negative disease can be further classified into those with multiple metastatic sites, with a 5-year overall survival rate of approximately 45%, and those with a single metastatic site, with a 5-year overall survival rate of 70%, he said in an interview.
“So when we talk about metastatic rhabdomyosarcoma, there actually is a diversity of outcomes, between really bad – those with fusion-positive disease – and not terrible – not great, but not terrible – for a selected group of patients with fusion-negative disease,” Dr. Hawkins said.
The poor prognosis for patients with metastatic fusion-positive disease prompted Dr. Reed and colleagues to rethink the entire approach to advanced cancers.
“If someone has a sarcoma, we know that we need to do surgery and radiation to the area, we know that localized disease does better than metastatic disease, and we generally hit it with some kind of chemotherapy that we call ‘standard of care,’ ” he said in an interview.
This approach is largely effective in some forms of cancer of bone and soft tissues, such as Ewing sarcoma, he notes, which has 5-year survival rates below 20% when treated with surgery and radiation only, but with the addition of chemotherapy has 5-year overall survival rates as high as 80%.
“At other times, with other sarcomas, the cure rate is abysmal, but we still call it standard of care,” Dr. Reed said.
For example, patients with metastatic fusion-positive RMS may have an initial response to chemotherapy, but most will eventually experience relapse and die of the disease.
“With some of the most common treatments, 70% of patients will have their cancers shrink by more than 50%, which is a major response, but the vast majority of them will have a recurrence later on,” Dr. Hawkins said.
He noted that the standard of care for patients with metastatic rhabdomyosarcoma, both with and without the PAX/FOX01 fusion, is chemotherapy, generally with the VAC regimen (vincristine, actinomycin D, and cyclophosphamide), although other agents such as doxorubicin, ifosfamide, etoposide, or irinotecan have also been tried, with little effect on event-free survival or overall survival rates.
A life too brief
Ricky Huff and his family know the course that the disease can take only too well. In 2015, his 5-month-old son, Theo, was diagnosed with metastatic rhabdomyosarcoma and put under the care of Damon Reed at Moffitt.
“During the whole course of treatment – I’m sure like many other parents – apart from relying on Damon and his treatment expertise to try to determine the best treatment options, I was reading everything under the sun to try to get a working knowledge of what Theo was up against, what his treatment and clinical trial options were, and what was the state of the science,” Mr. Huff says.
Unfortunately, the characteristics of Theo’s disease, including his very young age at onset and diagnosis of stage 4 metastatic disease, conspired against him, and despite undergoing 14 months of chemotherapy, Theo died of the disease in October 2016, 5 months shy of what would have been his second birthday.
In their grief, Mr. Huff, a real estate lawyer with a practice in Clearwater, Fla., and his wife, Leah, were determined to help other families of children with cancer and settled on the National Pediatric Cancer Foundation. Mr. Huff joined the board of directors of the foundation, which is collaborating with Moffitt Cancer Center on the adaptive therapy trial.
An evolutionary primer (cancer edition)
To get a better idea of just how adaptive therapy works, it is helpful to view cancer cells through the lens of species development, adaptation, extinction, and evolution.
“Cancer cells compete against each other in a dynamic environment. Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones,” Dr. Reed and colleagues wrote.
These influences can affect genetically identical cancer cells, which may begin to diverge from one another depending on their location in a tumor and the availability of nutrients, which in turn can result in two once-identical cells exhibiting different transcription rates for growth factors.
“Ultimately, this may affect the rate of progression through the cell cycle, leading to distinct rates of proliferation and mutational acquisition,” they wrote.
The diverging subpopulations will begin to develop different methods for adapting to the tumor microenvironment, with unique strategies for both accelerating growth and avoiding hazards such as chemotherapy drugs or radiation, the investigators explained.
“By the time a cancer becomes clinically apparent, cancer cells have transformed from a single clone into a diverse community of cell types evolving in response to a spatially and temporally heterogeneous tumor environment. Theoretically, a 10-gram cancer may contain the same order of magnitude of cancer cells as there are humans on earth, with tremendous diversity of phenotypes and environments,” they wrote.
Survival of the fittest
The competition of individuals within and between species described by Darwin also applies to cancer cells, in their interactions both with each other and with stromal cells and immune cells resulting in “the progressive replacement of less fit phenotypes by those that are more fit,” Dr. Reed and colleagues explained.
And just like the old joke about two hikers trying to escape from a charging grizzly bear (one says, “This is futile – we can’t outrun a grizzly,” and the other says, “I only have to outrun you!”), cancer cells only need to be more resistant to therapeutic attack than normal cells that are critical to function.
“This may explain why initial responses in certain solid tumors (notably rhabdomyosarcoma) do not predict eventual survival. The sensitivities of the dominant cancer cell populations dictate the initial response, but it is the ecology and evolution of the rare and more resistant populations that determine cure or relapse,” they wrote.
The endangered species list
As with many types of cancer, the current approach to treating pediatric sarcomas with curative intent is with a “first strike” approach, treating patients with surgery, radiation, and cytotoxic chemotherapy at the maximum tolerated dose for as long as needed or until unacceptable toxicities occur, with the intention of wiping out all cancer cells without permanently injuring normal cells.
The evolutionary analogy to this approach is a mass extinction event such as the meteor strike that is believed to have wiped out the dinosaurs roughly 66 million years ago. Fossil evidence suggests that the cataclysmic event resulted in the atmosphere being blanketed with dust particles that blocked sunlight and caused massive die-off of plants that dinosaurs needed to survive and were ill-adapted to do without.
In contrast, populations of smaller, more adaptable species of microbes, insects, and animals, including our mammalian ancestors, were able to survive and eventually flourish.
Many patients with localized cancers may be cured with up-front therapy, but others will have residual disease from populations of cells that are intrinsically resistant to therapy or have developed new evasion strategies.
Strike two and the MVP
Dr. Reed and colleagues liken the approach of second-line therapy for treatment of relapsed or refractory disease to the concept of “background extinctions,” using the fate of the passenger pigeon as an example of how a second-strike therapeutic strategy works.
Although the popular conception is that the passenger pigeon was hunted to extinction by humans, the species in fact died out because of many different factors, including loss of habitat, isolation of populations leading to a loss of genetic diversity, and disruption of breeding habits.
“Once first strikes of deforestation and hunting reduced the birds to small, fragmented populations, a series of what would otherwise have been minor second strikes pushed the passenger pigeon below its extinction threshold, or minimum viable population,” they said.
The analogy, as it applies to cancer therapy, is the use of second-line or follow-on therapy with one or more agents that the residual cells are at least in theory not resistant to. In the case of fusion-positive rhabdomyosarcoma, the drug most commonly added in the second-strike approach is vinorelbine.2
“Second strikes should be timed to occur around the time when the first strike has achieved its greatest effect, presumably at the point when the disease becomes clinically undetectable or at a measurable nadir,” Dr. Reed and colleagues wrote. “Ideally, second-strike therapies should have modes of action that require different resistance strategies by the cancer cells than those needed for resistance to the first strike.”
Adaptive therapy
As Dr. Reed and colleagues note, despite optimal therapy, 94% of patients with metastatic fusion-positive rhabdomyosarcoma will experience a relapse within 3 years of diagnosis.1 Clearly the scorched earth or “throw everything you have it” approach no longer works, and that’s where adaptive therapy comes in.
Here again, the authors rely on nature, or rather human interaction with nature, to devise a strategy for keeping the disease at bay when extinction of all cancerous cells cannot be achieved.
They cite the example of agricultural integrated pest management, which seeks to keep harmful insects in check by treating them to suppress but not completely destroy a population, then stopping the use of pesticides, and resuming only when the insect population spikes and again becomes a threat to crops.
“The goal is to limit crop damage while retaining the sensitivity of the insects to the pesticides. Resistance most often comes at a cost. In the absence of the pesticide, sensitive individuals will outcompete resistant individuals,” they wrote.
Adaptive therapy uses the same approach to reduce selection pressures that foster resistance, with patients treated only until a specific, predetermined response is achieved in the dominant population of chemosensitive cells. The treatment is then interrupted and reintroduced only when the tumor rebounds to a certain predetermined size.
In this scenario, cells that retain sensitivity to chemotherapy will be able to reproduce and proliferate more rapidly than drug-resistant cells, and the therapy can then be reintroduced. This strategy is less likely to cause the development and proliferation of resistant cells than conventional intensified chemotherapy, Dr. Reed and colleagues contend.
Putting it to the test
The clinical trial that Dr. Reed and colleagues have initiated, officially titled “Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma,” (NCT04388839) contains four arms: three experimental and one active comparator arm.
“We won’t randomize; we don’t feel that it would be fair to randomize patients, because these arms are so different from each other,” Dr. Reed said.
Arm A is the experimental first-strike arm, a 42-week course containing cyclophosphamide delivered intravenously over 60 minutes at a dose ranging from 220 mg to 1200 mg, vinorelbine delivered in an IV push over 6-10 minutes with a dose ranging from 4 mg to 25 mg, and actinomycin D administered via IV over 3-5 minutes at a dose ranging from 0.025 mg to 0.04 mg.
“The idea is that we take the standard of care, and we add a drug – vinorelbine – to make it stronger,” Dr. Reed said. “The idea is that the resistant cell, the cell that escapes, if we start hitting it on day 1 with vinorelbine, we might be able to drive it to extinction.”
Arm B, the second experimental arm, is the second-strike and maintenance arm, in which patients will receive conventional doses of vincristine, actinomycin D, and cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks, and will then be switched to up to 2 years of maintenance with vinorelbine and oral cyclophosphamide.
“Vinorelbine will be added when the cancer is declining or first goes into remission. We try not to wait 42 weeks, which is too long we think, by which time the cancer may be fully adapted and resistant,” he explained.
Arm C is the adaptive therapy arm, in which patients will receive VAC that starts and stops based on response, with the goal of prolonging time to disease progression rather than achieving CR.
Arm D is the active comparator arm, consisting of conventional chemotherapy based on published clinical trials, such as VAC for 42 weeks, or other standard-of-care regimens that may include irinotecan, doxorubicin, ifosfamide, and/or etoposide.
A change in thinking
Dr. Reed acknowledges that Arm C, the adaptive therapy arm, “definitely represents a change in thinking for pediatric oncology.”
“The idea is that if you could do this perfectly well, you would be able to take a patient who is diagnosed today and essentially ‘pause’ their disease for a while. Then 5 years from now, if there is a better medicine, you would have gotten that patient to that medicine.”
The optimal approach to treating metastatic fusion-positive rhabdomyosarcoma may be similar to that used for treatment of acute lymphoblastic leukemia, with induction, consolidation, and maintenance and the option of delayed intensification, he said.
“But we’re so far away from knowing which series to do that we just need to show that any series – any changing it up – is helpful.”
Dr. Reed said that when he started presenting the concept of adaptive therapy in clinical meetings in 2017, “I was told to come up with a better idea. There were several people who instantly got it, but most people would instantly get angry.”
The common refrain was that adaptive therapy was “giving up.”
But minds began to change in 2018, following presentation at the annual meeting of the American Society of Clinical Oncology of a European study showing that adding 6 months of low-dose chemotherapy maintenance to standard therapy improved the 5-year overall survival rate of pediatric rhabdomyosarcoma from 73.7% to 86.6%.2
Before presenting the idea of adaptive therapy to his colleagues, he ran it by the parents of children with advanced sarcomas, and many were on board with it, he said.
Ricky Huff said that had the option of adaptive therapy been available for Theo, he and his wife would have been willing to try it.
“Of course, everyone has the ability in hindsight to apply critical thinking to decisions that you made or could have made,” he said. “I think is true for many parents, who if they’re presented with information about options will say ‘well if there’s a 1 percent chance, I want that chance for my child, especially for a 5-month-old.”
The decision to choose adaptive therapy is a difficult decision to make, whether for oneself or for one’s son, because it isn’t curative.
“My wife and I have since had a conversation about this, and I do think we would have considered it, although through a lot of difficult conversations,” he said.
“After we got the pathology, knowing that it was metastatic, fusion-positive, and given his age, just doing a brief literature review on my own, I knew what we were up against using 20-year-old treatments, and that the chance of a cure was very, very small.”
If parents of children with metastatic, poor-prognosis rhabdomyosarcoma could be made to understand that adaptive therapy would entail shorter and fewer hospital stays, and cumulatively less toxic chemotherapy, and could prolong the lives of their children, the option might be more acceptable, he said.
And as Dr. Reed mentioned, prolonging time to progression offers hope of additional therapies to come.
“The whole time that my son was being treated, I hoped that there was going to be something else that came out, that a new trial would be launched because they found a way to drug a mutation, or treat it with immunotherapy – something that was going to give us a better option.”
Asked whether he would be willing to share his experiences in this article, Mr. Huff said that “I am willing to, in whatever small way I can, make an impact, and hopefully save another family from what we experienced.”
References
1. Reed DR et al. Cancer. 2020 Jun 1;126(11):2577-87 2. Bisogno G et al. J Clin Oncol. 2018;36:18_suppl,LBA-2
In 1859, Charles Darwin published “On the Origin of Species,” which outlined his world-shaking theory of evolution and its core principle of natural selection caused by environmental pressures that may determine whether an organism adapts and survives, or remains static, languishes, and eventually dies out.
The same forces that have influenced the size and shape of the beaks of finches in the Galapagos Islands, the length of giraffe necks in Africa, and the intestinal microbiomes of the nearly 8 billion human inhabitants of this planet also control whether malignant cells thrive and multiply, wither and die when assaulted by chemotherapy, or go into hiding, mutating and waiting for their next opportunity to erupt again and metastasize.
The ability of malignant cells to adapt to environmental pressures is “cancer’s most lethal and sophisticated property,” said Damon R. Reed, MD, program leader of the adolescent/young adult program at Moffitt Cancer Center in Tampa, Fla.
Dr. Reed and colleagues are developing methods to meet cancer on its own terms, applying evolutionary principles to the treatment of childhood fusion-positive rhabdomyosarcoma in an innovative, and some would say audacious, clinical trial.
Adaptive versus conventional therapy
The trial, now recruiting, is designed to evaluate each of four different strategies for chemotherapy schedules in patients with newly diagnosed metastatic fusion-positive rhabdomyosarcoma.
The trial contains four arms, three of which consist of either conventional chemotherapy based on published clinical trials, moving a second-line therapy to the first line, or adding maintenance therapy, all of which have the goal of inducing as many complete remissions as possible.
The remaining adaptive therapy arm, however, is entirely novel in approach, with therapy using a combination of chemotherapy drugs that will be started and interrupted based on tumor responses, with resumption of therapy on an adaptive schedule unique to each patient. The goal of treatment for patients enrolled in this arm will be prolongation of the time to disease progression, rather than complete remission.
Although some people might consider the adaptive therapy approach to be sacrificing the hope for a cure in exchange for palliation, the hard truth is that patients with fusion-positive rhabdomyosarcoma (in contrast to those with fusion-negative disease) have a dismal prognosis following relapse after up-front intensified therapy.
Instead, because a cure is exceedingly unlikely in patients with metastatic disease, the conventional idea of delivering the maximum tolerated dose of chemotherapy until disease progression could be replaced by an approach based on understanding of the evolution of cancer cells under selective pressures, Dr. Reed and colleagues contend.
“Although adaptive therapy would represent a major paradigm shift in pediatric oncology, this approach would exploit the chemotherapy-sensitive population to prevent the emergence of resistant populations, optimizing tumor control with less toxicity,” they wrote in a commentary published online in the journal Cancer.1
Poor survival with advanced disease
Childhood rhabdomyosarcoma (RMS) is a form of soft tissue sarcoma of mesenchymal origin. Approximately 25% of cases are parameningeal, arising from sites adjacent to the meninges of the nasopharynx, middle ear, paranasal sinuses, orbit, and other regions of the head and neck. Approximately 31% of cases arise in the genitourinary tract and 13% in the extremities, and other tumors occur less commonly in the trunk, chest wall, perineal/anal region, and abdomen.
The overall 5-year survival rate is approximately 71%.1
However, for patients with high-risk disease, a group that includes children 10 years of age or older with widespread disease with or without an activating PAX/FOX01 gene fusion, 5-year survival ranges from just 20% to 30% (Cancer Facts & Figures 2020).
“Among patients with metastatic disease, there is a clear difference in overall survival between those who have fusion-positive disease, where the 5-year overall survival is about 19%, and patients with fusion-negative disease,” said Douglas S. Hawkins, MD, chair of the children’s oncology group and professor of pediatrics at the University of Washington, Seattle, and associate chief in the division of hematology/oncology at Seattle Children’s Hospital.
Patients with fusion-negative disease can be further classified into those with multiple metastatic sites, with a 5-year overall survival rate of approximately 45%, and those with a single metastatic site, with a 5-year overall survival rate of 70%, he said in an interview.
“So when we talk about metastatic rhabdomyosarcoma, there actually is a diversity of outcomes, between really bad – those with fusion-positive disease – and not terrible – not great, but not terrible – for a selected group of patients with fusion-negative disease,” Dr. Hawkins said.
The poor prognosis for patients with metastatic fusion-positive disease prompted Dr. Reed and colleagues to rethink the entire approach to advanced cancers.
“If someone has a sarcoma, we know that we need to do surgery and radiation to the area, we know that localized disease does better than metastatic disease, and we generally hit it with some kind of chemotherapy that we call ‘standard of care,’ ” he said in an interview.
This approach is largely effective in some forms of cancer of bone and soft tissues, such as Ewing sarcoma, he notes, which has 5-year survival rates below 20% when treated with surgery and radiation only, but with the addition of chemotherapy has 5-year overall survival rates as high as 80%.
“At other times, with other sarcomas, the cure rate is abysmal, but we still call it standard of care,” Dr. Reed said.
For example, patients with metastatic fusion-positive RMS may have an initial response to chemotherapy, but most will eventually experience relapse and die of the disease.
“With some of the most common treatments, 70% of patients will have their cancers shrink by more than 50%, which is a major response, but the vast majority of them will have a recurrence later on,” Dr. Hawkins said.
He noted that the standard of care for patients with metastatic rhabdomyosarcoma, both with and without the PAX/FOX01 fusion, is chemotherapy, generally with the VAC regimen (vincristine, actinomycin D, and cyclophosphamide), although other agents such as doxorubicin, ifosfamide, etoposide, or irinotecan have also been tried, with little effect on event-free survival or overall survival rates.
A life too brief
Ricky Huff and his family know the course that the disease can take only too well. In 2015, his 5-month-old son, Theo, was diagnosed with metastatic rhabdomyosarcoma and put under the care of Damon Reed at Moffitt.
“During the whole course of treatment – I’m sure like many other parents – apart from relying on Damon and his treatment expertise to try to determine the best treatment options, I was reading everything under the sun to try to get a working knowledge of what Theo was up against, what his treatment and clinical trial options were, and what was the state of the science,” Mr. Huff says.
Unfortunately, the characteristics of Theo’s disease, including his very young age at onset and diagnosis of stage 4 metastatic disease, conspired against him, and despite undergoing 14 months of chemotherapy, Theo died of the disease in October 2016, 5 months shy of what would have been his second birthday.
In their grief, Mr. Huff, a real estate lawyer with a practice in Clearwater, Fla., and his wife, Leah, were determined to help other families of children with cancer and settled on the National Pediatric Cancer Foundation. Mr. Huff joined the board of directors of the foundation, which is collaborating with Moffitt Cancer Center on the adaptive therapy trial.
An evolutionary primer (cancer edition)
To get a better idea of just how adaptive therapy works, it is helpful to view cancer cells through the lens of species development, adaptation, extinction, and evolution.
“Cancer cells compete against each other in a dynamic environment. Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones,” Dr. Reed and colleagues wrote.
These influences can affect genetically identical cancer cells, which may begin to diverge from one another depending on their location in a tumor and the availability of nutrients, which in turn can result in two once-identical cells exhibiting different transcription rates for growth factors.
“Ultimately, this may affect the rate of progression through the cell cycle, leading to distinct rates of proliferation and mutational acquisition,” they wrote.
The diverging subpopulations will begin to develop different methods for adapting to the tumor microenvironment, with unique strategies for both accelerating growth and avoiding hazards such as chemotherapy drugs or radiation, the investigators explained.
“By the time a cancer becomes clinically apparent, cancer cells have transformed from a single clone into a diverse community of cell types evolving in response to a spatially and temporally heterogeneous tumor environment. Theoretically, a 10-gram cancer may contain the same order of magnitude of cancer cells as there are humans on earth, with tremendous diversity of phenotypes and environments,” they wrote.
Survival of the fittest
The competition of individuals within and between species described by Darwin also applies to cancer cells, in their interactions both with each other and with stromal cells and immune cells resulting in “the progressive replacement of less fit phenotypes by those that are more fit,” Dr. Reed and colleagues explained.
And just like the old joke about two hikers trying to escape from a charging grizzly bear (one says, “This is futile – we can’t outrun a grizzly,” and the other says, “I only have to outrun you!”), cancer cells only need to be more resistant to therapeutic attack than normal cells that are critical to function.
“This may explain why initial responses in certain solid tumors (notably rhabdomyosarcoma) do not predict eventual survival. The sensitivities of the dominant cancer cell populations dictate the initial response, but it is the ecology and evolution of the rare and more resistant populations that determine cure or relapse,” they wrote.
The endangered species list
As with many types of cancer, the current approach to treating pediatric sarcomas with curative intent is with a “first strike” approach, treating patients with surgery, radiation, and cytotoxic chemotherapy at the maximum tolerated dose for as long as needed or until unacceptable toxicities occur, with the intention of wiping out all cancer cells without permanently injuring normal cells.
The evolutionary analogy to this approach is a mass extinction event such as the meteor strike that is believed to have wiped out the dinosaurs roughly 66 million years ago. Fossil evidence suggests that the cataclysmic event resulted in the atmosphere being blanketed with dust particles that blocked sunlight and caused massive die-off of plants that dinosaurs needed to survive and were ill-adapted to do without.
In contrast, populations of smaller, more adaptable species of microbes, insects, and animals, including our mammalian ancestors, were able to survive and eventually flourish.
Many patients with localized cancers may be cured with up-front therapy, but others will have residual disease from populations of cells that are intrinsically resistant to therapy or have developed new evasion strategies.
Strike two and the MVP
Dr. Reed and colleagues liken the approach of second-line therapy for treatment of relapsed or refractory disease to the concept of “background extinctions,” using the fate of the passenger pigeon as an example of how a second-strike therapeutic strategy works.
Although the popular conception is that the passenger pigeon was hunted to extinction by humans, the species in fact died out because of many different factors, including loss of habitat, isolation of populations leading to a loss of genetic diversity, and disruption of breeding habits.
“Once first strikes of deforestation and hunting reduced the birds to small, fragmented populations, a series of what would otherwise have been minor second strikes pushed the passenger pigeon below its extinction threshold, or minimum viable population,” they said.
The analogy, as it applies to cancer therapy, is the use of second-line or follow-on therapy with one or more agents that the residual cells are at least in theory not resistant to. In the case of fusion-positive rhabdomyosarcoma, the drug most commonly added in the second-strike approach is vinorelbine.2
“Second strikes should be timed to occur around the time when the first strike has achieved its greatest effect, presumably at the point when the disease becomes clinically undetectable or at a measurable nadir,” Dr. Reed and colleagues wrote. “Ideally, second-strike therapies should have modes of action that require different resistance strategies by the cancer cells than those needed for resistance to the first strike.”
Adaptive therapy
As Dr. Reed and colleagues note, despite optimal therapy, 94% of patients with metastatic fusion-positive rhabdomyosarcoma will experience a relapse within 3 years of diagnosis.1 Clearly the scorched earth or “throw everything you have it” approach no longer works, and that’s where adaptive therapy comes in.
Here again, the authors rely on nature, or rather human interaction with nature, to devise a strategy for keeping the disease at bay when extinction of all cancerous cells cannot be achieved.
They cite the example of agricultural integrated pest management, which seeks to keep harmful insects in check by treating them to suppress but not completely destroy a population, then stopping the use of pesticides, and resuming only when the insect population spikes and again becomes a threat to crops.
“The goal is to limit crop damage while retaining the sensitivity of the insects to the pesticides. Resistance most often comes at a cost. In the absence of the pesticide, sensitive individuals will outcompete resistant individuals,” they wrote.
Adaptive therapy uses the same approach to reduce selection pressures that foster resistance, with patients treated only until a specific, predetermined response is achieved in the dominant population of chemosensitive cells. The treatment is then interrupted and reintroduced only when the tumor rebounds to a certain predetermined size.
In this scenario, cells that retain sensitivity to chemotherapy will be able to reproduce and proliferate more rapidly than drug-resistant cells, and the therapy can then be reintroduced. This strategy is less likely to cause the development and proliferation of resistant cells than conventional intensified chemotherapy, Dr. Reed and colleagues contend.
Putting it to the test
The clinical trial that Dr. Reed and colleagues have initiated, officially titled “Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma,” (NCT04388839) contains four arms: three experimental and one active comparator arm.
“We won’t randomize; we don’t feel that it would be fair to randomize patients, because these arms are so different from each other,” Dr. Reed said.
Arm A is the experimental first-strike arm, a 42-week course containing cyclophosphamide delivered intravenously over 60 minutes at a dose ranging from 220 mg to 1200 mg, vinorelbine delivered in an IV push over 6-10 minutes with a dose ranging from 4 mg to 25 mg, and actinomycin D administered via IV over 3-5 minutes at a dose ranging from 0.025 mg to 0.04 mg.
“The idea is that we take the standard of care, and we add a drug – vinorelbine – to make it stronger,” Dr. Reed said. “The idea is that the resistant cell, the cell that escapes, if we start hitting it on day 1 with vinorelbine, we might be able to drive it to extinction.”
Arm B, the second experimental arm, is the second-strike and maintenance arm, in which patients will receive conventional doses of vincristine, actinomycin D, and cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks, and will then be switched to up to 2 years of maintenance with vinorelbine and oral cyclophosphamide.
“Vinorelbine will be added when the cancer is declining or first goes into remission. We try not to wait 42 weeks, which is too long we think, by which time the cancer may be fully adapted and resistant,” he explained.
Arm C is the adaptive therapy arm, in which patients will receive VAC that starts and stops based on response, with the goal of prolonging time to disease progression rather than achieving CR.
Arm D is the active comparator arm, consisting of conventional chemotherapy based on published clinical trials, such as VAC for 42 weeks, or other standard-of-care regimens that may include irinotecan, doxorubicin, ifosfamide, and/or etoposide.
A change in thinking
Dr. Reed acknowledges that Arm C, the adaptive therapy arm, “definitely represents a change in thinking for pediatric oncology.”
“The idea is that if you could do this perfectly well, you would be able to take a patient who is diagnosed today and essentially ‘pause’ their disease for a while. Then 5 years from now, if there is a better medicine, you would have gotten that patient to that medicine.”
The optimal approach to treating metastatic fusion-positive rhabdomyosarcoma may be similar to that used for treatment of acute lymphoblastic leukemia, with induction, consolidation, and maintenance and the option of delayed intensification, he said.
“But we’re so far away from knowing which series to do that we just need to show that any series – any changing it up – is helpful.”
Dr. Reed said that when he started presenting the concept of adaptive therapy in clinical meetings in 2017, “I was told to come up with a better idea. There were several people who instantly got it, but most people would instantly get angry.”
The common refrain was that adaptive therapy was “giving up.”
But minds began to change in 2018, following presentation at the annual meeting of the American Society of Clinical Oncology of a European study showing that adding 6 months of low-dose chemotherapy maintenance to standard therapy improved the 5-year overall survival rate of pediatric rhabdomyosarcoma from 73.7% to 86.6%.2
Before presenting the idea of adaptive therapy to his colleagues, he ran it by the parents of children with advanced sarcomas, and many were on board with it, he said.
Ricky Huff said that had the option of adaptive therapy been available for Theo, he and his wife would have been willing to try it.
“Of course, everyone has the ability in hindsight to apply critical thinking to decisions that you made or could have made,” he said. “I think is true for many parents, who if they’re presented with information about options will say ‘well if there’s a 1 percent chance, I want that chance for my child, especially for a 5-month-old.”
The decision to choose adaptive therapy is a difficult decision to make, whether for oneself or for one’s son, because it isn’t curative.
“My wife and I have since had a conversation about this, and I do think we would have considered it, although through a lot of difficult conversations,” he said.
“After we got the pathology, knowing that it was metastatic, fusion-positive, and given his age, just doing a brief literature review on my own, I knew what we were up against using 20-year-old treatments, and that the chance of a cure was very, very small.”
If parents of children with metastatic, poor-prognosis rhabdomyosarcoma could be made to understand that adaptive therapy would entail shorter and fewer hospital stays, and cumulatively less toxic chemotherapy, and could prolong the lives of their children, the option might be more acceptable, he said.
And as Dr. Reed mentioned, prolonging time to progression offers hope of additional therapies to come.
“The whole time that my son was being treated, I hoped that there was going to be something else that came out, that a new trial would be launched because they found a way to drug a mutation, or treat it with immunotherapy – something that was going to give us a better option.”
Asked whether he would be willing to share his experiences in this article, Mr. Huff said that “I am willing to, in whatever small way I can, make an impact, and hopefully save another family from what we experienced.”
References
1. Reed DR et al. Cancer. 2020 Jun 1;126(11):2577-87 2. Bisogno G et al. J Clin Oncol. 2018;36:18_suppl,LBA-2
In 1859, Charles Darwin published “On the Origin of Species,” which outlined his world-shaking theory of evolution and its core principle of natural selection caused by environmental pressures that may determine whether an organism adapts and survives, or remains static, languishes, and eventually dies out.
The same forces that have influenced the size and shape of the beaks of finches in the Galapagos Islands, the length of giraffe necks in Africa, and the intestinal microbiomes of the nearly 8 billion human inhabitants of this planet also control whether malignant cells thrive and multiply, wither and die when assaulted by chemotherapy, or go into hiding, mutating and waiting for their next opportunity to erupt again and metastasize.
The ability of malignant cells to adapt to environmental pressures is “cancer’s most lethal and sophisticated property,” said Damon R. Reed, MD, program leader of the adolescent/young adult program at Moffitt Cancer Center in Tampa, Fla.
Dr. Reed and colleagues are developing methods to meet cancer on its own terms, applying evolutionary principles to the treatment of childhood fusion-positive rhabdomyosarcoma in an innovative, and some would say audacious, clinical trial.
Adaptive versus conventional therapy
The trial, now recruiting, is designed to evaluate each of four different strategies for chemotherapy schedules in patients with newly diagnosed metastatic fusion-positive rhabdomyosarcoma.
The trial contains four arms, three of which consist of either conventional chemotherapy based on published clinical trials, moving a second-line therapy to the first line, or adding maintenance therapy, all of which have the goal of inducing as many complete remissions as possible.
The remaining adaptive therapy arm, however, is entirely novel in approach, with therapy using a combination of chemotherapy drugs that will be started and interrupted based on tumor responses, with resumption of therapy on an adaptive schedule unique to each patient. The goal of treatment for patients enrolled in this arm will be prolongation of the time to disease progression, rather than complete remission.
Although some people might consider the adaptive therapy approach to be sacrificing the hope for a cure in exchange for palliation, the hard truth is that patients with fusion-positive rhabdomyosarcoma (in contrast to those with fusion-negative disease) have a dismal prognosis following relapse after up-front intensified therapy.
Instead, because a cure is exceedingly unlikely in patients with metastatic disease, the conventional idea of delivering the maximum tolerated dose of chemotherapy until disease progression could be replaced by an approach based on understanding of the evolution of cancer cells under selective pressures, Dr. Reed and colleagues contend.
“Although adaptive therapy would represent a major paradigm shift in pediatric oncology, this approach would exploit the chemotherapy-sensitive population to prevent the emergence of resistant populations, optimizing tumor control with less toxicity,” they wrote in a commentary published online in the journal Cancer.1
Poor survival with advanced disease
Childhood rhabdomyosarcoma (RMS) is a form of soft tissue sarcoma of mesenchymal origin. Approximately 25% of cases are parameningeal, arising from sites adjacent to the meninges of the nasopharynx, middle ear, paranasal sinuses, orbit, and other regions of the head and neck. Approximately 31% of cases arise in the genitourinary tract and 13% in the extremities, and other tumors occur less commonly in the trunk, chest wall, perineal/anal region, and abdomen.
The overall 5-year survival rate is approximately 71%.1
However, for patients with high-risk disease, a group that includes children 10 years of age or older with widespread disease with or without an activating PAX/FOX01 gene fusion, 5-year survival ranges from just 20% to 30% (Cancer Facts & Figures 2020).
“Among patients with metastatic disease, there is a clear difference in overall survival between those who have fusion-positive disease, where the 5-year overall survival is about 19%, and patients with fusion-negative disease,” said Douglas S. Hawkins, MD, chair of the children’s oncology group and professor of pediatrics at the University of Washington, Seattle, and associate chief in the division of hematology/oncology at Seattle Children’s Hospital.
Patients with fusion-negative disease can be further classified into those with multiple metastatic sites, with a 5-year overall survival rate of approximately 45%, and those with a single metastatic site, with a 5-year overall survival rate of 70%, he said in an interview.
“So when we talk about metastatic rhabdomyosarcoma, there actually is a diversity of outcomes, between really bad – those with fusion-positive disease – and not terrible – not great, but not terrible – for a selected group of patients with fusion-negative disease,” Dr. Hawkins said.
The poor prognosis for patients with metastatic fusion-positive disease prompted Dr. Reed and colleagues to rethink the entire approach to advanced cancers.
“If someone has a sarcoma, we know that we need to do surgery and radiation to the area, we know that localized disease does better than metastatic disease, and we generally hit it with some kind of chemotherapy that we call ‘standard of care,’ ” he said in an interview.
This approach is largely effective in some forms of cancer of bone and soft tissues, such as Ewing sarcoma, he notes, which has 5-year survival rates below 20% when treated with surgery and radiation only, but with the addition of chemotherapy has 5-year overall survival rates as high as 80%.
“At other times, with other sarcomas, the cure rate is abysmal, but we still call it standard of care,” Dr. Reed said.
For example, patients with metastatic fusion-positive RMS may have an initial response to chemotherapy, but most will eventually experience relapse and die of the disease.
“With some of the most common treatments, 70% of patients will have their cancers shrink by more than 50%, which is a major response, but the vast majority of them will have a recurrence later on,” Dr. Hawkins said.
He noted that the standard of care for patients with metastatic rhabdomyosarcoma, both with and without the PAX/FOX01 fusion, is chemotherapy, generally with the VAC regimen (vincristine, actinomycin D, and cyclophosphamide), although other agents such as doxorubicin, ifosfamide, etoposide, or irinotecan have also been tried, with little effect on event-free survival or overall survival rates.
A life too brief
Ricky Huff and his family know the course that the disease can take only too well. In 2015, his 5-month-old son, Theo, was diagnosed with metastatic rhabdomyosarcoma and put under the care of Damon Reed at Moffitt.
“During the whole course of treatment – I’m sure like many other parents – apart from relying on Damon and his treatment expertise to try to determine the best treatment options, I was reading everything under the sun to try to get a working knowledge of what Theo was up against, what his treatment and clinical trial options were, and what was the state of the science,” Mr. Huff says.
Unfortunately, the characteristics of Theo’s disease, including his very young age at onset and diagnosis of stage 4 metastatic disease, conspired against him, and despite undergoing 14 months of chemotherapy, Theo died of the disease in October 2016, 5 months shy of what would have been his second birthday.
In their grief, Mr. Huff, a real estate lawyer with a practice in Clearwater, Fla., and his wife, Leah, were determined to help other families of children with cancer and settled on the National Pediatric Cancer Foundation. Mr. Huff joined the board of directors of the foundation, which is collaborating with Moffitt Cancer Center on the adaptive therapy trial.
An evolutionary primer (cancer edition)
To get a better idea of just how adaptive therapy works, it is helpful to view cancer cells through the lens of species development, adaptation, extinction, and evolution.
“Cancer cells compete against each other in a dynamic environment. Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones,” Dr. Reed and colleagues wrote.
These influences can affect genetically identical cancer cells, which may begin to diverge from one another depending on their location in a tumor and the availability of nutrients, which in turn can result in two once-identical cells exhibiting different transcription rates for growth factors.
“Ultimately, this may affect the rate of progression through the cell cycle, leading to distinct rates of proliferation and mutational acquisition,” they wrote.
The diverging subpopulations will begin to develop different methods for adapting to the tumor microenvironment, with unique strategies for both accelerating growth and avoiding hazards such as chemotherapy drugs or radiation, the investigators explained.
“By the time a cancer becomes clinically apparent, cancer cells have transformed from a single clone into a diverse community of cell types evolving in response to a spatially and temporally heterogeneous tumor environment. Theoretically, a 10-gram cancer may contain the same order of magnitude of cancer cells as there are humans on earth, with tremendous diversity of phenotypes and environments,” they wrote.
Survival of the fittest
The competition of individuals within and between species described by Darwin also applies to cancer cells, in their interactions both with each other and with stromal cells and immune cells resulting in “the progressive replacement of less fit phenotypes by those that are more fit,” Dr. Reed and colleagues explained.
And just like the old joke about two hikers trying to escape from a charging grizzly bear (one says, “This is futile – we can’t outrun a grizzly,” and the other says, “I only have to outrun you!”), cancer cells only need to be more resistant to therapeutic attack than normal cells that are critical to function.
“This may explain why initial responses in certain solid tumors (notably rhabdomyosarcoma) do not predict eventual survival. The sensitivities of the dominant cancer cell populations dictate the initial response, but it is the ecology and evolution of the rare and more resistant populations that determine cure or relapse,” they wrote.
The endangered species list
As with many types of cancer, the current approach to treating pediatric sarcomas with curative intent is with a “first strike” approach, treating patients with surgery, radiation, and cytotoxic chemotherapy at the maximum tolerated dose for as long as needed or until unacceptable toxicities occur, with the intention of wiping out all cancer cells without permanently injuring normal cells.
The evolutionary analogy to this approach is a mass extinction event such as the meteor strike that is believed to have wiped out the dinosaurs roughly 66 million years ago. Fossil evidence suggests that the cataclysmic event resulted in the atmosphere being blanketed with dust particles that blocked sunlight and caused massive die-off of plants that dinosaurs needed to survive and were ill-adapted to do without.
In contrast, populations of smaller, more adaptable species of microbes, insects, and animals, including our mammalian ancestors, were able to survive and eventually flourish.
Many patients with localized cancers may be cured with up-front therapy, but others will have residual disease from populations of cells that are intrinsically resistant to therapy or have developed new evasion strategies.
Strike two and the MVP
Dr. Reed and colleagues liken the approach of second-line therapy for treatment of relapsed or refractory disease to the concept of “background extinctions,” using the fate of the passenger pigeon as an example of how a second-strike therapeutic strategy works.
Although the popular conception is that the passenger pigeon was hunted to extinction by humans, the species in fact died out because of many different factors, including loss of habitat, isolation of populations leading to a loss of genetic diversity, and disruption of breeding habits.
“Once first strikes of deforestation and hunting reduced the birds to small, fragmented populations, a series of what would otherwise have been minor second strikes pushed the passenger pigeon below its extinction threshold, or minimum viable population,” they said.
The analogy, as it applies to cancer therapy, is the use of second-line or follow-on therapy with one or more agents that the residual cells are at least in theory not resistant to. In the case of fusion-positive rhabdomyosarcoma, the drug most commonly added in the second-strike approach is vinorelbine.2
“Second strikes should be timed to occur around the time when the first strike has achieved its greatest effect, presumably at the point when the disease becomes clinically undetectable or at a measurable nadir,” Dr. Reed and colleagues wrote. “Ideally, second-strike therapies should have modes of action that require different resistance strategies by the cancer cells than those needed for resistance to the first strike.”
Adaptive therapy
As Dr. Reed and colleagues note, despite optimal therapy, 94% of patients with metastatic fusion-positive rhabdomyosarcoma will experience a relapse within 3 years of diagnosis.1 Clearly the scorched earth or “throw everything you have it” approach no longer works, and that’s where adaptive therapy comes in.
Here again, the authors rely on nature, or rather human interaction with nature, to devise a strategy for keeping the disease at bay when extinction of all cancerous cells cannot be achieved.
They cite the example of agricultural integrated pest management, which seeks to keep harmful insects in check by treating them to suppress but not completely destroy a population, then stopping the use of pesticides, and resuming only when the insect population spikes and again becomes a threat to crops.
“The goal is to limit crop damage while retaining the sensitivity of the insects to the pesticides. Resistance most often comes at a cost. In the absence of the pesticide, sensitive individuals will outcompete resistant individuals,” they wrote.
Adaptive therapy uses the same approach to reduce selection pressures that foster resistance, with patients treated only until a specific, predetermined response is achieved in the dominant population of chemosensitive cells. The treatment is then interrupted and reintroduced only when the tumor rebounds to a certain predetermined size.
In this scenario, cells that retain sensitivity to chemotherapy will be able to reproduce and proliferate more rapidly than drug-resistant cells, and the therapy can then be reintroduced. This strategy is less likely to cause the development and proliferation of resistant cells than conventional intensified chemotherapy, Dr. Reed and colleagues contend.
Putting it to the test
The clinical trial that Dr. Reed and colleagues have initiated, officially titled “Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma,” (NCT04388839) contains four arms: three experimental and one active comparator arm.
“We won’t randomize; we don’t feel that it would be fair to randomize patients, because these arms are so different from each other,” Dr. Reed said.
Arm A is the experimental first-strike arm, a 42-week course containing cyclophosphamide delivered intravenously over 60 minutes at a dose ranging from 220 mg to 1200 mg, vinorelbine delivered in an IV push over 6-10 minutes with a dose ranging from 4 mg to 25 mg, and actinomycin D administered via IV over 3-5 minutes at a dose ranging from 0.025 mg to 0.04 mg.
“The idea is that we take the standard of care, and we add a drug – vinorelbine – to make it stronger,” Dr. Reed said. “The idea is that the resistant cell, the cell that escapes, if we start hitting it on day 1 with vinorelbine, we might be able to drive it to extinction.”
Arm B, the second experimental arm, is the second-strike and maintenance arm, in which patients will receive conventional doses of vincristine, actinomycin D, and cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks, and will then be switched to up to 2 years of maintenance with vinorelbine and oral cyclophosphamide.
“Vinorelbine will be added when the cancer is declining or first goes into remission. We try not to wait 42 weeks, which is too long we think, by which time the cancer may be fully adapted and resistant,” he explained.
Arm C is the adaptive therapy arm, in which patients will receive VAC that starts and stops based on response, with the goal of prolonging time to disease progression rather than achieving CR.
Arm D is the active comparator arm, consisting of conventional chemotherapy based on published clinical trials, such as VAC for 42 weeks, or other standard-of-care regimens that may include irinotecan, doxorubicin, ifosfamide, and/or etoposide.
A change in thinking
Dr. Reed acknowledges that Arm C, the adaptive therapy arm, “definitely represents a change in thinking for pediatric oncology.”
“The idea is that if you could do this perfectly well, you would be able to take a patient who is diagnosed today and essentially ‘pause’ their disease for a while. Then 5 years from now, if there is a better medicine, you would have gotten that patient to that medicine.”
The optimal approach to treating metastatic fusion-positive rhabdomyosarcoma may be similar to that used for treatment of acute lymphoblastic leukemia, with induction, consolidation, and maintenance and the option of delayed intensification, he said.
“But we’re so far away from knowing which series to do that we just need to show that any series – any changing it up – is helpful.”
Dr. Reed said that when he started presenting the concept of adaptive therapy in clinical meetings in 2017, “I was told to come up with a better idea. There were several people who instantly got it, but most people would instantly get angry.”
The common refrain was that adaptive therapy was “giving up.”
But minds began to change in 2018, following presentation at the annual meeting of the American Society of Clinical Oncology of a European study showing that adding 6 months of low-dose chemotherapy maintenance to standard therapy improved the 5-year overall survival rate of pediatric rhabdomyosarcoma from 73.7% to 86.6%.2
Before presenting the idea of adaptive therapy to his colleagues, he ran it by the parents of children with advanced sarcomas, and many were on board with it, he said.
Ricky Huff said that had the option of adaptive therapy been available for Theo, he and his wife would have been willing to try it.
“Of course, everyone has the ability in hindsight to apply critical thinking to decisions that you made or could have made,” he said. “I think is true for many parents, who if they’re presented with information about options will say ‘well if there’s a 1 percent chance, I want that chance for my child, especially for a 5-month-old.”
The decision to choose adaptive therapy is a difficult decision to make, whether for oneself or for one’s son, because it isn’t curative.
“My wife and I have since had a conversation about this, and I do think we would have considered it, although through a lot of difficult conversations,” he said.
“After we got the pathology, knowing that it was metastatic, fusion-positive, and given his age, just doing a brief literature review on my own, I knew what we were up against using 20-year-old treatments, and that the chance of a cure was very, very small.”
If parents of children with metastatic, poor-prognosis rhabdomyosarcoma could be made to understand that adaptive therapy would entail shorter and fewer hospital stays, and cumulatively less toxic chemotherapy, and could prolong the lives of their children, the option might be more acceptable, he said.
And as Dr. Reed mentioned, prolonging time to progression offers hope of additional therapies to come.
“The whole time that my son was being treated, I hoped that there was going to be something else that came out, that a new trial would be launched because they found a way to drug a mutation, or treat it with immunotherapy – something that was going to give us a better option.”
Asked whether he would be willing to share his experiences in this article, Mr. Huff said that “I am willing to, in whatever small way I can, make an impact, and hopefully save another family from what we experienced.”
References
1. Reed DR et al. Cancer. 2020 Jun 1;126(11):2577-87 2. Bisogno G et al. J Clin Oncol. 2018;36:18_suppl,LBA-2
AGILE: ‘Exciting’ survival results for IDH1-mutated AML
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
AT ASH 2021
Isatuximab added to RVd boosts response in new myeloma
ATLANTA -
The drug is isatuximab (Sarclisa, Sanofi), an anti-CD38 antibody that was approved last year for use in patients with advanced disease.
Now it has shown benefit in patients who have been newly diagnosed with the disease. When isatuximab was added onto a usual triplet therapy for myeloma, it increased the likelihood that patients would be negative for minimal residual disease (MRD) at the end of the induction phase of treatment, thereby increasing their chances for a successful autologous stem cell transplant (ASCT).
The new results come from the GMMG-HD7 trial, in which all patients were treated with the triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd).
Some patients, after randomization, also received isatuximab, and in this group, the MRD-negativity rate was 50.1% at the end of induction therapy compared with 35.6% for patients treated with RVd alone.
Patients who are MRD-negative at the time of ASCT have significantly better outcomes than patients who remain MRD-positive.
“Isa-RVd is the first regimen to demonstrate significant MRD-negativity benefit at the end of induction versus RVd in a phase 3 trial,” reported Hartmut Goldschmidt, MD, from University Hospital Heidelberg, Germany.
“The benefits of the addition of Isa to RVd versus RVd regarding MRD negativity after induction therapy was consistent in all subgroups,” he added.
Dr. Goldschmidt spoke at a press briefing prior to his presentation of the data here at the annual meeting of the American Society of Hematology (ASH).
“I think that these data are encouraging, but they are preliminary, and we need mature data to be absolutely certain about whether this presents a major advance in treatment,” commented Ravi Vij, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis. Dr. Vij was not involved in the study.
“We know that for transplant-eligible patients, for whom this trial was conducted, the field is moving toward giving four drugs for induction,” he said in an interview with this news organization.
He noted that the combination of RVd with the other currently available anti-CD38 antibody, daratumumab (Darzalex), was approved for this indication in the United States in Jan. 2021.
Dr. Vij said that isatuximab has been slow to catch on in the United States both because it was approved after clinicians had already become familiar with daratumumab and because it is given intravenously, compared with subcutaneous administration of the latest formulation of daratumumab.
“Whereas isatuximab can take an hour-and-a-half with each infusion, daratumumab takes 5 minutes for an injection and the patient is out of there, so it is convenient both for the patient and the treating institution,” he said.
MRD vs. CR?
Dr. Goldschmidt was asked during the briefing about whether MRD-negativity or complete response rates are better predictors of progression-free survival (PFS). He replied that with current standardized sequencing techniques and sensitivity down to 10-6, “it’s a big benefit to analyze MRD negativity, and there is ongoing discussion between colleagues from the myeloma group with the Food and Drug Administration about how we can merge the data and predict PFS and overall survival.”
Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer, Vancouver, who moderated the briefing, commented that “we’re desperately looking for surrogate markers to speed up answers to clinical trials, and I think MRD in myeloma is quickly becoming a very important surrogate marker.”
GMMG-7 results
For their trial, Dr. Goldschmidt and colleagues enrolled 662 patients with newly diagnosed multiple myeloma who were candidates for high-dose therapy and ASCT and after stratification by revised International Staging System (r-ISS) criteria, randomly assigned them six three-week cycles of induction therapy with Isa-RVd or RVd alone.
Following ASCT, patients were again randomized to maintenance with either isatuximab plus lenalidomide or lenalidomide alone.
As noted before, MRD rates at the end of induction were 50.1% with Isa-RVd versus 35.6% with RVd alone, translating to a hazard ratio favoring the four-drug combination of 1.83 (P < .001).
Treatment with Isa-RVd was the only significant predictor for the likelihood of MRD negativity in a multivariate analysis controlling for treatment group, r-ISS status, performance status, renal impairment, age, and sex.
Although the rate of complete responses at the end of induction was similar between the treatment groups, the rate of very good partial response or better was higher with the isatuximab-containing combination (77.3% vs. 60.5%; P < .001).
The respective rates of disease progression at the end of induction in the Isa-RVd and RVd groups were 1.5% versus 4.0%.
The rates of adverse events were generally similar between the groups, except a higher proportion of patients had leukocytopenia or neutropenia in the Isa-RVd than the RVdgroup (26.4% vs. 9.1%). There were four deaths in the Isa-RVd group and eight in the RVd group. Most of the deaths were attributable to disease progression or COVID-19, said Dr. Goldschmidt.
The study was funded by Sanofi. Dr. Goldschmidt has disclosed honoraria and research grants from Sanofi and others. Dr. Vij has disclosed honoraria or advisory board activities from various companies, including Sanofi. Dr. Sehn is a consultant for and has received honoraria from various companies, not including Sanofi.
A version of this article first appeared on Medscape.com.
ATLANTA -
The drug is isatuximab (Sarclisa, Sanofi), an anti-CD38 antibody that was approved last year for use in patients with advanced disease.
Now it has shown benefit in patients who have been newly diagnosed with the disease. When isatuximab was added onto a usual triplet therapy for myeloma, it increased the likelihood that patients would be negative for minimal residual disease (MRD) at the end of the induction phase of treatment, thereby increasing their chances for a successful autologous stem cell transplant (ASCT).
The new results come from the GMMG-HD7 trial, in which all patients were treated with the triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd).
Some patients, after randomization, also received isatuximab, and in this group, the MRD-negativity rate was 50.1% at the end of induction therapy compared with 35.6% for patients treated with RVd alone.
Patients who are MRD-negative at the time of ASCT have significantly better outcomes than patients who remain MRD-positive.
“Isa-RVd is the first regimen to demonstrate significant MRD-negativity benefit at the end of induction versus RVd in a phase 3 trial,” reported Hartmut Goldschmidt, MD, from University Hospital Heidelberg, Germany.
“The benefits of the addition of Isa to RVd versus RVd regarding MRD negativity after induction therapy was consistent in all subgroups,” he added.
Dr. Goldschmidt spoke at a press briefing prior to his presentation of the data here at the annual meeting of the American Society of Hematology (ASH).
“I think that these data are encouraging, but they are preliminary, and we need mature data to be absolutely certain about whether this presents a major advance in treatment,” commented Ravi Vij, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis. Dr. Vij was not involved in the study.
“We know that for transplant-eligible patients, for whom this trial was conducted, the field is moving toward giving four drugs for induction,” he said in an interview with this news organization.
He noted that the combination of RVd with the other currently available anti-CD38 antibody, daratumumab (Darzalex), was approved for this indication in the United States in Jan. 2021.
Dr. Vij said that isatuximab has been slow to catch on in the United States both because it was approved after clinicians had already become familiar with daratumumab and because it is given intravenously, compared with subcutaneous administration of the latest formulation of daratumumab.
“Whereas isatuximab can take an hour-and-a-half with each infusion, daratumumab takes 5 minutes for an injection and the patient is out of there, so it is convenient both for the patient and the treating institution,” he said.
MRD vs. CR?
Dr. Goldschmidt was asked during the briefing about whether MRD-negativity or complete response rates are better predictors of progression-free survival (PFS). He replied that with current standardized sequencing techniques and sensitivity down to 10-6, “it’s a big benefit to analyze MRD negativity, and there is ongoing discussion between colleagues from the myeloma group with the Food and Drug Administration about how we can merge the data and predict PFS and overall survival.”
Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer, Vancouver, who moderated the briefing, commented that “we’re desperately looking for surrogate markers to speed up answers to clinical trials, and I think MRD in myeloma is quickly becoming a very important surrogate marker.”
GMMG-7 results
For their trial, Dr. Goldschmidt and colleagues enrolled 662 patients with newly diagnosed multiple myeloma who were candidates for high-dose therapy and ASCT and after stratification by revised International Staging System (r-ISS) criteria, randomly assigned them six three-week cycles of induction therapy with Isa-RVd or RVd alone.
Following ASCT, patients were again randomized to maintenance with either isatuximab plus lenalidomide or lenalidomide alone.
As noted before, MRD rates at the end of induction were 50.1% with Isa-RVd versus 35.6% with RVd alone, translating to a hazard ratio favoring the four-drug combination of 1.83 (P < .001).
Treatment with Isa-RVd was the only significant predictor for the likelihood of MRD negativity in a multivariate analysis controlling for treatment group, r-ISS status, performance status, renal impairment, age, and sex.
Although the rate of complete responses at the end of induction was similar between the treatment groups, the rate of very good partial response or better was higher with the isatuximab-containing combination (77.3% vs. 60.5%; P < .001).
The respective rates of disease progression at the end of induction in the Isa-RVd and RVd groups were 1.5% versus 4.0%.
The rates of adverse events were generally similar between the groups, except a higher proportion of patients had leukocytopenia or neutropenia in the Isa-RVd than the RVdgroup (26.4% vs. 9.1%). There were four deaths in the Isa-RVd group and eight in the RVd group. Most of the deaths were attributable to disease progression or COVID-19, said Dr. Goldschmidt.
The study was funded by Sanofi. Dr. Goldschmidt has disclosed honoraria and research grants from Sanofi and others. Dr. Vij has disclosed honoraria or advisory board activities from various companies, including Sanofi. Dr. Sehn is a consultant for and has received honoraria from various companies, not including Sanofi.
A version of this article first appeared on Medscape.com.
ATLANTA -
The drug is isatuximab (Sarclisa, Sanofi), an anti-CD38 antibody that was approved last year for use in patients with advanced disease.
Now it has shown benefit in patients who have been newly diagnosed with the disease. When isatuximab was added onto a usual triplet therapy for myeloma, it increased the likelihood that patients would be negative for minimal residual disease (MRD) at the end of the induction phase of treatment, thereby increasing their chances for a successful autologous stem cell transplant (ASCT).
The new results come from the GMMG-HD7 trial, in which all patients were treated with the triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd).
Some patients, after randomization, also received isatuximab, and in this group, the MRD-negativity rate was 50.1% at the end of induction therapy compared with 35.6% for patients treated with RVd alone.
Patients who are MRD-negative at the time of ASCT have significantly better outcomes than patients who remain MRD-positive.
“Isa-RVd is the first regimen to demonstrate significant MRD-negativity benefit at the end of induction versus RVd in a phase 3 trial,” reported Hartmut Goldschmidt, MD, from University Hospital Heidelberg, Germany.
“The benefits of the addition of Isa to RVd versus RVd regarding MRD negativity after induction therapy was consistent in all subgroups,” he added.
Dr. Goldschmidt spoke at a press briefing prior to his presentation of the data here at the annual meeting of the American Society of Hematology (ASH).
“I think that these data are encouraging, but they are preliminary, and we need mature data to be absolutely certain about whether this presents a major advance in treatment,” commented Ravi Vij, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis. Dr. Vij was not involved in the study.
“We know that for transplant-eligible patients, for whom this trial was conducted, the field is moving toward giving four drugs for induction,” he said in an interview with this news organization.
He noted that the combination of RVd with the other currently available anti-CD38 antibody, daratumumab (Darzalex), was approved for this indication in the United States in Jan. 2021.
Dr. Vij said that isatuximab has been slow to catch on in the United States both because it was approved after clinicians had already become familiar with daratumumab and because it is given intravenously, compared with subcutaneous administration of the latest formulation of daratumumab.
“Whereas isatuximab can take an hour-and-a-half with each infusion, daratumumab takes 5 minutes for an injection and the patient is out of there, so it is convenient both for the patient and the treating institution,” he said.
MRD vs. CR?
Dr. Goldschmidt was asked during the briefing about whether MRD-negativity or complete response rates are better predictors of progression-free survival (PFS). He replied that with current standardized sequencing techniques and sensitivity down to 10-6, “it’s a big benefit to analyze MRD negativity, and there is ongoing discussion between colleagues from the myeloma group with the Food and Drug Administration about how we can merge the data and predict PFS and overall survival.”
Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer, Vancouver, who moderated the briefing, commented that “we’re desperately looking for surrogate markers to speed up answers to clinical trials, and I think MRD in myeloma is quickly becoming a very important surrogate marker.”
GMMG-7 results
For their trial, Dr. Goldschmidt and colleagues enrolled 662 patients with newly diagnosed multiple myeloma who were candidates for high-dose therapy and ASCT and after stratification by revised International Staging System (r-ISS) criteria, randomly assigned them six three-week cycles of induction therapy with Isa-RVd or RVd alone.
Following ASCT, patients were again randomized to maintenance with either isatuximab plus lenalidomide or lenalidomide alone.
As noted before, MRD rates at the end of induction were 50.1% with Isa-RVd versus 35.6% with RVd alone, translating to a hazard ratio favoring the four-drug combination of 1.83 (P < .001).
Treatment with Isa-RVd was the only significant predictor for the likelihood of MRD negativity in a multivariate analysis controlling for treatment group, r-ISS status, performance status, renal impairment, age, and sex.
Although the rate of complete responses at the end of induction was similar between the treatment groups, the rate of very good partial response or better was higher with the isatuximab-containing combination (77.3% vs. 60.5%; P < .001).
The respective rates of disease progression at the end of induction in the Isa-RVd and RVd groups were 1.5% versus 4.0%.
The rates of adverse events were generally similar between the groups, except a higher proportion of patients had leukocytopenia or neutropenia in the Isa-RVd than the RVdgroup (26.4% vs. 9.1%). There were four deaths in the Isa-RVd group and eight in the RVd group. Most of the deaths were attributable to disease progression or COVID-19, said Dr. Goldschmidt.
The study was funded by Sanofi. Dr. Goldschmidt has disclosed honoraria and research grants from Sanofi and others. Dr. Vij has disclosed honoraria or advisory board activities from various companies, including Sanofi. Dr. Sehn is a consultant for and has received honoraria from various companies, not including Sanofi.
A version of this article first appeared on Medscape.com.
AT ASH 2021
‘Outstanding data’: Mosunetuzumab in r/r follicular lymphoma
An experimental bi-specific monoclonal antibody known as mosunetuzumab has induced high response rates and long-duration responses as monotherapy for patients with heavily pretreated, relapsed or refractory follicular lymphoma in a phase 2 expansion study.
At a median follow-up of 18.3 months, 54 of 90 patients (60%) had a complete response, and 18 (20%) had a partial response after treatment with mosunetuzumab, reported L. Elizabeth Budde, MD, PhD, from City of Hope Comprehensive Cancer Center in Duarte, Calif.
In contrast, the complete response rate for historical controls was just 14% (P < .0001), Dr. Budde noted.
“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented.
Budde was speaking at a press briefing prior to her presentation of the data at the annual meeting of the American Society of Hematology (ASH), held in a hybrid live/virtual format.
The manufacturer, Genentech, said in a statement that based on these “highly positive results,” it plans to submit the new data to the U.S. Food and Drug Administration (FDA) in the near future for approval consideration.
If approved, mosunetuzumab has the potential to be a first-in-class CD20xCD3 T-cell engaging bispecific antibody in non-Hodgkin lymphoma, the company added.
“Outstanding” data
A lymphoma specialist who was not involved in the study told this news organization that he was favorably impressed by the findings.
“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis.
“I think as a single agent — if it does get approval — it will be a really valuable addition to the armamentarium in follicular lymphoma,” he said.
Dr. Kahl pointed to a separate phase 1b study, also presented at the meeting, suggesting that the combination of mosunetuzumab and lenalidomide (Revlimid) was safe and showed promising antitumor activity in patients with follicular lymphoma that has relapsed after at least 1 line of therapy.
“I’m very interested to see how mosunetuzumab plus lenalidomide pans out in the long run,” he said.
Study details
Mosunetuzumab engages T cells and redirects them to eliminate malignant B cells. It has the potential to be used as an off-the-shelf product, Dr. Budde said.
In the single-arm phase 2 expansion trial, Dr. Budde and colleagues enrolled 90 patients with grades 1 to 3a follicular lymphoma whose disease relapsed or was refractory to at least two prior lines of therapy, including at least one anti-CD20 monoclonal antibody, and at least one alkylating agent.
Patients were treated with step-up dosing for the first 21-day cycle to mitigate the cytokine release syndrome. They then received eight cycles if they had a complete response, and 17 cycles if they had a partial response or stable disease after eight cycles.
The primary endpoint was complete response rate by independent review, which was 60%, and the overall response rate (ORR), a secondary efficacy endpoint, was 80%.
There were no significant differences in CR or ORR rates among subgroups according to patient age, number of prior lines of therapy, relapsed or refractory disease to last prior line of therapy, double-refractory disease, or disease progression within 24 months of primary therapy.
The median duration of response among all responders was 22.8 months, with a median time to first response of 1.4 months. The 12- and 18-months event-free rates were 62% and 57%, respectively.
The safety profile was manageable, Dr. Budde said, with grade 3 or 4 drug-related adverse events occurring in about half of patients, and serious adverse events occurring in a third.
There were two deaths during the study, but neither was judged to be related to mosunetuzumab, and there were only two events leading to drug discontinuation.
Cytokine release syndrome (CRS) of any grade occurred in 40 patients (44.4%), but only 1 patient each had a grade 3 or 4 CR. The median time to CRS onset was 5.2 hours in cycle 1, and 26.6 hours in subsequent cycles. The median duration of CRS was 3 days. Ten patients had CRS managed with corticosteroids, and seven had it managed with tocilizumab.
Immune effector cell-associated neurotoxicity syndrome (ICANS) events were infrequent, and all were grade 1 or 2 in severity.
The study was supported by Genentech. Dr. Budde disclosed consulting for the company and others. Dr. Kahl has previously disclosed financial considerations with AbbVie.
A version of this article first appeared on Medscape.com.
This article was updated 12/12/21.
An experimental bi-specific monoclonal antibody known as mosunetuzumab has induced high response rates and long-duration responses as monotherapy for patients with heavily pretreated, relapsed or refractory follicular lymphoma in a phase 2 expansion study.
At a median follow-up of 18.3 months, 54 of 90 patients (60%) had a complete response, and 18 (20%) had a partial response after treatment with mosunetuzumab, reported L. Elizabeth Budde, MD, PhD, from City of Hope Comprehensive Cancer Center in Duarte, Calif.
In contrast, the complete response rate for historical controls was just 14% (P < .0001), Dr. Budde noted.
“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented.
Budde was speaking at a press briefing prior to her presentation of the data at the annual meeting of the American Society of Hematology (ASH), held in a hybrid live/virtual format.
The manufacturer, Genentech, said in a statement that based on these “highly positive results,” it plans to submit the new data to the U.S. Food and Drug Administration (FDA) in the near future for approval consideration.
If approved, mosunetuzumab has the potential to be a first-in-class CD20xCD3 T-cell engaging bispecific antibody in non-Hodgkin lymphoma, the company added.
“Outstanding” data
A lymphoma specialist who was not involved in the study told this news organization that he was favorably impressed by the findings.
“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis.
“I think as a single agent — if it does get approval — it will be a really valuable addition to the armamentarium in follicular lymphoma,” he said.
Dr. Kahl pointed to a separate phase 1b study, also presented at the meeting, suggesting that the combination of mosunetuzumab and lenalidomide (Revlimid) was safe and showed promising antitumor activity in patients with follicular lymphoma that has relapsed after at least 1 line of therapy.
“I’m very interested to see how mosunetuzumab plus lenalidomide pans out in the long run,” he said.
Study details
Mosunetuzumab engages T cells and redirects them to eliminate malignant B cells. It has the potential to be used as an off-the-shelf product, Dr. Budde said.
In the single-arm phase 2 expansion trial, Dr. Budde and colleagues enrolled 90 patients with grades 1 to 3a follicular lymphoma whose disease relapsed or was refractory to at least two prior lines of therapy, including at least one anti-CD20 monoclonal antibody, and at least one alkylating agent.
Patients were treated with step-up dosing for the first 21-day cycle to mitigate the cytokine release syndrome. They then received eight cycles if they had a complete response, and 17 cycles if they had a partial response or stable disease after eight cycles.
The primary endpoint was complete response rate by independent review, which was 60%, and the overall response rate (ORR), a secondary efficacy endpoint, was 80%.
There were no significant differences in CR or ORR rates among subgroups according to patient age, number of prior lines of therapy, relapsed or refractory disease to last prior line of therapy, double-refractory disease, or disease progression within 24 months of primary therapy.
The median duration of response among all responders was 22.8 months, with a median time to first response of 1.4 months. The 12- and 18-months event-free rates were 62% and 57%, respectively.
The safety profile was manageable, Dr. Budde said, with grade 3 or 4 drug-related adverse events occurring in about half of patients, and serious adverse events occurring in a third.
There were two deaths during the study, but neither was judged to be related to mosunetuzumab, and there were only two events leading to drug discontinuation.
Cytokine release syndrome (CRS) of any grade occurred in 40 patients (44.4%), but only 1 patient each had a grade 3 or 4 CR. The median time to CRS onset was 5.2 hours in cycle 1, and 26.6 hours in subsequent cycles. The median duration of CRS was 3 days. Ten patients had CRS managed with corticosteroids, and seven had it managed with tocilizumab.
Immune effector cell-associated neurotoxicity syndrome (ICANS) events were infrequent, and all were grade 1 or 2 in severity.
The study was supported by Genentech. Dr. Budde disclosed consulting for the company and others. Dr. Kahl has previously disclosed financial considerations with AbbVie.
A version of this article first appeared on Medscape.com.
This article was updated 12/12/21.
An experimental bi-specific monoclonal antibody known as mosunetuzumab has induced high response rates and long-duration responses as monotherapy for patients with heavily pretreated, relapsed or refractory follicular lymphoma in a phase 2 expansion study.
At a median follow-up of 18.3 months, 54 of 90 patients (60%) had a complete response, and 18 (20%) had a partial response after treatment with mosunetuzumab, reported L. Elizabeth Budde, MD, PhD, from City of Hope Comprehensive Cancer Center in Duarte, Calif.
In contrast, the complete response rate for historical controls was just 14% (P < .0001), Dr. Budde noted.
“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented.
Budde was speaking at a press briefing prior to her presentation of the data at the annual meeting of the American Society of Hematology (ASH), held in a hybrid live/virtual format.
The manufacturer, Genentech, said in a statement that based on these “highly positive results,” it plans to submit the new data to the U.S. Food and Drug Administration (FDA) in the near future for approval consideration.
If approved, mosunetuzumab has the potential to be a first-in-class CD20xCD3 T-cell engaging bispecific antibody in non-Hodgkin lymphoma, the company added.
“Outstanding” data
A lymphoma specialist who was not involved in the study told this news organization that he was favorably impressed by the findings.
“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis.
“I think as a single agent — if it does get approval — it will be a really valuable addition to the armamentarium in follicular lymphoma,” he said.
Dr. Kahl pointed to a separate phase 1b study, also presented at the meeting, suggesting that the combination of mosunetuzumab and lenalidomide (Revlimid) was safe and showed promising antitumor activity in patients with follicular lymphoma that has relapsed after at least 1 line of therapy.
“I’m very interested to see how mosunetuzumab plus lenalidomide pans out in the long run,” he said.
Study details
Mosunetuzumab engages T cells and redirects them to eliminate malignant B cells. It has the potential to be used as an off-the-shelf product, Dr. Budde said.
In the single-arm phase 2 expansion trial, Dr. Budde and colleagues enrolled 90 patients with grades 1 to 3a follicular lymphoma whose disease relapsed or was refractory to at least two prior lines of therapy, including at least one anti-CD20 monoclonal antibody, and at least one alkylating agent.
Patients were treated with step-up dosing for the first 21-day cycle to mitigate the cytokine release syndrome. They then received eight cycles if they had a complete response, and 17 cycles if they had a partial response or stable disease after eight cycles.
The primary endpoint was complete response rate by independent review, which was 60%, and the overall response rate (ORR), a secondary efficacy endpoint, was 80%.
There were no significant differences in CR or ORR rates among subgroups according to patient age, number of prior lines of therapy, relapsed or refractory disease to last prior line of therapy, double-refractory disease, or disease progression within 24 months of primary therapy.
The median duration of response among all responders was 22.8 months, with a median time to first response of 1.4 months. The 12- and 18-months event-free rates were 62% and 57%, respectively.
The safety profile was manageable, Dr. Budde said, with grade 3 or 4 drug-related adverse events occurring in about half of patients, and serious adverse events occurring in a third.
There were two deaths during the study, but neither was judged to be related to mosunetuzumab, and there were only two events leading to drug discontinuation.
Cytokine release syndrome (CRS) of any grade occurred in 40 patients (44.4%), but only 1 patient each had a grade 3 or 4 CR. The median time to CRS onset was 5.2 hours in cycle 1, and 26.6 hours in subsequent cycles. The median duration of CRS was 3 days. Ten patients had CRS managed with corticosteroids, and seven had it managed with tocilizumab.
Immune effector cell-associated neurotoxicity syndrome (ICANS) events were infrequent, and all were grade 1 or 2 in severity.
The study was supported by Genentech. Dr. Budde disclosed consulting for the company and others. Dr. Kahl has previously disclosed financial considerations with AbbVie.
A version of this article first appeared on Medscape.com.
This article was updated 12/12/21.
AT ASH 2021
‘Remarkable’ results with CAR T cells could make chemo obsolete
ATLANTA — Chimeric antigen receptor, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.
In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.
In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.
The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.
“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.
Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.
“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”
In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.
The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”
“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.
Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.
For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.
Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.
ZUMA-7 results
THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.
As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).
In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).
Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.
In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.
Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.
Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.
TRANSFORM results
The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.
A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.
As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).
The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.
“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.
Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.
ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.
A version of this article first appeared on Medscape.com.
ATLANTA — Chimeric antigen receptor, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.
In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.
In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.
The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.
“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.
Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.
“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”
In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.
The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”
“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.
Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.
For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.
Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.
ZUMA-7 results
THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.
As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).
In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).
Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.
In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.
Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.
Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.
TRANSFORM results
The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.
A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.
As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).
The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.
“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.
Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.
ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.
A version of this article first appeared on Medscape.com.
ATLANTA — Chimeric antigen receptor, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.
In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.
In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.
The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.
“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.
Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.
“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”
In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.
The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”
“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.
Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.
For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.
Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.
ZUMA-7 results
THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.
As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).
In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).
Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.
In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.
Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.
Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.
TRANSFORM results
The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.
A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.
As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).
The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.
“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.
Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.
ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.
A version of this article first appeared on Medscape.com.
AT ASH 2021
Liver cancer risk lingers even after HCV eradication
Although the risk for liver cancer diminishes for patients with hepatitis C virus (HCV) infections for whom the virus is eliminated with direct-acting antiviral (DAA) drugs, these patients are not out of the woods, and those who do not have a sustained viral response (SVR) are at substantially higher risk of developing hepatocellular carcinoma (HCC), results of a large study show.
Among the patients with liver cirrhosis from HCV infections treated at 30 centers in Italy, a large percentage had an SVR after treatment with DAA drugs. Only a small percentage of this group subsequently developed HCC.
In contrast, not having an SVR was associated with a more than sevenfold higher risk for liver cancer, said Loreta A. Kondili, MD, PhD, from the Center for Global Health at the Istituto Superiore di Sanità, Rome, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Failure to achieve SVR after DAA treatment is strongly associated with the probability of HCC development. Older age, [HCV] genotype 3, and low platelet counts and albumin levels are independent factors of HCC development despite viral eradication,” she said.
Cohort study
The study findings come from the PITER Cohort Study, a prospective, multicenter observational study of a representative sample of patients with HCV.
Dr. Kondili and colleagues assessed the medium- and long-term effects of DAA therapy on HCC rates among patients with HCV-induced liver cirrhosis. Patients who had undergone a liver transplant or who had been previously diagnosed with HCC were excluded.
The investigators identified a total of 2,214 DAA-treated patients, of whom 149 (6.7%) developed de novo HCC after a median follow-up of 30 months.
From the total group, 2,064 (93%) patients had an SVR, 119 of whom (5.8%) developed HCC. Of these patients who developed HCC, 80% were diagnosed with stage B or C disease in accordance with the Barcelona Clinic Liver Cancer staging system.
For the remaining 150 patients who did not have an SVR, 30 (20%) developed de novo HCC, a difference that translated into an adjusted hazard ratio (aHR) for HCC of 7.38 (P < .01).
The time from the end of DAA therapy to a diagnosis of HCC was shorter for patients who did not have an SVR. For these patients, the 2-year HCC-free survival rate was 81%, compared with 98% for patients who had an SVR (P < .001).
As reported by Dr. Kondili, among patients who achieved an SVR, the variables significantly associated with HCC risk included older age (aHR, 1.06), platelet counts greater than the reference limit of 150,000 μL (aHR, 2.43), albumin levels >3.5 g/dL (aHR, 2.36), and diabetes (aHR, 1.53; all these variables were significant by confidence intervals).
In all, 26% of these patients died during the follow-up period, and 7.6% underwent liver transplant.
Of the patients still alive at the end of the follow-up period, 38% had active HCC.
Long-term follow-up required
“It’s useful to think of hepatitis C as a viral infection on one hand [and] a liver disease on the other,” commented Raymond T. Chung, MD, director of the Hepatology and Liver Center and vice chief of gastroenterology at Massachusetts General Hospital, Boston.
“In terms of thinking of elimination, we can eradicate the virus in most patients with virtually 100% success with antivirals. This has given us a false sense of comfort that it’s a ‘one and done’ process, and patients can more or less enjoy the rest of their lives free of hepatitis C,” he said.
Dr. Chung, who was not involved in the study, emphasized that despite the elimination of the virus, patients may still have significant liver fibrosis or cirrhosis. It is imperative that these patients be monitored for signs of cancer, he said.
“This is what’s important about staging patients and understanding how severe their liver disease is, because if there is advanced fibrosis, bridging fibrosis, or cirrhosis, these are patients who are going to require long-term oncology care. Their infectious disease is eliminated, but the liver disease remains,” he said.
Dr. Chung also noted that rates of liver cancer, decompensation, and liver failure are higher among patients with untreated HCV than among patients whose HCV has been eradicated or suppressed with drug treatment. In addition, patients with untreated HCV are at greater risk of requiring transplant than are patients with HCV that was treated, and there remains a residual cancer risk for patients who become HCV seronegative.
The study was funded by the Italian Ministry of Health. Dr. Kondili has financial relationships with Gilead Science and AbbVie. Dr. Chung reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Although the risk for liver cancer diminishes for patients with hepatitis C virus (HCV) infections for whom the virus is eliminated with direct-acting antiviral (DAA) drugs, these patients are not out of the woods, and those who do not have a sustained viral response (SVR) are at substantially higher risk of developing hepatocellular carcinoma (HCC), results of a large study show.
Among the patients with liver cirrhosis from HCV infections treated at 30 centers in Italy, a large percentage had an SVR after treatment with DAA drugs. Only a small percentage of this group subsequently developed HCC.
In contrast, not having an SVR was associated with a more than sevenfold higher risk for liver cancer, said Loreta A. Kondili, MD, PhD, from the Center for Global Health at the Istituto Superiore di Sanità, Rome, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Failure to achieve SVR after DAA treatment is strongly associated with the probability of HCC development. Older age, [HCV] genotype 3, and low platelet counts and albumin levels are independent factors of HCC development despite viral eradication,” she said.
Cohort study
The study findings come from the PITER Cohort Study, a prospective, multicenter observational study of a representative sample of patients with HCV.
Dr. Kondili and colleagues assessed the medium- and long-term effects of DAA therapy on HCC rates among patients with HCV-induced liver cirrhosis. Patients who had undergone a liver transplant or who had been previously diagnosed with HCC were excluded.
The investigators identified a total of 2,214 DAA-treated patients, of whom 149 (6.7%) developed de novo HCC after a median follow-up of 30 months.
From the total group, 2,064 (93%) patients had an SVR, 119 of whom (5.8%) developed HCC. Of these patients who developed HCC, 80% were diagnosed with stage B or C disease in accordance with the Barcelona Clinic Liver Cancer staging system.
For the remaining 150 patients who did not have an SVR, 30 (20%) developed de novo HCC, a difference that translated into an adjusted hazard ratio (aHR) for HCC of 7.38 (P < .01).
The time from the end of DAA therapy to a diagnosis of HCC was shorter for patients who did not have an SVR. For these patients, the 2-year HCC-free survival rate was 81%, compared with 98% for patients who had an SVR (P < .001).
As reported by Dr. Kondili, among patients who achieved an SVR, the variables significantly associated with HCC risk included older age (aHR, 1.06), platelet counts greater than the reference limit of 150,000 μL (aHR, 2.43), albumin levels >3.5 g/dL (aHR, 2.36), and diabetes (aHR, 1.53; all these variables were significant by confidence intervals).
In all, 26% of these patients died during the follow-up period, and 7.6% underwent liver transplant.
Of the patients still alive at the end of the follow-up period, 38% had active HCC.
Long-term follow-up required
“It’s useful to think of hepatitis C as a viral infection on one hand [and] a liver disease on the other,” commented Raymond T. Chung, MD, director of the Hepatology and Liver Center and vice chief of gastroenterology at Massachusetts General Hospital, Boston.
“In terms of thinking of elimination, we can eradicate the virus in most patients with virtually 100% success with antivirals. This has given us a false sense of comfort that it’s a ‘one and done’ process, and patients can more or less enjoy the rest of their lives free of hepatitis C,” he said.
Dr. Chung, who was not involved in the study, emphasized that despite the elimination of the virus, patients may still have significant liver fibrosis or cirrhosis. It is imperative that these patients be monitored for signs of cancer, he said.
“This is what’s important about staging patients and understanding how severe their liver disease is, because if there is advanced fibrosis, bridging fibrosis, or cirrhosis, these are patients who are going to require long-term oncology care. Their infectious disease is eliminated, but the liver disease remains,” he said.
Dr. Chung also noted that rates of liver cancer, decompensation, and liver failure are higher among patients with untreated HCV than among patients whose HCV has been eradicated or suppressed with drug treatment. In addition, patients with untreated HCV are at greater risk of requiring transplant than are patients with HCV that was treated, and there remains a residual cancer risk for patients who become HCV seronegative.
The study was funded by the Italian Ministry of Health. Dr. Kondili has financial relationships with Gilead Science and AbbVie. Dr. Chung reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Although the risk for liver cancer diminishes for patients with hepatitis C virus (HCV) infections for whom the virus is eliminated with direct-acting antiviral (DAA) drugs, these patients are not out of the woods, and those who do not have a sustained viral response (SVR) are at substantially higher risk of developing hepatocellular carcinoma (HCC), results of a large study show.
Among the patients with liver cirrhosis from HCV infections treated at 30 centers in Italy, a large percentage had an SVR after treatment with DAA drugs. Only a small percentage of this group subsequently developed HCC.
In contrast, not having an SVR was associated with a more than sevenfold higher risk for liver cancer, said Loreta A. Kondili, MD, PhD, from the Center for Global Health at the Istituto Superiore di Sanità, Rome, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Failure to achieve SVR after DAA treatment is strongly associated with the probability of HCC development. Older age, [HCV] genotype 3, and low platelet counts and albumin levels are independent factors of HCC development despite viral eradication,” she said.
Cohort study
The study findings come from the PITER Cohort Study, a prospective, multicenter observational study of a representative sample of patients with HCV.
Dr. Kondili and colleagues assessed the medium- and long-term effects of DAA therapy on HCC rates among patients with HCV-induced liver cirrhosis. Patients who had undergone a liver transplant or who had been previously diagnosed with HCC were excluded.
The investigators identified a total of 2,214 DAA-treated patients, of whom 149 (6.7%) developed de novo HCC after a median follow-up of 30 months.
From the total group, 2,064 (93%) patients had an SVR, 119 of whom (5.8%) developed HCC. Of these patients who developed HCC, 80% were diagnosed with stage B or C disease in accordance with the Barcelona Clinic Liver Cancer staging system.
For the remaining 150 patients who did not have an SVR, 30 (20%) developed de novo HCC, a difference that translated into an adjusted hazard ratio (aHR) for HCC of 7.38 (P < .01).
The time from the end of DAA therapy to a diagnosis of HCC was shorter for patients who did not have an SVR. For these patients, the 2-year HCC-free survival rate was 81%, compared with 98% for patients who had an SVR (P < .001).
As reported by Dr. Kondili, among patients who achieved an SVR, the variables significantly associated with HCC risk included older age (aHR, 1.06), platelet counts greater than the reference limit of 150,000 μL (aHR, 2.43), albumin levels >3.5 g/dL (aHR, 2.36), and diabetes (aHR, 1.53; all these variables were significant by confidence intervals).
In all, 26% of these patients died during the follow-up period, and 7.6% underwent liver transplant.
Of the patients still alive at the end of the follow-up period, 38% had active HCC.
Long-term follow-up required
“It’s useful to think of hepatitis C as a viral infection on one hand [and] a liver disease on the other,” commented Raymond T. Chung, MD, director of the Hepatology and Liver Center and vice chief of gastroenterology at Massachusetts General Hospital, Boston.
“In terms of thinking of elimination, we can eradicate the virus in most patients with virtually 100% success with antivirals. This has given us a false sense of comfort that it’s a ‘one and done’ process, and patients can more or less enjoy the rest of their lives free of hepatitis C,” he said.
Dr. Chung, who was not involved in the study, emphasized that despite the elimination of the virus, patients may still have significant liver fibrosis or cirrhosis. It is imperative that these patients be monitored for signs of cancer, he said.
“This is what’s important about staging patients and understanding how severe their liver disease is, because if there is advanced fibrosis, bridging fibrosis, or cirrhosis, these are patients who are going to require long-term oncology care. Their infectious disease is eliminated, but the liver disease remains,” he said.
Dr. Chung also noted that rates of liver cancer, decompensation, and liver failure are higher among patients with untreated HCV than among patients whose HCV has been eradicated or suppressed with drug treatment. In addition, patients with untreated HCV are at greater risk of requiring transplant than are patients with HCV that was treated, and there remains a residual cancer risk for patients who become HCV seronegative.
The study was funded by the Italian Ministry of Health. Dr. Kondili has financial relationships with Gilead Science and AbbVie. Dr. Chung reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ASH meeting: Diversity, inclusion, immunotherapy, and COVID-19
In 2021, the American Society of Hematology will be hosting its annual meeting in a hybrid format. Content will be presented both live and in person at the Georgia World Congress Center in Atlanta and also online for those who can’t or don’t want to be there in person.
Inevitably during the ongoing pandemic, the meeting will contain key sessions on COVID-19 in hematology, including a plenary presentation outlining a biologic mechanism for the increased coagulopathy with SARS-CoV-2 infections.
In addition, there will be a scientific symposium on COVID-19 vaccination in immunocompromised patients and a special moderated session summarizing nine abstracts on the science of thrombosis in COVID-19, outcomes in patients with hematologic disease, and vaccine responses.
And speaking of COVID, lest anyone forget, annual meeting attendees will be required to be fully vaccinated and masked. Free COVID-19 testing will be available at stations situated throughout the convention center.
Diversifying care
chair of the ASH committee on communications and chief of the division of hematology at the Sylvester Comprehensive Cancer Center at the University of Miami.
For example, investigators at Massachusetts General Hospital in Boston will present new data on code-status transitions among patients with poor-prognosis high-risk acute myeloid leukemia (AML) who are approaching the end of life. Their findings suggest that physician-patient discussions about the goals of care may occur too late in the course of illness for many patients (abstract 109).
“While there have been many advances in the treatment of acute myeloid leukemia, and in fact there has been significant progress even among high-risk patients, addressing end-of-life issues is an often neglected area,” commented briefing participant Martin A. Tallman, MD, from Memorial Sloan Kettering Cancer Center, New York, who is also the current ASH president.
On a more upbeat note, Dr. Tallman also pointed to the results of the phase 3, randomized AGILE trial as an example of progress in AML, especially for patients with newly diagnosed high-risk disease who have mutations in IDH1. This trial investigated a new approach to treatment, with a combination of the combination of the IDH1 inhibitor ivosidenib (Tibsovo) and azacitidine, and compared it with azacitidine alone. The investigators assessed impact on event-free survival, overall survival, and clinical responses (abstract 697).
Dr. Tallman also highlighted abstracts touching on racial, social, and socioeconomic contributors to health care disparities among children with acute lymphoblastic leukemia (ALL; abstract 211) and on clinical trial enrollment characteristics and outcomes for Black and Hispanic adolescents and young adults with ALL (abstract 337).
Immunotherapy advances
Some of the most eagerly awaited abstracts will be highlighting advances in immunotherapy for hematologic malignancies, and these were previewed by Cynthia E. Dunbar, MD, ASH secretary and chief of the Translational Stem Cell Biology Branch within the Intramural Research Program of the National Heart, Lung, and Blood Institute in Bethesda, Md.
These abstracts include the primary analysis of the ZUMA-7 trial, a randomized, phase 3 study comparing the chimeric antigen receptor T-cell (CAR T) construct axicabtagene ciloleucel (axi-cel; Yescarta) with standard of care in patients with relapsed or refractory large B-cell lymphomas (LBCLs; abstract 2) and the interim analysis of the randomized, phase 3 Transform Study comparing the CAR T construct lisocabtagene maralecleucl (liso-cel; Breyanzi) with salvage chemotherapy in patients with relapsed/refractory LBCL (abstract 91).
“Over 500 patients were enrolled in the two studies, and both abstracts report significantly longer survival without relapse in the CAR T arm – for instance, fourfold higher in ZUMA-7, compared to standard of care,” Dr. Dunbar said at the briefing.
“These abstracts provide really critical information to patients, their treating physicians, and the payers who are trying to decide whether use of these expensive, complex, and potentially toxic CAR T-cell therapies are justified, compared to standard therapy,” she said.
Dr. Dunbar also highlighted an abstract on the addition of the anti-CD38 monoclonal antibody isatuximab (Sarclisa) to lenalidomide, bortezomib, and dexamethasone as induction therapy for patients with newly diagnosed multiple myeloma who are eligible for stem cell transplantation (abstract 463).
“The authors report that patients on the isatuximab arm had significantly fewer tumor cells following treatment,” Dr. Dunbar said. “We have come a long way beyond treating myeloma with a single drug, with remissions now measured in many years instead of 1 or 2 following initiation of treatment, and this abstract is another demonstration that novel combinations of multiple agents are really making a difference in this very debilitating disease.”
She also cited an abstract (abstract 127) on monotherapy with the novel bispecific T-cell–engaging monoclonal antibody mosunetuzumab for treatment of patients with follicular lymphoma that has relapsed or is refractory to at least two prior lines of therapy.
Old disorders, new insights
Other abstracts highlighted at the premeeting press briefing included a study that found a high prevalence of monoclonal gammopathy in persons at risk for multiple myeloma (abstract 152) and another with the surprising finding that clonal hematopoiesis, a risk factor myeloid malignancies, may be protective against Alzheimer’s disease (abstract 5).
In addition, a long-term follow-up study of patients with transfusion-dependent beta-thalassemia treated with gene therapy showed that some patients have become transfusion independent and iron homeostasis was restored (abstract 573).
Presentations from CDC and FDA
Dr. Sekeres highlighted other events of interest scheduled for ASH 2021, including a Grassroots Network Lunch featuring a discussion with Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention in Atlanta, and a joint symposium between ASH and the Food and Drug Administration on newly approved drugs in hematology.
Dr. Sekeres has disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb. Dr. Dunbar reported no relevant conflicts of interest. Dr. Tallman disclosed consulting/advising with and research funding from multiple entities.
A version of this article first appeared on Medscape.com.
In 2021, the American Society of Hematology will be hosting its annual meeting in a hybrid format. Content will be presented both live and in person at the Georgia World Congress Center in Atlanta and also online for those who can’t or don’t want to be there in person.
Inevitably during the ongoing pandemic, the meeting will contain key sessions on COVID-19 in hematology, including a plenary presentation outlining a biologic mechanism for the increased coagulopathy with SARS-CoV-2 infections.
In addition, there will be a scientific symposium on COVID-19 vaccination in immunocompromised patients and a special moderated session summarizing nine abstracts on the science of thrombosis in COVID-19, outcomes in patients with hematologic disease, and vaccine responses.
And speaking of COVID, lest anyone forget, annual meeting attendees will be required to be fully vaccinated and masked. Free COVID-19 testing will be available at stations situated throughout the convention center.
Diversifying care
chair of the ASH committee on communications and chief of the division of hematology at the Sylvester Comprehensive Cancer Center at the University of Miami.
For example, investigators at Massachusetts General Hospital in Boston will present new data on code-status transitions among patients with poor-prognosis high-risk acute myeloid leukemia (AML) who are approaching the end of life. Their findings suggest that physician-patient discussions about the goals of care may occur too late in the course of illness for many patients (abstract 109).
“While there have been many advances in the treatment of acute myeloid leukemia, and in fact there has been significant progress even among high-risk patients, addressing end-of-life issues is an often neglected area,” commented briefing participant Martin A. Tallman, MD, from Memorial Sloan Kettering Cancer Center, New York, who is also the current ASH president.
On a more upbeat note, Dr. Tallman also pointed to the results of the phase 3, randomized AGILE trial as an example of progress in AML, especially for patients with newly diagnosed high-risk disease who have mutations in IDH1. This trial investigated a new approach to treatment, with a combination of the combination of the IDH1 inhibitor ivosidenib (Tibsovo) and azacitidine, and compared it with azacitidine alone. The investigators assessed impact on event-free survival, overall survival, and clinical responses (abstract 697).
Dr. Tallman also highlighted abstracts touching on racial, social, and socioeconomic contributors to health care disparities among children with acute lymphoblastic leukemia (ALL; abstract 211) and on clinical trial enrollment characteristics and outcomes for Black and Hispanic adolescents and young adults with ALL (abstract 337).
Immunotherapy advances
Some of the most eagerly awaited abstracts will be highlighting advances in immunotherapy for hematologic malignancies, and these were previewed by Cynthia E. Dunbar, MD, ASH secretary and chief of the Translational Stem Cell Biology Branch within the Intramural Research Program of the National Heart, Lung, and Blood Institute in Bethesda, Md.
These abstracts include the primary analysis of the ZUMA-7 trial, a randomized, phase 3 study comparing the chimeric antigen receptor T-cell (CAR T) construct axicabtagene ciloleucel (axi-cel; Yescarta) with standard of care in patients with relapsed or refractory large B-cell lymphomas (LBCLs; abstract 2) and the interim analysis of the randomized, phase 3 Transform Study comparing the CAR T construct lisocabtagene maralecleucl (liso-cel; Breyanzi) with salvage chemotherapy in patients with relapsed/refractory LBCL (abstract 91).
“Over 500 patients were enrolled in the two studies, and both abstracts report significantly longer survival without relapse in the CAR T arm – for instance, fourfold higher in ZUMA-7, compared to standard of care,” Dr. Dunbar said at the briefing.
“These abstracts provide really critical information to patients, their treating physicians, and the payers who are trying to decide whether use of these expensive, complex, and potentially toxic CAR T-cell therapies are justified, compared to standard therapy,” she said.
Dr. Dunbar also highlighted an abstract on the addition of the anti-CD38 monoclonal antibody isatuximab (Sarclisa) to lenalidomide, bortezomib, and dexamethasone as induction therapy for patients with newly diagnosed multiple myeloma who are eligible for stem cell transplantation (abstract 463).
“The authors report that patients on the isatuximab arm had significantly fewer tumor cells following treatment,” Dr. Dunbar said. “We have come a long way beyond treating myeloma with a single drug, with remissions now measured in many years instead of 1 or 2 following initiation of treatment, and this abstract is another demonstration that novel combinations of multiple agents are really making a difference in this very debilitating disease.”
She also cited an abstract (abstract 127) on monotherapy with the novel bispecific T-cell–engaging monoclonal antibody mosunetuzumab for treatment of patients with follicular lymphoma that has relapsed or is refractory to at least two prior lines of therapy.
Old disorders, new insights
Other abstracts highlighted at the premeeting press briefing included a study that found a high prevalence of monoclonal gammopathy in persons at risk for multiple myeloma (abstract 152) and another with the surprising finding that clonal hematopoiesis, a risk factor myeloid malignancies, may be protective against Alzheimer’s disease (abstract 5).
In addition, a long-term follow-up study of patients with transfusion-dependent beta-thalassemia treated with gene therapy showed that some patients have become transfusion independent and iron homeostasis was restored (abstract 573).
Presentations from CDC and FDA
Dr. Sekeres highlighted other events of interest scheduled for ASH 2021, including a Grassroots Network Lunch featuring a discussion with Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention in Atlanta, and a joint symposium between ASH and the Food and Drug Administration on newly approved drugs in hematology.
Dr. Sekeres has disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb. Dr. Dunbar reported no relevant conflicts of interest. Dr. Tallman disclosed consulting/advising with and research funding from multiple entities.
A version of this article first appeared on Medscape.com.
In 2021, the American Society of Hematology will be hosting its annual meeting in a hybrid format. Content will be presented both live and in person at the Georgia World Congress Center in Atlanta and also online for those who can’t or don’t want to be there in person.
Inevitably during the ongoing pandemic, the meeting will contain key sessions on COVID-19 in hematology, including a plenary presentation outlining a biologic mechanism for the increased coagulopathy with SARS-CoV-2 infections.
In addition, there will be a scientific symposium on COVID-19 vaccination in immunocompromised patients and a special moderated session summarizing nine abstracts on the science of thrombosis in COVID-19, outcomes in patients with hematologic disease, and vaccine responses.
And speaking of COVID, lest anyone forget, annual meeting attendees will be required to be fully vaccinated and masked. Free COVID-19 testing will be available at stations situated throughout the convention center.
Diversifying care
chair of the ASH committee on communications and chief of the division of hematology at the Sylvester Comprehensive Cancer Center at the University of Miami.
For example, investigators at Massachusetts General Hospital in Boston will present new data on code-status transitions among patients with poor-prognosis high-risk acute myeloid leukemia (AML) who are approaching the end of life. Their findings suggest that physician-patient discussions about the goals of care may occur too late in the course of illness for many patients (abstract 109).
“While there have been many advances in the treatment of acute myeloid leukemia, and in fact there has been significant progress even among high-risk patients, addressing end-of-life issues is an often neglected area,” commented briefing participant Martin A. Tallman, MD, from Memorial Sloan Kettering Cancer Center, New York, who is also the current ASH president.
On a more upbeat note, Dr. Tallman also pointed to the results of the phase 3, randomized AGILE trial as an example of progress in AML, especially for patients with newly diagnosed high-risk disease who have mutations in IDH1. This trial investigated a new approach to treatment, with a combination of the combination of the IDH1 inhibitor ivosidenib (Tibsovo) and azacitidine, and compared it with azacitidine alone. The investigators assessed impact on event-free survival, overall survival, and clinical responses (abstract 697).
Dr. Tallman also highlighted abstracts touching on racial, social, and socioeconomic contributors to health care disparities among children with acute lymphoblastic leukemia (ALL; abstract 211) and on clinical trial enrollment characteristics and outcomes for Black and Hispanic adolescents and young adults with ALL (abstract 337).
Immunotherapy advances
Some of the most eagerly awaited abstracts will be highlighting advances in immunotherapy for hematologic malignancies, and these were previewed by Cynthia E. Dunbar, MD, ASH secretary and chief of the Translational Stem Cell Biology Branch within the Intramural Research Program of the National Heart, Lung, and Blood Institute in Bethesda, Md.
These abstracts include the primary analysis of the ZUMA-7 trial, a randomized, phase 3 study comparing the chimeric antigen receptor T-cell (CAR T) construct axicabtagene ciloleucel (axi-cel; Yescarta) with standard of care in patients with relapsed or refractory large B-cell lymphomas (LBCLs; abstract 2) and the interim analysis of the randomized, phase 3 Transform Study comparing the CAR T construct lisocabtagene maralecleucl (liso-cel; Breyanzi) with salvage chemotherapy in patients with relapsed/refractory LBCL (abstract 91).
“Over 500 patients were enrolled in the two studies, and both abstracts report significantly longer survival without relapse in the CAR T arm – for instance, fourfold higher in ZUMA-7, compared to standard of care,” Dr. Dunbar said at the briefing.
“These abstracts provide really critical information to patients, their treating physicians, and the payers who are trying to decide whether use of these expensive, complex, and potentially toxic CAR T-cell therapies are justified, compared to standard therapy,” she said.
Dr. Dunbar also highlighted an abstract on the addition of the anti-CD38 monoclonal antibody isatuximab (Sarclisa) to lenalidomide, bortezomib, and dexamethasone as induction therapy for patients with newly diagnosed multiple myeloma who are eligible for stem cell transplantation (abstract 463).
“The authors report that patients on the isatuximab arm had significantly fewer tumor cells following treatment,” Dr. Dunbar said. “We have come a long way beyond treating myeloma with a single drug, with remissions now measured in many years instead of 1 or 2 following initiation of treatment, and this abstract is another demonstration that novel combinations of multiple agents are really making a difference in this very debilitating disease.”
She also cited an abstract (abstract 127) on monotherapy with the novel bispecific T-cell–engaging monoclonal antibody mosunetuzumab for treatment of patients with follicular lymphoma that has relapsed or is refractory to at least two prior lines of therapy.
Old disorders, new insights
Other abstracts highlighted at the premeeting press briefing included a study that found a high prevalence of monoclonal gammopathy in persons at risk for multiple myeloma (abstract 152) and another with the surprising finding that clonal hematopoiesis, a risk factor myeloid malignancies, may be protective against Alzheimer’s disease (abstract 5).
In addition, a long-term follow-up study of patients with transfusion-dependent beta-thalassemia treated with gene therapy showed that some patients have become transfusion independent and iron homeostasis was restored (abstract 573).
Presentations from CDC and FDA
Dr. Sekeres highlighted other events of interest scheduled for ASH 2021, including a Grassroots Network Lunch featuring a discussion with Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention in Atlanta, and a joint symposium between ASH and the Food and Drug Administration on newly approved drugs in hematology.
Dr. Sekeres has disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb. Dr. Dunbar reported no relevant conflicts of interest. Dr. Tallman disclosed consulting/advising with and research funding from multiple entities.
A version of this article first appeared on Medscape.com.
NAFLD, ALD prevalent among teens, young adults
Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.
In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
Liver stiffness measured
Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.
The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.
The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.
The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.
They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.
The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
Uncovering a high prevalence of ALD and NAFLD
The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.
The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.
Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.
Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.
Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.
Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
Is drinking underreported?
In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.
Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.
“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.
“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.
Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”
Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.
No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.
In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
Liver stiffness measured
Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.
The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.
The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.
The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.
They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.
The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
Uncovering a high prevalence of ALD and NAFLD
The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.
The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.
Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.
Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.
Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.
Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
Is drinking underreported?
In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.
Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.
“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.
“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.
Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”
Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.
No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.
In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
Liver stiffness measured
Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.
The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.
The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.
The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.
They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.
The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
Uncovering a high prevalence of ALD and NAFLD
The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.
The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.
Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.
Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.
Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.
Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
Is drinking underreported?
In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.
Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.
“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.
“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.
Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”
Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.
No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.