Randy Dotinga

Not too long ago, prostate-cancer genetics didn’t mean much to patient care. But in recent years, the landscape of therapy has transformed as researchers have discovered links between multiple genes and aggressive tumors. 

Now, as a hematologist-oncologist explained to attendees at an Association of VA Hematology/Oncology regional meeting in Detroit, genetic tests can guide treatment for some—but not all—men with prostate cancer.

For patients with mutations, appropriate supplemental medications “can improve overall outcomes and have a long-standing impact on patients” said Scott J. Dawsey, MD, of the John D. Dingell Veterans Affairs Medical Center in Detroit in an interview following the AVAHO meeting, which focused on the management of prostate cancer.

As Dawsey explained, about 10% of patients with prostate cancer appear to have genetic mutations, although the exact percentage is unclear. The mutations are especially common in metastatic forms of prostate cancer. They’re estimated to be present in 11.8%-16.2% of those cases.

While these proportions are relatively small, the number of overall prostate-cancer cases with mutations is large due to the high burden of the disease, Dawsey said. Prostate cancer is by far the most common cancer in men, and estimated 299,010 cases will be diagnosed in the United States this year.

According to Dawsey, genetic mutations seem to boost the risk of more aggressive disease—and the risk of other malignancies—by disrupting DNA repair. This process can lead to even more mutations that may “make the cancer behave and grow more aggressively.”

But not all prostate cancer patients need to undergo genetic testing. Dawsey urged colleagues to figure out which patients should be tested by consulting National Comprehensive Cancer Network (NCCN) guidelines and the newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway.

The two sets of recommendations agree on germline testing in patients with cases that are metastatic, very high risk, and high risk. Lower-risk cases should only be tested if patients meet family history criteria. The sets of guidelines also recommend somatic testing in patients with metastatic cancer.

In addition to providing guidance about treatment, genetic test results can have implications regarding other potential malignancies that may affect patients, Dawsey said. The results may also have implications for cancer risk in family members.

Several drugs are now available for patients with genetic mutations, including checkpoint inhibitors and PARP inhibitors. The drugs, which have unique mechanisms of action, are given in addition to standard prostate cancer treatments, he said.

“If a patient doesn’t have one of these genetic changes,” he said, “these drugs aren’t an option.”

A long list of drugs or combinations of drugs are in clinical trials, including the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors olaparib, abiraterone, and niraparib and the checkpoint inhibitors nivolumab and cemiplimab.

The drugs generally improve response rates and progression-free survival, Dawsey said, and patients are generally able to tolerate them. In regard to which drugs to choose, he suggested consulting the and NCCN guidelines and the VA oncology clinical pathway for prostate cancer.

Not too long ago, prostate-cancer genetics didn’t mean much to patient care. But in recent years, the landscape of therapy has transformed as researchers have discovered links between multiple genes and aggressive tumors. 

Now, as a hematologist-oncologist explained to attendees at an Association of VA Hematology/Oncology regional meeting in Detroit, genetic tests can guide treatment for some—but not all—men with prostate cancer.

For patients with mutations, appropriate supplemental medications “can improve overall outcomes and have a long-standing impact on patients” said Scott J. Dawsey, MD, of the John D. Dingell Veterans Affairs Medical Center in Detroit in an interview following the AVAHO meeting, which focused on the management of prostate cancer.

As Dawsey explained, about 10% of patients with prostate cancer appear to have genetic mutations, although the exact percentage is unclear. The mutations are especially common in metastatic forms of prostate cancer. They’re estimated to be present in 11.8%-16.2% of those cases.

While these proportions are relatively small, the number of overall prostate-cancer cases with mutations is large due to the high burden of the disease, Dawsey said. Prostate cancer is by far the most common cancer in men, and estimated 299,010 cases will be diagnosed in the United States this year.

According to Dawsey, genetic mutations seem to boost the risk of more aggressive disease—and the risk of other malignancies—by disrupting DNA repair. This process can lead to even more mutations that may “make the cancer behave and grow more aggressively.”

But not all prostate cancer patients need to undergo genetic testing. Dawsey urged colleagues to figure out which patients should be tested by consulting National Comprehensive Cancer Network (NCCN) guidelines and the newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway.

The two sets of recommendations agree on germline testing in patients with cases that are metastatic, very high risk, and high risk. Lower-risk cases should only be tested if patients meet family history criteria. The sets of guidelines also recommend somatic testing in patients with metastatic cancer.

In addition to providing guidance about treatment, genetic test results can have implications regarding other potential malignancies that may affect patients, Dawsey said. The results may also have implications for cancer risk in family members.

Several drugs are now available for patients with genetic mutations, including checkpoint inhibitors and PARP inhibitors. The drugs, which have unique mechanisms of action, are given in addition to standard prostate cancer treatments, he said.

“If a patient doesn’t have one of these genetic changes,” he said, “these drugs aren’t an option.”

A long list of drugs or combinations of drugs are in clinical trials, including the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors olaparib, abiraterone, and niraparib and the checkpoint inhibitors nivolumab and cemiplimab.

The drugs generally improve response rates and progression-free survival, Dawsey said, and patients are generally able to tolerate them. In regard to which drugs to choose, he suggested consulting the and NCCN guidelines and the VA oncology clinical pathway for prostate cancer.

Not too long ago, prostate-cancer genetics didn’t mean much to patient care. But in recent years, the landscape of therapy has transformed as researchers have discovered links between multiple genes and aggressive tumors. 

Now, as a hematologist-oncologist explained to attendees at an Association of VA Hematology/Oncology regional meeting in Detroit, genetic tests can guide treatment for some—but not all—men with prostate cancer.

For patients with mutations, appropriate supplemental medications “can improve overall outcomes and have a long-standing impact on patients” said Scott J. Dawsey, MD, of the John D. Dingell Veterans Affairs Medical Center in Detroit in an interview following the AVAHO meeting, which focused on the management of prostate cancer.

As Dawsey explained, about 10% of patients with prostate cancer appear to have genetic mutations, although the exact percentage is unclear. The mutations are especially common in metastatic forms of prostate cancer. They’re estimated to be present in 11.8%-16.2% of those cases.

While these proportions are relatively small, the number of overall prostate-cancer cases with mutations is large due to the high burden of the disease, Dawsey said. Prostate cancer is by far the most common cancer in men, and estimated 299,010 cases will be diagnosed in the United States this year.

According to Dawsey, genetic mutations seem to boost the risk of more aggressive disease—and the risk of other malignancies—by disrupting DNA repair. This process can lead to even more mutations that may “make the cancer behave and grow more aggressively.”

But not all prostate cancer patients need to undergo genetic testing. Dawsey urged colleagues to figure out which patients should be tested by consulting National Comprehensive Cancer Network (NCCN) guidelines and the newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway.

The two sets of recommendations agree on germline testing in patients with cases that are metastatic, very high risk, and high risk. Lower-risk cases should only be tested if patients meet family history criteria. The sets of guidelines also recommend somatic testing in patients with metastatic cancer.

In addition to providing guidance about treatment, genetic test results can have implications regarding other potential malignancies that may affect patients, Dawsey said. The results may also have implications for cancer risk in family members.

Several drugs are now available for patients with genetic mutations, including checkpoint inhibitors and PARP inhibitors. The drugs, which have unique mechanisms of action, are given in addition to standard prostate cancer treatments, he said.

“If a patient doesn’t have one of these genetic changes,” he said, “these drugs aren’t an option.”

A long list of drugs or combinations of drugs are in clinical trials, including the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors olaparib, abiraterone, and niraparib and the checkpoint inhibitors nivolumab and cemiplimab.

The drugs generally improve response rates and progression-free survival, Dawsey said, and patients are generally able to tolerate them. In regard to which drugs to choose, he suggested consulting the and NCCN guidelines and the VA oncology clinical pathway for prostate cancer.

The Centers for Medicare & Medicaid Services (CMS) has announced the conclusion of a program that provided billions in early Medicare payments to those affected by the Change Healthcare/UnitedHealth Group cyberattack last winter. The Accelerated and Advance Payment program, which began in early March to assist hospitals and practices facing significant reimbursement delays, will stop accepting applications after July 12, 2024.

CMS reported that the program advanced more than $2.55 billion in Medicare payments to > 4200 Part A providers, including hospitals, and more than $717.18 million in payments to Part B suppliers such as physicians, nonphysician practitioners, and durable medical equipment suppliers.

According to CMS, the Medicare billing system is now functioning properly, and 96% of the early payments have been recovered. The advances were to represent ≤ 30 days of typical claims payments in a 3-month period of 2023, with full repayment expected within 90 days through “automatic recoupment from Medicare claims” — no extensions allowed.

The agency took a victory lap regarding its response. “In the face of one of the most widespread cyberattacks on the US health care industry, CMS promptly took action to get providers and suppliers access to the funds they needed to continue providing patients with vital care,” CMS Administrator Chiquita Brooks-LaSure said in a statement. “Our efforts helped minimize the disruptive fallout from this incident, and we will remain vigilant to be ready to address future events.”

Ongoing Concerns from Health Care Organizations

Ben Teicher, an American Hospital Association spokesman, said that the organization hopes that CMS will be responsive if there’s more need for action after the advance payment program expires. The organization represents about 5000 hospitals, health care systems, and other providers.

“Our members report that the aftereffects of this event will likely be felt throughout the remainder of the year,” he said. According to Teicher, hospitals remain concerned about their ability to process claims and appeal denials, the safety of reconnecting to cyber services, and access to information needed to bill patients and reconcile payments.

In addition, hospitals are concerned about “financial support to mitigate the considerable costs incurred as a result of the cyberattack,” he said.

Charlene MacDonald, executive vice-president of public affairs at the Federation of American Hospitals, which represents more than 1000 for-profit hospitals, sent a statement to this news organization that said some providers “are still feeling the effects of care denials and delays caused by insurer inaction.

“We appreciate that the Administration acted within its authority to support providers during this unprecedented crisis and blunt these devastating impacts, especially because a vast majority of managed care companies failed to step up to the plate,” she said. “It is now time to shift our focus to holding plans accountable for using tactics to delay and deny needed patient care.”

Cyberattack Impact and Response

The ransom-based cyberattack against Change Healthcare/UnitedHealth Group targeted an electronic data interchange clearing house processing payer reimbursement systems, disrupting cash flows at hospitals and medical practices, and affecting patient access to prescriptions and life-saving therapy.

Change Healthcare — part of the UnitedHealth Group subsidiary Optum — processes half of all medical claims, according to a Department of Justice lawsuit. The American Hospital Association described the cyberattack as “the most significant and consequential incident of its kind” in US history.

By late March, UnitedHealth Group said nearly all medical and pharmacy claims were processing properly, while a deputy secretary of the US Department of Health & Human Services told clinicians that officials were focusing on the last group of clinicians who were facing cash-flow problems.

Still, a senior advisor with CMS told providers at that time that “we have heard from so many providers over the last several weeks who are really struggling to make ends meet right now or who are worried that they will not be able to make payroll in the weeks to come.”

Randy Dotinga is a freelance health/medical reporter and board member of the Association of Health Care Journalists.

A version of this article appeared on Medscape.com.

The Centers for Medicare & Medicaid Services (CMS) has announced the conclusion of a program that provided billions in early Medicare payments to those affected by the Change Healthcare/UnitedHealth Group cyberattack last winter. The Accelerated and Advance Payment program, which began in early March to assist hospitals and practices facing significant reimbursement delays, will stop accepting applications after July 12, 2024.

CMS reported that the program advanced more than $2.55 billion in Medicare payments to > 4200 Part A providers, including hospitals, and more than $717.18 million in payments to Part B suppliers such as physicians, nonphysician practitioners, and durable medical equipment suppliers.

According to CMS, the Medicare billing system is now functioning properly, and 96% of the early payments have been recovered. The advances were to represent ≤ 30 days of typical claims payments in a 3-month period of 2023, with full repayment expected within 90 days through “automatic recoupment from Medicare claims” — no extensions allowed.

The agency took a victory lap regarding its response. “In the face of one of the most widespread cyberattacks on the US health care industry, CMS promptly took action to get providers and suppliers access to the funds they needed to continue providing patients with vital care,” CMS Administrator Chiquita Brooks-LaSure said in a statement. “Our efforts helped minimize the disruptive fallout from this incident, and we will remain vigilant to be ready to address future events.”

Ongoing Concerns from Health Care Organizations

Ben Teicher, an American Hospital Association spokesman, said that the organization hopes that CMS will be responsive if there’s more need for action after the advance payment program expires. The organization represents about 5000 hospitals, health care systems, and other providers.

“Our members report that the aftereffects of this event will likely be felt throughout the remainder of the year,” he said. According to Teicher, hospitals remain concerned about their ability to process claims and appeal denials, the safety of reconnecting to cyber services, and access to information needed to bill patients and reconcile payments.

In addition, hospitals are concerned about “financial support to mitigate the considerable costs incurred as a result of the cyberattack,” he said.

Charlene MacDonald, executive vice-president of public affairs at the Federation of American Hospitals, which represents more than 1000 for-profit hospitals, sent a statement to this news organization that said some providers “are still feeling the effects of care denials and delays caused by insurer inaction.

“We appreciate that the Administration acted within its authority to support providers during this unprecedented crisis and blunt these devastating impacts, especially because a vast majority of managed care companies failed to step up to the plate,” she said. “It is now time to shift our focus to holding plans accountable for using tactics to delay and deny needed patient care.”

Cyberattack Impact and Response

The ransom-based cyberattack against Change Healthcare/UnitedHealth Group targeted an electronic data interchange clearing house processing payer reimbursement systems, disrupting cash flows at hospitals and medical practices, and affecting patient access to prescriptions and life-saving therapy.

Change Healthcare — part of the UnitedHealth Group subsidiary Optum — processes half of all medical claims, according to a Department of Justice lawsuit. The American Hospital Association described the cyberattack as “the most significant and consequential incident of its kind” in US history.

By late March, UnitedHealth Group said nearly all medical and pharmacy claims were processing properly, while a deputy secretary of the US Department of Health & Human Services told clinicians that officials were focusing on the last group of clinicians who were facing cash-flow problems.

Still, a senior advisor with CMS told providers at that time that “we have heard from so many providers over the last several weeks who are really struggling to make ends meet right now or who are worried that they will not be able to make payroll in the weeks to come.”

Randy Dotinga is a freelance health/medical reporter and board member of the Association of Health Care Journalists.

A version of this article appeared on Medscape.com.

The Centers for Medicare & Medicaid Services (CMS) has announced the conclusion of a program that provided billions in early Medicare payments to those affected by the Change Healthcare/UnitedHealth Group cyberattack last winter. The Accelerated and Advance Payment program, which began in early March to assist hospitals and practices facing significant reimbursement delays, will stop accepting applications after July 12, 2024.

CMS reported that the program advanced more than $2.55 billion in Medicare payments to > 4200 Part A providers, including hospitals, and more than $717.18 million in payments to Part B suppliers such as physicians, nonphysician practitioners, and durable medical equipment suppliers.

According to CMS, the Medicare billing system is now functioning properly, and 96% of the early payments have been recovered. The advances were to represent ≤ 30 days of typical claims payments in a 3-month period of 2023, with full repayment expected within 90 days through “automatic recoupment from Medicare claims” — no extensions allowed.

The agency took a victory lap regarding its response. “In the face of one of the most widespread cyberattacks on the US health care industry, CMS promptly took action to get providers and suppliers access to the funds they needed to continue providing patients with vital care,” CMS Administrator Chiquita Brooks-LaSure said in a statement. “Our efforts helped minimize the disruptive fallout from this incident, and we will remain vigilant to be ready to address future events.”

Ongoing Concerns from Health Care Organizations

Ben Teicher, an American Hospital Association spokesman, said that the organization hopes that CMS will be responsive if there’s more need for action after the advance payment program expires. The organization represents about 5000 hospitals, health care systems, and other providers.

“Our members report that the aftereffects of this event will likely be felt throughout the remainder of the year,” he said. According to Teicher, hospitals remain concerned about their ability to process claims and appeal denials, the safety of reconnecting to cyber services, and access to information needed to bill patients and reconcile payments.

In addition, hospitals are concerned about “financial support to mitigate the considerable costs incurred as a result of the cyberattack,” he said.

Charlene MacDonald, executive vice-president of public affairs at the Federation of American Hospitals, which represents more than 1000 for-profit hospitals, sent a statement to this news organization that said some providers “are still feeling the effects of care denials and delays caused by insurer inaction.

“We appreciate that the Administration acted within its authority to support providers during this unprecedented crisis and blunt these devastating impacts, especially because a vast majority of managed care companies failed to step up to the plate,” she said. “It is now time to shift our focus to holding plans accountable for using tactics to delay and deny needed patient care.”

Cyberattack Impact and Response

The ransom-based cyberattack against Change Healthcare/UnitedHealth Group targeted an electronic data interchange clearing house processing payer reimbursement systems, disrupting cash flows at hospitals and medical practices, and affecting patient access to prescriptions and life-saving therapy.

Change Healthcare — part of the UnitedHealth Group subsidiary Optum — processes half of all medical claims, according to a Department of Justice lawsuit. The American Hospital Association described the cyberattack as “the most significant and consequential incident of its kind” in US history.

By late March, UnitedHealth Group said nearly all medical and pharmacy claims were processing properly, while a deputy secretary of the US Department of Health & Human Services told clinicians that officials were focusing on the last group of clinicians who were facing cash-flow problems.

Still, a senior advisor with CMS told providers at that time that “we have heard from so many providers over the last several weeks who are really struggling to make ends meet right now or who are worried that they will not be able to make payroll in the weeks to come.”

Randy Dotinga is a freelance health/medical reporter and board member of the Association of Health Care Journalists.

A version of this article appeared on Medscape.com.

When she got the news that her young son had been diagnosed with the rare blood disorder known as transfusion-dependent beta thalassemia, Yusara Ahmed knew the drill. Her sister had also experienced the inherited condition and needed to undergo regular blood transfusions simply to survive.

With luck, maybe Ms. Ahmed’s son could follow in his aunt’s footsteps and get a stem cell transplant from a compatible family donor. But while little Yusuf Saeed has a twin sister of his own, she wasn’t a match. Without another treatment option, he’d face the prospect of a lifetime not only cut short but burdened by multiple monthly transfusions and severe limitations.

Then came glimpses of hope. One of Yusuf’s physicians at Cohen Children’s Medical Center in Long Island, New York, told Yusuf’s mother about a new kind of gene therapy on the horizon. But it took time to get FDA approval. Yusuf grew older, heading toward his teenage years, when regular transfusions would be a huge burden. “He’s turning 5 and 6, and there’s nothing,” Ms. Ahmed recalled, and the family worried.

Finally, the FDA approved the one-time treatment — betibeglogene autotemcel (beti-cel, Zynteglo) in 2022. By January 2024, the hospital was ready to treat Yusuf. At age 8, he became the first patient in the state of New York to undergo gene therapy for beta thalassemia.

A medical team infused Yusuf with his own stem cells, which had been genetically engineered to boost production of hemoglobin and prevent thalassemia’s devastating effects.

There are caveats about the treatment. It’s an extraordinarily expensive therapy that can be performed at only a few institutions. And it’s so brand new that caveats may not even have appeared yet. Yet, for kids like Yusuf, the gene therapy could transform a life.

“We feel like a weight has been lifted,” Ms. Ahmed said in an interview. “It’s something we’ve been waiting for.”
 

Anemia Becomes a Lifetime Threat

Among all genetic diseases, thalassemia stands alone. It’s the most common condition caused by a single gene, according to Hanny Al-Samkari, MD, a hematologist/clinical investigator at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.

Millions of people have the thalassemia trait, especially in southern Europe, the Middle East, southeast Asia, and Africa, Dr. Al-Samkari said. (Yusuf’s parents are from Pakistan.)

The trait, which appears to provide protection against malaria, may cause mild anemia in some cases but is otherwise harmless. However, a child born to parents with the same kind of trait has a high risk of developing alpha thalassemia or beta thalassemia. Like his aunt, Yusuf developed beta thalassemia, which is generally more severe. Yusuf’s bleeding disorder requires him to be transfusion-dependent.

In these patients, the disease disrupts the production of red blood cells in the bone marrow, Dr. Al-Samkari said. Hemoglobin levels can fall to 7 or 8 g/dL, compared with the normal levels of 12-16 g/dL in adults. “They’re chronically anemic, and that low hemoglobin that leads to things you associate with anemia: fatigue, reduced exercise tolerance, mind fog, challenges with work or school, and hypersomnolence.”

In addition, the bones become thinner and more brittle, he said, leading to fractures.

Transfusions are one treatment option, but they’re needed for a lifetime and cause their own problems, such as iron overload. Care of thalassemia patients “becomes quite complex and quite challenging for both families and medical institutions,” Alexis A. Thompson MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, Pennsylvania, said in an interview.

Yusara Ahmed remembers her sister’s endless visits to the hospital after she was diagnosed at age 4. “We were all very traumatized by the hospital environment,” she said. But good news came in 2008, a few years later, when her sister was able to get a stem cell transplant from their brother.

But while stem cell transplants can be curative, most children don’t have a relative who can be a suitable match as a donor, Dr. Thompson said. Now, gene therapy offers another option, by turning a patient into his or her own matched donor.
 

Stem Cells Out, Stem Cells In

Last year, Yusuf went to Cohen Children’s Medical Center to donate stem cells, which were sent to a laboratory where they were genetically engineered to add copies of the beta-globin gene. Then, in January 2024, the modified stem cells were infused back into Yusuf after he underwent chemotherapy to make room for them in his bone marrow.

In April, a bald-headed Yusuf played with toy dinosaurs while his mother and clinicians met the media at a hospital press conference about his so-far-successful treatment. Early reports about the efficacy of the treatment suggest it may be the proverbial “game changer” for many of the estimated 100,000-plus people in the world who are diagnosed with transfusion-dependent beta thalassemia each year.

Over a median follow-up of 29.5 months, 20 of 22 patients treated with beti-cel no longer needed transfusions, according to a 2022 open-label phase 3 study published in the New England Journal of Medicine. Only one adverse event — thrombocytopenia in one patient — was considered both serious and related to the treatment, the industry-funded trial reported.
 

Costly Treatment Seems to Be Cost-Effective

As of 2022, gene therapy for transfusion-dependent beta thalassemia was listed as $2.8 million per treatment making it the most expensive single-treatment therapy ever approved in the United States. The price is “extraordinary,” said Dr. Thompson. “For some families, it gives them pause when they first hear about it.”

The hospital makes the case to insurers that covering the treatment is cost-effective in the long run, considering the high cost of traditional treatment, she said. “We’ve been very successful in getting coverage.”

In addition, the independent Institute for Clinical and Economic Review reported in 2022 that the treatment will be cost-effective at the “anticipated price of $2.1 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a 5-year period.”
 

Moving Forward, Clinicians Want to Reduce Complications

What’s next for transfusion-dependent beta thalassemia treatment? Earlier this year, the FDA approved a second gene therapy treatment called exagamglogene autotemcel (exa-cel, Casgevy). “We’re just beginning to evaluate individuals for the product, and we intend to make it available for families as well,” Dr. Thompson said.

In the bigger picture, she said gene therapy still has room for improvement. The need for chemotherapy is one target. According to her, it causes most of the complications related to gene therapy.

“Chemotherapy is a part of all gene therapies today because one has to make space in the bone marrow in order to have modified stem cells to come back to settle in and grow,” she said.

One strategy is to reduce the number of stem cells that are required for the therapy to work. “That would essentially eliminate the need for chemotherapy,” she said. “We’re not there yet.”

Another goal is to reduce the small risk of complications from gene therapy itself, she said. “Overall, though, this doesn’t detract us at all from being very excited about how well children are doing with the current approach. We’re very enthusiastic and very confident in recommending it to families.”
 

Back on Long Island, a Sense of Relief

Several months after his treatment, Yusuf is doing well. His hemoglobin levels are increasing, and his bone marrow has grown back, his mother said. He’s being home-schooled for the time being because he still faces a risk of infection. (Ms. Ahmed, a stay-at-home mom, has worked a teacher and mosque volunteer. Her husband runs a consumer electronics business.)

As Yusuf gets better, his parents hope they’ll soon be able to take a long trip back home to Pakistan to see relatives. They’ll be able to share their son with family along with something else: a sense of relief.

Dr. Al-Samkari discloses consulting for Agios. Dr. Thompson discloses research for Beam, Bluebird Bio, Editas, Novartis, and Novo Nordisk and consulting for Beam, Bluebird Bio, Editas, Roche, and Vertex.

When she got the news that her young son had been diagnosed with the rare blood disorder known as transfusion-dependent beta thalassemia, Yusara Ahmed knew the drill. Her sister had also experienced the inherited condition and needed to undergo regular blood transfusions simply to survive.

With luck, maybe Ms. Ahmed’s son could follow in his aunt’s footsteps and get a stem cell transplant from a compatible family donor. But while little Yusuf Saeed has a twin sister of his own, she wasn’t a match. Without another treatment option, he’d face the prospect of a lifetime not only cut short but burdened by multiple monthly transfusions and severe limitations.

Then came glimpses of hope. One of Yusuf’s physicians at Cohen Children’s Medical Center in Long Island, New York, told Yusuf’s mother about a new kind of gene therapy on the horizon. But it took time to get FDA approval. Yusuf grew older, heading toward his teenage years, when regular transfusions would be a huge burden. “He’s turning 5 and 6, and there’s nothing,” Ms. Ahmed recalled, and the family worried.

Finally, the FDA approved the one-time treatment — betibeglogene autotemcel (beti-cel, Zynteglo) in 2022. By January 2024, the hospital was ready to treat Yusuf. At age 8, he became the first patient in the state of New York to undergo gene therapy for beta thalassemia.

A medical team infused Yusuf with his own stem cells, which had been genetically engineered to boost production of hemoglobin and prevent thalassemia’s devastating effects.

There are caveats about the treatment. It’s an extraordinarily expensive therapy that can be performed at only a few institutions. And it’s so brand new that caveats may not even have appeared yet. Yet, for kids like Yusuf, the gene therapy could transform a life.

“We feel like a weight has been lifted,” Ms. Ahmed said in an interview. “It’s something we’ve been waiting for.”
 

Anemia Becomes a Lifetime Threat

Among all genetic diseases, thalassemia stands alone. It’s the most common condition caused by a single gene, according to Hanny Al-Samkari, MD, a hematologist/clinical investigator at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.

Millions of people have the thalassemia trait, especially in southern Europe, the Middle East, southeast Asia, and Africa, Dr. Al-Samkari said. (Yusuf’s parents are from Pakistan.)

The trait, which appears to provide protection against malaria, may cause mild anemia in some cases but is otherwise harmless. However, a child born to parents with the same kind of trait has a high risk of developing alpha thalassemia or beta thalassemia. Like his aunt, Yusuf developed beta thalassemia, which is generally more severe. Yusuf’s bleeding disorder requires him to be transfusion-dependent.

In these patients, the disease disrupts the production of red blood cells in the bone marrow, Dr. Al-Samkari said. Hemoglobin levels can fall to 7 or 8 g/dL, compared with the normal levels of 12-16 g/dL in adults. “They’re chronically anemic, and that low hemoglobin that leads to things you associate with anemia: fatigue, reduced exercise tolerance, mind fog, challenges with work or school, and hypersomnolence.”

In addition, the bones become thinner and more brittle, he said, leading to fractures.

Transfusions are one treatment option, but they’re needed for a lifetime and cause their own problems, such as iron overload. Care of thalassemia patients “becomes quite complex and quite challenging for both families and medical institutions,” Alexis A. Thompson MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, Pennsylvania, said in an interview.

Yusara Ahmed remembers her sister’s endless visits to the hospital after she was diagnosed at age 4. “We were all very traumatized by the hospital environment,” she said. But good news came in 2008, a few years later, when her sister was able to get a stem cell transplant from their brother.

But while stem cell transplants can be curative, most children don’t have a relative who can be a suitable match as a donor, Dr. Thompson said. Now, gene therapy offers another option, by turning a patient into his or her own matched donor.
 

Stem Cells Out, Stem Cells In

Last year, Yusuf went to Cohen Children’s Medical Center to donate stem cells, which were sent to a laboratory where they were genetically engineered to add copies of the beta-globin gene. Then, in January 2024, the modified stem cells were infused back into Yusuf after he underwent chemotherapy to make room for them in his bone marrow.

In April, a bald-headed Yusuf played with toy dinosaurs while his mother and clinicians met the media at a hospital press conference about his so-far-successful treatment. Early reports about the efficacy of the treatment suggest it may be the proverbial “game changer” for many of the estimated 100,000-plus people in the world who are diagnosed with transfusion-dependent beta thalassemia each year.

Over a median follow-up of 29.5 months, 20 of 22 patients treated with beti-cel no longer needed transfusions, according to a 2022 open-label phase 3 study published in the New England Journal of Medicine. Only one adverse event — thrombocytopenia in one patient — was considered both serious and related to the treatment, the industry-funded trial reported.
 

Costly Treatment Seems to Be Cost-Effective

As of 2022, gene therapy for transfusion-dependent beta thalassemia was listed as $2.8 million per treatment making it the most expensive single-treatment therapy ever approved in the United States. The price is “extraordinary,” said Dr. Thompson. “For some families, it gives them pause when they first hear about it.”

The hospital makes the case to insurers that covering the treatment is cost-effective in the long run, considering the high cost of traditional treatment, she said. “We’ve been very successful in getting coverage.”

In addition, the independent Institute for Clinical and Economic Review reported in 2022 that the treatment will be cost-effective at the “anticipated price of $2.1 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a 5-year period.”
 

Moving Forward, Clinicians Want to Reduce Complications

What’s next for transfusion-dependent beta thalassemia treatment? Earlier this year, the FDA approved a second gene therapy treatment called exagamglogene autotemcel (exa-cel, Casgevy). “We’re just beginning to evaluate individuals for the product, and we intend to make it available for families as well,” Dr. Thompson said.

In the bigger picture, she said gene therapy still has room for improvement. The need for chemotherapy is one target. According to her, it causes most of the complications related to gene therapy.

“Chemotherapy is a part of all gene therapies today because one has to make space in the bone marrow in order to have modified stem cells to come back to settle in and grow,” she said.

One strategy is to reduce the number of stem cells that are required for the therapy to work. “That would essentially eliminate the need for chemotherapy,” she said. “We’re not there yet.”

Another goal is to reduce the small risk of complications from gene therapy itself, she said. “Overall, though, this doesn’t detract us at all from being very excited about how well children are doing with the current approach. We’re very enthusiastic and very confident in recommending it to families.”
 

Back on Long Island, a Sense of Relief

Several months after his treatment, Yusuf is doing well. His hemoglobin levels are increasing, and his bone marrow has grown back, his mother said. He’s being home-schooled for the time being because he still faces a risk of infection. (Ms. Ahmed, a stay-at-home mom, has worked a teacher and mosque volunteer. Her husband runs a consumer electronics business.)

As Yusuf gets better, his parents hope they’ll soon be able to take a long trip back home to Pakistan to see relatives. They’ll be able to share their son with family along with something else: a sense of relief.

Dr. Al-Samkari discloses consulting for Agios. Dr. Thompson discloses research for Beam, Bluebird Bio, Editas, Novartis, and Novo Nordisk and consulting for Beam, Bluebird Bio, Editas, Roche, and Vertex.

When she got the news that her young son had been diagnosed with the rare blood disorder known as transfusion-dependent beta thalassemia, Yusara Ahmed knew the drill. Her sister had also experienced the inherited condition and needed to undergo regular blood transfusions simply to survive.

With luck, maybe Ms. Ahmed’s son could follow in his aunt’s footsteps and get a stem cell transplant from a compatible family donor. But while little Yusuf Saeed has a twin sister of his own, she wasn’t a match. Without another treatment option, he’d face the prospect of a lifetime not only cut short but burdened by multiple monthly transfusions and severe limitations.

Then came glimpses of hope. One of Yusuf’s physicians at Cohen Children’s Medical Center in Long Island, New York, told Yusuf’s mother about a new kind of gene therapy on the horizon. But it took time to get FDA approval. Yusuf grew older, heading toward his teenage years, when regular transfusions would be a huge burden. “He’s turning 5 and 6, and there’s nothing,” Ms. Ahmed recalled, and the family worried.

Finally, the FDA approved the one-time treatment — betibeglogene autotemcel (beti-cel, Zynteglo) in 2022. By January 2024, the hospital was ready to treat Yusuf. At age 8, he became the first patient in the state of New York to undergo gene therapy for beta thalassemia.

A medical team infused Yusuf with his own stem cells, which had been genetically engineered to boost production of hemoglobin and prevent thalassemia’s devastating effects.

There are caveats about the treatment. It’s an extraordinarily expensive therapy that can be performed at only a few institutions. And it’s so brand new that caveats may not even have appeared yet. Yet, for kids like Yusuf, the gene therapy could transform a life.

“We feel like a weight has been lifted,” Ms. Ahmed said in an interview. “It’s something we’ve been waiting for.”
 

Anemia Becomes a Lifetime Threat

Among all genetic diseases, thalassemia stands alone. It’s the most common condition caused by a single gene, according to Hanny Al-Samkari, MD, a hematologist/clinical investigator at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.

Millions of people have the thalassemia trait, especially in southern Europe, the Middle East, southeast Asia, and Africa, Dr. Al-Samkari said. (Yusuf’s parents are from Pakistan.)

The trait, which appears to provide protection against malaria, may cause mild anemia in some cases but is otherwise harmless. However, a child born to parents with the same kind of trait has a high risk of developing alpha thalassemia or beta thalassemia. Like his aunt, Yusuf developed beta thalassemia, which is generally more severe. Yusuf’s bleeding disorder requires him to be transfusion-dependent.

In these patients, the disease disrupts the production of red blood cells in the bone marrow, Dr. Al-Samkari said. Hemoglobin levels can fall to 7 or 8 g/dL, compared with the normal levels of 12-16 g/dL in adults. “They’re chronically anemic, and that low hemoglobin that leads to things you associate with anemia: fatigue, reduced exercise tolerance, mind fog, challenges with work or school, and hypersomnolence.”

In addition, the bones become thinner and more brittle, he said, leading to fractures.

Transfusions are one treatment option, but they’re needed for a lifetime and cause their own problems, such as iron overload. Care of thalassemia patients “becomes quite complex and quite challenging for both families and medical institutions,” Alexis A. Thompson MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, Pennsylvania, said in an interview.

Yusara Ahmed remembers her sister’s endless visits to the hospital after she was diagnosed at age 4. “We were all very traumatized by the hospital environment,” she said. But good news came in 2008, a few years later, when her sister was able to get a stem cell transplant from their brother.

But while stem cell transplants can be curative, most children don’t have a relative who can be a suitable match as a donor, Dr. Thompson said. Now, gene therapy offers another option, by turning a patient into his or her own matched donor.
 

Stem Cells Out, Stem Cells In

Last year, Yusuf went to Cohen Children’s Medical Center to donate stem cells, which were sent to a laboratory where they were genetically engineered to add copies of the beta-globin gene. Then, in January 2024, the modified stem cells were infused back into Yusuf after he underwent chemotherapy to make room for them in his bone marrow.

In April, a bald-headed Yusuf played with toy dinosaurs while his mother and clinicians met the media at a hospital press conference about his so-far-successful treatment. Early reports about the efficacy of the treatment suggest it may be the proverbial “game changer” for many of the estimated 100,000-plus people in the world who are diagnosed with transfusion-dependent beta thalassemia each year.

Over a median follow-up of 29.5 months, 20 of 22 patients treated with beti-cel no longer needed transfusions, according to a 2022 open-label phase 3 study published in the New England Journal of Medicine. Only one adverse event — thrombocytopenia in one patient — was considered both serious and related to the treatment, the industry-funded trial reported.
 

Costly Treatment Seems to Be Cost-Effective

As of 2022, gene therapy for transfusion-dependent beta thalassemia was listed as $2.8 million per treatment making it the most expensive single-treatment therapy ever approved in the United States. The price is “extraordinary,” said Dr. Thompson. “For some families, it gives them pause when they first hear about it.”

The hospital makes the case to insurers that covering the treatment is cost-effective in the long run, considering the high cost of traditional treatment, she said. “We’ve been very successful in getting coverage.”

In addition, the independent Institute for Clinical and Economic Review reported in 2022 that the treatment will be cost-effective at the “anticipated price of $2.1 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a 5-year period.”
 

Moving Forward, Clinicians Want to Reduce Complications

What’s next for transfusion-dependent beta thalassemia treatment? Earlier this year, the FDA approved a second gene therapy treatment called exagamglogene autotemcel (exa-cel, Casgevy). “We’re just beginning to evaluate individuals for the product, and we intend to make it available for families as well,” Dr. Thompson said.

In the bigger picture, she said gene therapy still has room for improvement. The need for chemotherapy is one target. According to her, it causes most of the complications related to gene therapy.

“Chemotherapy is a part of all gene therapies today because one has to make space in the bone marrow in order to have modified stem cells to come back to settle in and grow,” she said.

One strategy is to reduce the number of stem cells that are required for the therapy to work. “That would essentially eliminate the need for chemotherapy,” she said. “We’re not there yet.”

Another goal is to reduce the small risk of complications from gene therapy itself, she said. “Overall, though, this doesn’t detract us at all from being very excited about how well children are doing with the current approach. We’re very enthusiastic and very confident in recommending it to families.”
 

Back on Long Island, a Sense of Relief

Several months after his treatment, Yusuf is doing well. His hemoglobin levels are increasing, and his bone marrow has grown back, his mother said. He’s being home-schooled for the time being because he still faces a risk of infection. (Ms. Ahmed, a stay-at-home mom, has worked a teacher and mosque volunteer. Her husband runs a consumer electronics business.)

As Yusuf gets better, his parents hope they’ll soon be able to take a long trip back home to Pakistan to see relatives. They’ll be able to share their son with family along with something else: a sense of relief.

Dr. Al-Samkari discloses consulting for Agios. Dr. Thompson discloses research for Beam, Bluebird Bio, Editas, Novartis, and Novo Nordisk and consulting for Beam, Bluebird Bio, Editas, Roche, and Vertex.

The addition of an anti-CD38 monoclonal antibody to the standard first-line combination treatment significantly improved outcomes in newly diagnosed, transplant-ineligible patients with multiple myeloma (MM), according to an interim analysis of an open-label, randomized, phase 3 trial.

Patients who took isatuximab (Sarclisa) plus bortezomib, lenalidomide, and dexamethasone (VRd) reached higher estimated progression-free survival at a median 59.7 months vs. those who took VRd alone (63.2% vs. 45.2%, respectively, 98.5% CI, hazard ratio [HR] = 0.60, P < .001), reported Thierry Facon, MD, professor of hematology at Lille University Hospital, France, and colleagues at the annual meeting of the American Society of Clinical Oncology in Chicago. The study was simultaneously published in The New England Journal of Medicine.

“The significant progression-free benefit observed with Sarclisa with combination therapy compared to VRd is important and encouraging for patients with newly diagnosed multiple myeloma,” Dr. Facon said in an interview. The findings demonstrated the VRd-isatuximab’s potential as “a first-in-class combination to address gaps in care for newly diagnosed multiple myeloma transplant-ineligible patients,” he said.

According to Dr. Facon, more than 180,000 people worldwide are diagnosed with MM each year, he said, making it the second-most common hematologic malignancy. 

“There is a need for new frontline therapeutic options for all MM patients,” he said. “Effective frontline therapy has the potential to modify the course of the disease, which is a key outcome for transplant-ineligible patients who often face high rates of attrition in later lines of therapy.”

For the industry-funded IMROZ study, researchers recruited patients aged 18-80 at 93 sites in 21 nations from 2017-2019. All were ineligible for transplant due to comorbidities or being aged 65 or older. Exclusions included Eastern Cooperative Oncology Group (ECOG) performance status scores of more than 2.

The subjects were randomly assigned in a 3-to-2 ratio to isatuximab-VRd (n = 265) or VRd alone (n = 181) and received four induction cycles (6 weeks per cycle) followed by 4-week cycles of continuous treatment until disease progression, unacceptable adverse event, or other criteria for discontinuation. If progression occurred, patients could be switched from the VRd-only group to the isatuximab-VRd group.

The median age in both the isatuximab-VRd and VRd groups was 72. The percentages of women were 46.0% and 48.1%, respectively, and 72.5% and 72.4%, respectively, were White. The next largest race/ethnic group was Asian (11.7% and 9.4%, respectively). Almost all had ECOG status of 0 or 1 (88.7% and 89.5%, respectively).

At study cut-off in September 2023, the percentages of subjects in the isatuximab-VRd and VRd groups who were still receiving treatment were 47.2% and 24.3%, respectively.

An intention-to-treat analysis found that the two groups had similar rates of overall response (91.3% for isatuximab-VRd vs. 92.3% for VRd), but the isatuximab-VRd group had higher complete or better response (74.7% vs. 64.1%, P = .01).

The percentage of patients who were minimal residual disease (MRD)-negative and had a complete response was also higher in the VRd-isatuximab group vs. the VRd group (55.5% vs. 40.9%, respectively, P = .003). A total of 26.0% of patients in the VRd-isatuximab group died vs. 32.6% in the VRd group; the estimated overall survival rates at 60 months were 72.3% and 66.3%, respectively, HR = 0.78, 99.97% CI).

As for adverse events, grade 5 events were more common in the VRd-isatuximab group (11.0% vs. 5.5%), as were deaths within the first 60 days of treatment (1.5% vs. 0.6%). “The difference was driven in part by different treatment exposures,” the researchers reported. Treatment-emergent events led to treatment discontinuation in 22.8% and 26.0% of patients, respectively.

“The safety and tolerability of Sarclisa observed was consistent with the established safety profile of Sarclisa and VRd with no new safety signals observed,” Dr. Facon said.

In an interview, Zandra Klippel, MD, global product head for multiple myeloma at Sanofi — the maker of isatuximab and funder of the study — said the Food and Drug Administration has accepted a priority review application for the investigational use of isatuximab in combination with VRd for the treatment of patients with transplant-ineligible, newly diagnosed MM.

“Our FDA approval date is expected on September 27, 2024,” Dr. Klippel said. “If all goes well, we anticipate launching as early as 2024 in the US and rolling out in other key countries starting in 2025 and continuing through 2026.”

Dr. Klippel added that isatuximab “continues to be evaluated in multiple ongoing phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum.”

In an interview, Sagar Lonial, MD, chair and professor of hematology and medical oncology and chief medical officer at Winship Cancer Institute at Emory University in Atlanta, said the study is “important.”

However, Dr. Lonial, who is familiar with the findings but didn’t take part in the study, said it’s difficult to understand the impact of the treatment on frail patients. It appears that the combination treatment may be good for frail patients, he said, “but I need to better understand the magnitude of the benefit in that subset a little more.”

As for adverse events, he said “they are what would be expected for a trial like this.”

Pneumonia and COVID-19 infections were higher in the VRd-isatuximab group, he said, and “we know in general that vaccine responses are blocked by CD38 antibodies.” This can be managed, he said, via intravenous immunoglobulin support.

Manni Mohyuddin, MD, assistant professor at Huntsman Cancer Institute in Utah, said in an interview that the findings suggest that in older, fit patients, “you can get fairly good outcomes without use of transplant.”

In the United States, many more patients in the cohort would have been considered transplant-eligible, he said, and not eliminated from consideration for transplant due to age over 65. However, as patients age, “you get more diminishing returns for transplants,” said Dr. Mohyuddin, who is familiar with the study findings but didn’t take part in the research.

All the drugs in the new combination are FDA approved, he said, although the combination isn’t. “I suspect this will make it to our guidelines very soon and then be reimbursed by insurance companies and Medicare.”

The study was funded by Sanofi and an M.D. Anderson Cancer Center support grant. Dr. Facon has no disclosures. Other study authors report multiple ties relationships with various drug makers. Dr. Lonial disclosed ties with Takeda, Amgen, Novartis, BMS, GSK, AbbVie, Genentech, Pfizer, Regeneron, Janssen, AstraZeneca, and TG Therapeutics). Dr. Mohyuddin disclosed a relationship with Janssen.

The addition of an anti-CD38 monoclonal antibody to the standard first-line combination treatment significantly improved outcomes in newly diagnosed, transplant-ineligible patients with multiple myeloma (MM), according to an interim analysis of an open-label, randomized, phase 3 trial.

Patients who took isatuximab (Sarclisa) plus bortezomib, lenalidomide, and dexamethasone (VRd) reached higher estimated progression-free survival at a median 59.7 months vs. those who took VRd alone (63.2% vs. 45.2%, respectively, 98.5% CI, hazard ratio [HR] = 0.60, P < .001), reported Thierry Facon, MD, professor of hematology at Lille University Hospital, France, and colleagues at the annual meeting of the American Society of Clinical Oncology in Chicago. The study was simultaneously published in The New England Journal of Medicine.

“The significant progression-free benefit observed with Sarclisa with combination therapy compared to VRd is important and encouraging for patients with newly diagnosed multiple myeloma,” Dr. Facon said in an interview. The findings demonstrated the VRd-isatuximab’s potential as “a first-in-class combination to address gaps in care for newly diagnosed multiple myeloma transplant-ineligible patients,” he said.

According to Dr. Facon, more than 180,000 people worldwide are diagnosed with MM each year, he said, making it the second-most common hematologic malignancy. 

“There is a need for new frontline therapeutic options for all MM patients,” he said. “Effective frontline therapy has the potential to modify the course of the disease, which is a key outcome for transplant-ineligible patients who often face high rates of attrition in later lines of therapy.”

For the industry-funded IMROZ study, researchers recruited patients aged 18-80 at 93 sites in 21 nations from 2017-2019. All were ineligible for transplant due to comorbidities or being aged 65 or older. Exclusions included Eastern Cooperative Oncology Group (ECOG) performance status scores of more than 2.

The subjects were randomly assigned in a 3-to-2 ratio to isatuximab-VRd (n = 265) or VRd alone (n = 181) and received four induction cycles (6 weeks per cycle) followed by 4-week cycles of continuous treatment until disease progression, unacceptable adverse event, or other criteria for discontinuation. If progression occurred, patients could be switched from the VRd-only group to the isatuximab-VRd group.

The median age in both the isatuximab-VRd and VRd groups was 72. The percentages of women were 46.0% and 48.1%, respectively, and 72.5% and 72.4%, respectively, were White. The next largest race/ethnic group was Asian (11.7% and 9.4%, respectively). Almost all had ECOG status of 0 or 1 (88.7% and 89.5%, respectively).

At study cut-off in September 2023, the percentages of subjects in the isatuximab-VRd and VRd groups who were still receiving treatment were 47.2% and 24.3%, respectively.

An intention-to-treat analysis found that the two groups had similar rates of overall response (91.3% for isatuximab-VRd vs. 92.3% for VRd), but the isatuximab-VRd group had higher complete or better response (74.7% vs. 64.1%, P = .01).

The percentage of patients who were minimal residual disease (MRD)-negative and had a complete response was also higher in the VRd-isatuximab group vs. the VRd group (55.5% vs. 40.9%, respectively, P = .003). A total of 26.0% of patients in the VRd-isatuximab group died vs. 32.6% in the VRd group; the estimated overall survival rates at 60 months were 72.3% and 66.3%, respectively, HR = 0.78, 99.97% CI).

As for adverse events, grade 5 events were more common in the VRd-isatuximab group (11.0% vs. 5.5%), as were deaths within the first 60 days of treatment (1.5% vs. 0.6%). “The difference was driven in part by different treatment exposures,” the researchers reported. Treatment-emergent events led to treatment discontinuation in 22.8% and 26.0% of patients, respectively.

“The safety and tolerability of Sarclisa observed was consistent with the established safety profile of Sarclisa and VRd with no new safety signals observed,” Dr. Facon said.

In an interview, Zandra Klippel, MD, global product head for multiple myeloma at Sanofi — the maker of isatuximab and funder of the study — said the Food and Drug Administration has accepted a priority review application for the investigational use of isatuximab in combination with VRd for the treatment of patients with transplant-ineligible, newly diagnosed MM.

“Our FDA approval date is expected on September 27, 2024,” Dr. Klippel said. “If all goes well, we anticipate launching as early as 2024 in the US and rolling out in other key countries starting in 2025 and continuing through 2026.”

Dr. Klippel added that isatuximab “continues to be evaluated in multiple ongoing phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum.”

In an interview, Sagar Lonial, MD, chair and professor of hematology and medical oncology and chief medical officer at Winship Cancer Institute at Emory University in Atlanta, said the study is “important.”

However, Dr. Lonial, who is familiar with the findings but didn’t take part in the study, said it’s difficult to understand the impact of the treatment on frail patients. It appears that the combination treatment may be good for frail patients, he said, “but I need to better understand the magnitude of the benefit in that subset a little more.”

As for adverse events, he said “they are what would be expected for a trial like this.”

Pneumonia and COVID-19 infections were higher in the VRd-isatuximab group, he said, and “we know in general that vaccine responses are blocked by CD38 antibodies.” This can be managed, he said, via intravenous immunoglobulin support.

Manni Mohyuddin, MD, assistant professor at Huntsman Cancer Institute in Utah, said in an interview that the findings suggest that in older, fit patients, “you can get fairly good outcomes without use of transplant.”

In the United States, many more patients in the cohort would have been considered transplant-eligible, he said, and not eliminated from consideration for transplant due to age over 65. However, as patients age, “you get more diminishing returns for transplants,” said Dr. Mohyuddin, who is familiar with the study findings but didn’t take part in the research.

All the drugs in the new combination are FDA approved, he said, although the combination isn’t. “I suspect this will make it to our guidelines very soon and then be reimbursed by insurance companies and Medicare.”

The study was funded by Sanofi and an M.D. Anderson Cancer Center support grant. Dr. Facon has no disclosures. Other study authors report multiple ties relationships with various drug makers. Dr. Lonial disclosed ties with Takeda, Amgen, Novartis, BMS, GSK, AbbVie, Genentech, Pfizer, Regeneron, Janssen, AstraZeneca, and TG Therapeutics). Dr. Mohyuddin disclosed a relationship with Janssen.

The addition of an anti-CD38 monoclonal antibody to the standard first-line combination treatment significantly improved outcomes in newly diagnosed, transplant-ineligible patients with multiple myeloma (MM), according to an interim analysis of an open-label, randomized, phase 3 trial.

Patients who took isatuximab (Sarclisa) plus bortezomib, lenalidomide, and dexamethasone (VRd) reached higher estimated progression-free survival at a median 59.7 months vs. those who took VRd alone (63.2% vs. 45.2%, respectively, 98.5% CI, hazard ratio [HR] = 0.60, P < .001), reported Thierry Facon, MD, professor of hematology at Lille University Hospital, France, and colleagues at the annual meeting of the American Society of Clinical Oncology in Chicago. The study was simultaneously published in The New England Journal of Medicine.

“The significant progression-free benefit observed with Sarclisa with combination therapy compared to VRd is important and encouraging for patients with newly diagnosed multiple myeloma,” Dr. Facon said in an interview. The findings demonstrated the VRd-isatuximab’s potential as “a first-in-class combination to address gaps in care for newly diagnosed multiple myeloma transplant-ineligible patients,” he said.

According to Dr. Facon, more than 180,000 people worldwide are diagnosed with MM each year, he said, making it the second-most common hematologic malignancy. 

“There is a need for new frontline therapeutic options for all MM patients,” he said. “Effective frontline therapy has the potential to modify the course of the disease, which is a key outcome for transplant-ineligible patients who often face high rates of attrition in later lines of therapy.”

For the industry-funded IMROZ study, researchers recruited patients aged 18-80 at 93 sites in 21 nations from 2017-2019. All were ineligible for transplant due to comorbidities or being aged 65 or older. Exclusions included Eastern Cooperative Oncology Group (ECOG) performance status scores of more than 2.

The subjects were randomly assigned in a 3-to-2 ratio to isatuximab-VRd (n = 265) or VRd alone (n = 181) and received four induction cycles (6 weeks per cycle) followed by 4-week cycles of continuous treatment until disease progression, unacceptable adverse event, or other criteria for discontinuation. If progression occurred, patients could be switched from the VRd-only group to the isatuximab-VRd group.

The median age in both the isatuximab-VRd and VRd groups was 72. The percentages of women were 46.0% and 48.1%, respectively, and 72.5% and 72.4%, respectively, were White. The next largest race/ethnic group was Asian (11.7% and 9.4%, respectively). Almost all had ECOG status of 0 or 1 (88.7% and 89.5%, respectively).

At study cut-off in September 2023, the percentages of subjects in the isatuximab-VRd and VRd groups who were still receiving treatment were 47.2% and 24.3%, respectively.

An intention-to-treat analysis found that the two groups had similar rates of overall response (91.3% for isatuximab-VRd vs. 92.3% for VRd), but the isatuximab-VRd group had higher complete or better response (74.7% vs. 64.1%, P = .01).

The percentage of patients who were minimal residual disease (MRD)-negative and had a complete response was also higher in the VRd-isatuximab group vs. the VRd group (55.5% vs. 40.9%, respectively, P = .003). A total of 26.0% of patients in the VRd-isatuximab group died vs. 32.6% in the VRd group; the estimated overall survival rates at 60 months were 72.3% and 66.3%, respectively, HR = 0.78, 99.97% CI).

As for adverse events, grade 5 events were more common in the VRd-isatuximab group (11.0% vs. 5.5%), as were deaths within the first 60 days of treatment (1.5% vs. 0.6%). “The difference was driven in part by different treatment exposures,” the researchers reported. Treatment-emergent events led to treatment discontinuation in 22.8% and 26.0% of patients, respectively.

“The safety and tolerability of Sarclisa observed was consistent with the established safety profile of Sarclisa and VRd with no new safety signals observed,” Dr. Facon said.

In an interview, Zandra Klippel, MD, global product head for multiple myeloma at Sanofi — the maker of isatuximab and funder of the study — said the Food and Drug Administration has accepted a priority review application for the investigational use of isatuximab in combination with VRd for the treatment of patients with transplant-ineligible, newly diagnosed MM.

“Our FDA approval date is expected on September 27, 2024,” Dr. Klippel said. “If all goes well, we anticipate launching as early as 2024 in the US and rolling out in other key countries starting in 2025 and continuing through 2026.”

Dr. Klippel added that isatuximab “continues to be evaluated in multiple ongoing phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum.”

In an interview, Sagar Lonial, MD, chair and professor of hematology and medical oncology and chief medical officer at Winship Cancer Institute at Emory University in Atlanta, said the study is “important.”

However, Dr. Lonial, who is familiar with the findings but didn’t take part in the study, said it’s difficult to understand the impact of the treatment on frail patients. It appears that the combination treatment may be good for frail patients, he said, “but I need to better understand the magnitude of the benefit in that subset a little more.”

As for adverse events, he said “they are what would be expected for a trial like this.”

Pneumonia and COVID-19 infections were higher in the VRd-isatuximab group, he said, and “we know in general that vaccine responses are blocked by CD38 antibodies.” This can be managed, he said, via intravenous immunoglobulin support.

Manni Mohyuddin, MD, assistant professor at Huntsman Cancer Institute in Utah, said in an interview that the findings suggest that in older, fit patients, “you can get fairly good outcomes without use of transplant.”

In the United States, many more patients in the cohort would have been considered transplant-eligible, he said, and not eliminated from consideration for transplant due to age over 65. However, as patients age, “you get more diminishing returns for transplants,” said Dr. Mohyuddin, who is familiar with the study findings but didn’t take part in the research.

All the drugs in the new combination are FDA approved, he said, although the combination isn’t. “I suspect this will make it to our guidelines very soon and then be reimbursed by insurance companies and Medicare.”

The study was funded by Sanofi and an M.D. Anderson Cancer Center support grant. Dr. Facon has no disclosures. Other study authors report multiple ties relationships with various drug makers. Dr. Lonial disclosed ties with Takeda, Amgen, Novartis, BMS, GSK, AbbVie, Genentech, Pfizer, Regeneron, Janssen, AstraZeneca, and TG Therapeutics). Dr. Mohyuddin disclosed a relationship with Janssen.

Dual therapy of ibrutinib (Imbruvica) and venetoclax (Venclexta) produced “promising” and comparable efficacy across cohorts of patients with mantle cell lymphoma (MCL) and TP53 mutations, a new analysis of the randomized, double-blind, phase 3 Sympatico study finds.

In first-line patients (n = 29) and relapsed/refractory patients (n = 45) with TP53 mutations, complete response rates were 55% and 58%, respectively, reported hematologist-oncologist Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, and colleagues, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“These results are encouraging in light of the poor responses and shorter survival outcomes with standard chemotherapy,” Dr. Wang said in an ASCO presentation.

The current standard of care for relapsed/refractory MCL includes Bruton tyrosine kinase inhibitors for first relapse and CAR T-cell therapy (CAR-T) for second relapse in eligible patients or pirtobrutinib (Jaypirca) in patients ineligible for CAR T-cell therapy, Ohio State University Comprehensive Cancer Center hematology specialist Narendranath Epperla, MD, MS, said in an interview. Dr. Epperla is familiar with the new study findings but didn’t take part in the research.

Options for third relapse and beyond include clinical trial, rituximab [Rituxan] and lenalidomide [Revlimid], and bortezomib [Velcade],” Dr. Epperla said. “Venetoclax is not currently FDA-approved but can also be considered at third relapse.”

Better therapies are needed for a number of reasons, including poor outcomes in high-risk patients, such as those with TP53 mutations and those who progress following CAR T, Dr. Epperla said. Also, “as the novel agents are being moved into earlier lines of therapy, there remains an unmet need in those who progress on these agents with fewer options in the relapsed setting.”

At last December’s American Society of Hematology annual meeting, Dr. Wang and colleagues reported on the primary analysis results from the Sympatico study. Patients with relapsed/refractory MCL after 1-5 prior therapies were randomly assigned to receive 560 mg of ibrutinib once daily with either placebo (n = 133) or 400 mg daily of venetoclax after ramp-up (n = 134) for 2 years. Then subjects continued taking ibrutinib alone until their disease progressed or they reached unacceptable toxicity.

At a median follow-up of 51.2 months, median progression-free survival was longer in the ibrutinib-venetoclax group vs. ibrutinib alone (hazard ratio [HR] = 0.65, 95% CI, P = .0052).

The new analysis pools several cohorts of patients with TP53 mutations who all took the combination therapy: 5 from a safety run-in phase, 40 from the randomized phase, and 29 from a first-line cohort (median age at baseline = 67).

Median overall survival was not reached in the first-line group and 35.0 months in the relapsed/refractory group (total = 47.1 months). Median progress-free survival in the groups was 22.0 months and 20.9 months, respectively, and median duration of response was 20.5 months and 26.5 months, respectively.

With regard to the new findings, “it is good to see the responses with ibrutinib and venetoclax were deep and durable,” Dr. Epperla said. The combination treatment “provides a good alternative option for TP53-mutated MCL patients who are ineligible for CAR-T.”

Dr. Epperla added that the findings about the addition of ibrutinib could apply to newer-generation Bruton tyrosine kinase inhibitors that have relatively better safety profiles.

However, Dr. Epperla cautioned that the treatment needs to be weighed against the toxicity and cost of the regimen of ibrutinib and venetoclax for 2 years then single-agent ibrutinib until progression or unacceptable toxicity.

This news organization reported in 2023 that estimated net spending on ibrutinib per Medicare data increased by nearly half from 2014-2020, reaching $11,980 in 2020 vs. $7,787 for venetoclax.

Dr. Epperla also noted that “there are newer therapies that are emerging, such as T-cell-engaging bispecific antibodies, and they have shown promising results.”

In an interview, Brad S. Kahl, MD, a hematologist-oncologist at Washington University, St. Louis, said the improvement in outcomes are “modestly significant.”

Dr. Kahl, who is familiar with the study findings but didn’t take part in the research, said it is “worth adding the venetoclax, particularly in these biologically high risk patients with p53 mutations. Venetoclax is not FDA-approved, so insurance approval will need to be determined on a case-by-case basis. The combination is very expensive.”

Dr. Kahl agreed with Dr. Epperla that the findings could be extrapolated to other Bruton tyrosine kinase inhibitors.

The study was funded by Pharmacyclics, an AbbVie Company. Dr. Epperla disclosed relationships with BeiGene and Eli Lilly. Dr. Kahl reported ties with AstraZeneca, BeiGene, Abbvie, and Genentech.

Dual therapy of ibrutinib (Imbruvica) and venetoclax (Venclexta) produced “promising” and comparable efficacy across cohorts of patients with mantle cell lymphoma (MCL) and TP53 mutations, a new analysis of the randomized, double-blind, phase 3 Sympatico study finds.

In first-line patients (n = 29) and relapsed/refractory patients (n = 45) with TP53 mutations, complete response rates were 55% and 58%, respectively, reported hematologist-oncologist Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, and colleagues, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“These results are encouraging in light of the poor responses and shorter survival outcomes with standard chemotherapy,” Dr. Wang said in an ASCO presentation.

The current standard of care for relapsed/refractory MCL includes Bruton tyrosine kinase inhibitors for first relapse and CAR T-cell therapy (CAR-T) for second relapse in eligible patients or pirtobrutinib (Jaypirca) in patients ineligible for CAR T-cell therapy, Ohio State University Comprehensive Cancer Center hematology specialist Narendranath Epperla, MD, MS, said in an interview. Dr. Epperla is familiar with the new study findings but didn’t take part in the research.

Options for third relapse and beyond include clinical trial, rituximab [Rituxan] and lenalidomide [Revlimid], and bortezomib [Velcade],” Dr. Epperla said. “Venetoclax is not currently FDA-approved but can also be considered at third relapse.”

Better therapies are needed for a number of reasons, including poor outcomes in high-risk patients, such as those with TP53 mutations and those who progress following CAR T, Dr. Epperla said. Also, “as the novel agents are being moved into earlier lines of therapy, there remains an unmet need in those who progress on these agents with fewer options in the relapsed setting.”

At last December’s American Society of Hematology annual meeting, Dr. Wang and colleagues reported on the primary analysis results from the Sympatico study. Patients with relapsed/refractory MCL after 1-5 prior therapies were randomly assigned to receive 560 mg of ibrutinib once daily with either placebo (n = 133) or 400 mg daily of venetoclax after ramp-up (n = 134) for 2 years. Then subjects continued taking ibrutinib alone until their disease progressed or they reached unacceptable toxicity.

At a median follow-up of 51.2 months, median progression-free survival was longer in the ibrutinib-venetoclax group vs. ibrutinib alone (hazard ratio [HR] = 0.65, 95% CI, P = .0052).

The new analysis pools several cohorts of patients with TP53 mutations who all took the combination therapy: 5 from a safety run-in phase, 40 from the randomized phase, and 29 from a first-line cohort (median age at baseline = 67).

Median overall survival was not reached in the first-line group and 35.0 months in the relapsed/refractory group (total = 47.1 months). Median progress-free survival in the groups was 22.0 months and 20.9 months, respectively, and median duration of response was 20.5 months and 26.5 months, respectively.

With regard to the new findings, “it is good to see the responses with ibrutinib and venetoclax were deep and durable,” Dr. Epperla said. The combination treatment “provides a good alternative option for TP53-mutated MCL patients who are ineligible for CAR-T.”

Dr. Epperla added that the findings about the addition of ibrutinib could apply to newer-generation Bruton tyrosine kinase inhibitors that have relatively better safety profiles.

However, Dr. Epperla cautioned that the treatment needs to be weighed against the toxicity and cost of the regimen of ibrutinib and venetoclax for 2 years then single-agent ibrutinib until progression or unacceptable toxicity.

This news organization reported in 2023 that estimated net spending on ibrutinib per Medicare data increased by nearly half from 2014-2020, reaching $11,980 in 2020 vs. $7,787 for venetoclax.

Dr. Epperla also noted that “there are newer therapies that are emerging, such as T-cell-engaging bispecific antibodies, and they have shown promising results.”

In an interview, Brad S. Kahl, MD, a hematologist-oncologist at Washington University, St. Louis, said the improvement in outcomes are “modestly significant.”

Dr. Kahl, who is familiar with the study findings but didn’t take part in the research, said it is “worth adding the venetoclax, particularly in these biologically high risk patients with p53 mutations. Venetoclax is not FDA-approved, so insurance approval will need to be determined on a case-by-case basis. The combination is very expensive.”

Dr. Kahl agreed with Dr. Epperla that the findings could be extrapolated to other Bruton tyrosine kinase inhibitors.

The study was funded by Pharmacyclics, an AbbVie Company. Dr. Epperla disclosed relationships with BeiGene and Eli Lilly. Dr. Kahl reported ties with AstraZeneca, BeiGene, Abbvie, and Genentech.

Dual therapy of ibrutinib (Imbruvica) and venetoclax (Venclexta) produced “promising” and comparable efficacy across cohorts of patients with mantle cell lymphoma (MCL) and TP53 mutations, a new analysis of the randomized, double-blind, phase 3 Sympatico study finds.

In first-line patients (n = 29) and relapsed/refractory patients (n = 45) with TP53 mutations, complete response rates were 55% and 58%, respectively, reported hematologist-oncologist Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, and colleagues, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“These results are encouraging in light of the poor responses and shorter survival outcomes with standard chemotherapy,” Dr. Wang said in an ASCO presentation.

The current standard of care for relapsed/refractory MCL includes Bruton tyrosine kinase inhibitors for first relapse and CAR T-cell therapy (CAR-T) for second relapse in eligible patients or pirtobrutinib (Jaypirca) in patients ineligible for CAR T-cell therapy, Ohio State University Comprehensive Cancer Center hematology specialist Narendranath Epperla, MD, MS, said in an interview. Dr. Epperla is familiar with the new study findings but didn’t take part in the research.

Options for third relapse and beyond include clinical trial, rituximab [Rituxan] and lenalidomide [Revlimid], and bortezomib [Velcade],” Dr. Epperla said. “Venetoclax is not currently FDA-approved but can also be considered at third relapse.”

Better therapies are needed for a number of reasons, including poor outcomes in high-risk patients, such as those with TP53 mutations and those who progress following CAR T, Dr. Epperla said. Also, “as the novel agents are being moved into earlier lines of therapy, there remains an unmet need in those who progress on these agents with fewer options in the relapsed setting.”

At last December’s American Society of Hematology annual meeting, Dr. Wang and colleagues reported on the primary analysis results from the Sympatico study. Patients with relapsed/refractory MCL after 1-5 prior therapies were randomly assigned to receive 560 mg of ibrutinib once daily with either placebo (n = 133) or 400 mg daily of venetoclax after ramp-up (n = 134) for 2 years. Then subjects continued taking ibrutinib alone until their disease progressed or they reached unacceptable toxicity.

At a median follow-up of 51.2 months, median progression-free survival was longer in the ibrutinib-venetoclax group vs. ibrutinib alone (hazard ratio [HR] = 0.65, 95% CI, P = .0052).

The new analysis pools several cohorts of patients with TP53 mutations who all took the combination therapy: 5 from a safety run-in phase, 40 from the randomized phase, and 29 from a first-line cohort (median age at baseline = 67).

Median overall survival was not reached in the first-line group and 35.0 months in the relapsed/refractory group (total = 47.1 months). Median progress-free survival in the groups was 22.0 months and 20.9 months, respectively, and median duration of response was 20.5 months and 26.5 months, respectively.

With regard to the new findings, “it is good to see the responses with ibrutinib and venetoclax were deep and durable,” Dr. Epperla said. The combination treatment “provides a good alternative option for TP53-mutated MCL patients who are ineligible for CAR-T.”

Dr. Epperla added that the findings about the addition of ibrutinib could apply to newer-generation Bruton tyrosine kinase inhibitors that have relatively better safety profiles.

However, Dr. Epperla cautioned that the treatment needs to be weighed against the toxicity and cost of the regimen of ibrutinib and venetoclax for 2 years then single-agent ibrutinib until progression or unacceptable toxicity.

This news organization reported in 2023 that estimated net spending on ibrutinib per Medicare data increased by nearly half from 2014-2020, reaching $11,980 in 2020 vs. $7,787 for venetoclax.

Dr. Epperla also noted that “there are newer therapies that are emerging, such as T-cell-engaging bispecific antibodies, and they have shown promising results.”

In an interview, Brad S. Kahl, MD, a hematologist-oncologist at Washington University, St. Louis, said the improvement in outcomes are “modestly significant.”

Dr. Kahl, who is familiar with the study findings but didn’t take part in the research, said it is “worth adding the venetoclax, particularly in these biologically high risk patients with p53 mutations. Venetoclax is not FDA-approved, so insurance approval will need to be determined on a case-by-case basis. The combination is very expensive.”

Dr. Kahl agreed with Dr. Epperla that the findings could be extrapolated to other Bruton tyrosine kinase inhibitors.

The study was funded by Pharmacyclics, an AbbVie Company. Dr. Epperla disclosed relationships with BeiGene and Eli Lilly. Dr. Kahl reported ties with AstraZeneca, BeiGene, Abbvie, and Genentech.

In just 4 years, there’s been a significant evolution in the profile of pediatric and young adult patients who’ve taken the chimeric antigen receptor (CAR) T-cell immunotherapy known as tisagenlecleucel (Kymriah) for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), a new industry-funded study finds.

It’s becoming more common for patients with less severe disease to undergo the treatment, often bypassing hematopoietic stem cell transplantation (HSCT), and survival is on the rise.

From 2018 to 2022, the percentage of patients in an international cohort who had disease burden of ≥50% fell from 18% to 4%, researchers reported at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Median relapse-free survival in patients who didn’t undergo post-infusion HSCT grew from 18 months in 2018 to 27 months in 2020. It was not estimable in 2021.

“This introduction of the therapy is changing the treatment landscape of how we look at refractory B-ALL, where the standard of care previously would be to proceed to transplant. This therapy is actually reducing the use of transplant, which has lots of morbidity and mortality associated with it,” Texas Children’s Cancer Center hematologist-oncologist Rayne H. Rouce, MD, who led the study, said in an interview.

Tisagenlecleucel received Food and Drug Administration approval in 2017, said Nirali N. Shah, MD, MHSc, head of the Pediatric Oncology Branch’s Hematologic Malignancies Section at the National Cancer Institute, in an interview. Dr. Shah is familiar with the study findings but didn’t take part in the research.

Remission rates have been around 60%-70%, Dr. Shah said, although that rate is “likely higher” now because of gains in experience and improvement in disease burden prior to therapy. 

The new findings fill a knowledge gap about real-world outcomes since a lot of the prior data was based on investigational CAR T-cell products, she said.

The noninterventional, prospective, longitudinal study, funded by tisagenlecleucel manufacturer Novartis, tracked 974 patients up to age 25 who received tisagenlecleucel in the United States, Canada, Korea, and Taiwan.

The study found that between 2018 and 2022:

• The percentage of patients who received treatment while in morphological complete remission grew from 34% to 51%.
• The percentages who were in third or greater relapse fell from 14% to 2%.
• The percentages undergoing ≥1 HSCT before tisagenlecleucel infusion fell from 37% to 15%.
• Overall, 34.5% of 911 patients received post-infusion HSCT.

In the big picture, the findings suggest that the therapy can be considered more than “a last resort for patients in a second or greater relapse or who are refractory,” Dr. Rouce said. By offering CAR T-cell therapy to earlier-stage patients, she said, “when they’re less sick, when they have less comorbidities, and when their organs are functioning better, we could potentially save them from having to go on to a transplant.”

Dr. Shah said the findings indicate that “a substantial number of patients are surviving. It’s remarkable actually. Prior to tisagenlecleucel, patients had dismal outcomes from standard chemotherapy.”

She added that the study suggests “providers are getting much more comfortable with getting their patients in the best shape prior to getting CAR T-cell therapy. Outcomes are improving as providers expand the use of CAR T-cell therapy to patients who are less heavily pretreated and have lower disease burden.”

Moving forward, “at some point there will likely be a plateau in terms of how good the outcomes can be.” And there will be discussion of the role of HSCT.

“We’ll figure out some of the nuances about which patients need transplants and which can avoid them. But curative potential is growing. With or without transplant, this is ultimately going to lead to a much higher fraction of patients being cured who previously would not have been cured,” she said. “That’s the bottom line.”

As for adverse effects, Dr. Shah said “disease burden has a pretty direct relationship with side effects and toxicities. If you have more disease, you have more severe side effects.”

Reducing disease burden will reduce side effects, she said. Also, “we’re getting a lot better at managing these toxicities. Eliminating some of the more toxic chemotherapy through earlier use of CAR T-cells in chemotherapy-refractory patients may well help reduce therapy burden and improve long-term survival outcomes, she added.

As for cost, drugs.com reports that the therapy runs to more than $612,000 per infusion. But Dr. Shah said insurers are covering the treatment. She added that there are efforts to expand the indication so CAR T-cell therapy can be used earlier in patients who are chemotherapy-refractory.

Novartis funded the study. Dr. Shah discloses ties with Lentigen, VOR, and CARGO, ImmunoACT, and Sobi. Dr. Rouce reports relationships with Pfizer and Novartis.

In just 4 years, there’s been a significant evolution in the profile of pediatric and young adult patients who’ve taken the chimeric antigen receptor (CAR) T-cell immunotherapy known as tisagenlecleucel (Kymriah) for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), a new industry-funded study finds.

It’s becoming more common for patients with less severe disease to undergo the treatment, often bypassing hematopoietic stem cell transplantation (HSCT), and survival is on the rise.

From 2018 to 2022, the percentage of patients in an international cohort who had disease burden of ≥50% fell from 18% to 4%, researchers reported at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Median relapse-free survival in patients who didn’t undergo post-infusion HSCT grew from 18 months in 2018 to 27 months in 2020. It was not estimable in 2021.

“This introduction of the therapy is changing the treatment landscape of how we look at refractory B-ALL, where the standard of care previously would be to proceed to transplant. This therapy is actually reducing the use of transplant, which has lots of morbidity and mortality associated with it,” Texas Children’s Cancer Center hematologist-oncologist Rayne H. Rouce, MD, who led the study, said in an interview.

Tisagenlecleucel received Food and Drug Administration approval in 2017, said Nirali N. Shah, MD, MHSc, head of the Pediatric Oncology Branch’s Hematologic Malignancies Section at the National Cancer Institute, in an interview. Dr. Shah is familiar with the study findings but didn’t take part in the research.

Remission rates have been around 60%-70%, Dr. Shah said, although that rate is “likely higher” now because of gains in experience and improvement in disease burden prior to therapy. 

The new findings fill a knowledge gap about real-world outcomes since a lot of the prior data was based on investigational CAR T-cell products, she said.

The noninterventional, prospective, longitudinal study, funded by tisagenlecleucel manufacturer Novartis, tracked 974 patients up to age 25 who received tisagenlecleucel in the United States, Canada, Korea, and Taiwan.

The study found that between 2018 and 2022:

• The percentage of patients who received treatment while in morphological complete remission grew from 34% to 51%.
• The percentages who were in third or greater relapse fell from 14% to 2%.
• The percentages undergoing ≥1 HSCT before tisagenlecleucel infusion fell from 37% to 15%.
• Overall, 34.5% of 911 patients received post-infusion HSCT.

In the big picture, the findings suggest that the therapy can be considered more than “a last resort for patients in a second or greater relapse or who are refractory,” Dr. Rouce said. By offering CAR T-cell therapy to earlier-stage patients, she said, “when they’re less sick, when they have less comorbidities, and when their organs are functioning better, we could potentially save them from having to go on to a transplant.”

Dr. Shah said the findings indicate that “a substantial number of patients are surviving. It’s remarkable actually. Prior to tisagenlecleucel, patients had dismal outcomes from standard chemotherapy.”

She added that the study suggests “providers are getting much more comfortable with getting their patients in the best shape prior to getting CAR T-cell therapy. Outcomes are improving as providers expand the use of CAR T-cell therapy to patients who are less heavily pretreated and have lower disease burden.”

Moving forward, “at some point there will likely be a plateau in terms of how good the outcomes can be.” And there will be discussion of the role of HSCT.

“We’ll figure out some of the nuances about which patients need transplants and which can avoid them. But curative potential is growing. With or without transplant, this is ultimately going to lead to a much higher fraction of patients being cured who previously would not have been cured,” she said. “That’s the bottom line.”

As for adverse effects, Dr. Shah said “disease burden has a pretty direct relationship with side effects and toxicities. If you have more disease, you have more severe side effects.”

Reducing disease burden will reduce side effects, she said. Also, “we’re getting a lot better at managing these toxicities. Eliminating some of the more toxic chemotherapy through earlier use of CAR T-cells in chemotherapy-refractory patients may well help reduce therapy burden and improve long-term survival outcomes, she added.

As for cost, drugs.com reports that the therapy runs to more than $612,000 per infusion. But Dr. Shah said insurers are covering the treatment. She added that there are efforts to expand the indication so CAR T-cell therapy can be used earlier in patients who are chemotherapy-refractory.

Novartis funded the study. Dr. Shah discloses ties with Lentigen, VOR, and CARGO, ImmunoACT, and Sobi. Dr. Rouce reports relationships with Pfizer and Novartis.

In just 4 years, there’s been a significant evolution in the profile of pediatric and young adult patients who’ve taken the chimeric antigen receptor (CAR) T-cell immunotherapy known as tisagenlecleucel (Kymriah) for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), a new industry-funded study finds.

It’s becoming more common for patients with less severe disease to undergo the treatment, often bypassing hematopoietic stem cell transplantation (HSCT), and survival is on the rise.

From 2018 to 2022, the percentage of patients in an international cohort who had disease burden of ≥50% fell from 18% to 4%, researchers reported at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Median relapse-free survival in patients who didn’t undergo post-infusion HSCT grew from 18 months in 2018 to 27 months in 2020. It was not estimable in 2021.

“This introduction of the therapy is changing the treatment landscape of how we look at refractory B-ALL, where the standard of care previously would be to proceed to transplant. This therapy is actually reducing the use of transplant, which has lots of morbidity and mortality associated with it,” Texas Children’s Cancer Center hematologist-oncologist Rayne H. Rouce, MD, who led the study, said in an interview.

Tisagenlecleucel received Food and Drug Administration approval in 2017, said Nirali N. Shah, MD, MHSc, head of the Pediatric Oncology Branch’s Hematologic Malignancies Section at the National Cancer Institute, in an interview. Dr. Shah is familiar with the study findings but didn’t take part in the research.

Remission rates have been around 60%-70%, Dr. Shah said, although that rate is “likely higher” now because of gains in experience and improvement in disease burden prior to therapy. 

The new findings fill a knowledge gap about real-world outcomes since a lot of the prior data was based on investigational CAR T-cell products, she said.

The noninterventional, prospective, longitudinal study, funded by tisagenlecleucel manufacturer Novartis, tracked 974 patients up to age 25 who received tisagenlecleucel in the United States, Canada, Korea, and Taiwan.

The study found that between 2018 and 2022:

• The percentage of patients who received treatment while in morphological complete remission grew from 34% to 51%.
• The percentages who were in third or greater relapse fell from 14% to 2%.
• The percentages undergoing ≥1 HSCT before tisagenlecleucel infusion fell from 37% to 15%.
• Overall, 34.5% of 911 patients received post-infusion HSCT.

In the big picture, the findings suggest that the therapy can be considered more than “a last resort for patients in a second or greater relapse or who are refractory,” Dr. Rouce said. By offering CAR T-cell therapy to earlier-stage patients, she said, “when they’re less sick, when they have less comorbidities, and when their organs are functioning better, we could potentially save them from having to go on to a transplant.”

Dr. Shah said the findings indicate that “a substantial number of patients are surviving. It’s remarkable actually. Prior to tisagenlecleucel, patients had dismal outcomes from standard chemotherapy.”

She added that the study suggests “providers are getting much more comfortable with getting their patients in the best shape prior to getting CAR T-cell therapy. Outcomes are improving as providers expand the use of CAR T-cell therapy to patients who are less heavily pretreated and have lower disease burden.”

Moving forward, “at some point there will likely be a plateau in terms of how good the outcomes can be.” And there will be discussion of the role of HSCT.

“We’ll figure out some of the nuances about which patients need transplants and which can avoid them. But curative potential is growing. With or without transplant, this is ultimately going to lead to a much higher fraction of patients being cured who previously would not have been cured,” she said. “That’s the bottom line.”

As for adverse effects, Dr. Shah said “disease burden has a pretty direct relationship with side effects and toxicities. If you have more disease, you have more severe side effects.”

Reducing disease burden will reduce side effects, she said. Also, “we’re getting a lot better at managing these toxicities. Eliminating some of the more toxic chemotherapy through earlier use of CAR T-cells in chemotherapy-refractory patients may well help reduce therapy burden and improve long-term survival outcomes, she added.

As for cost, drugs.com reports that the therapy runs to more than $612,000 per infusion. But Dr. Shah said insurers are covering the treatment. She added that there are efforts to expand the indication so CAR T-cell therapy can be used earlier in patients who are chemotherapy-refractory.

Novartis funded the study. Dr. Shah discloses ties with Lentigen, VOR, and CARGO, ImmunoACT, and Sobi. Dr. Rouce reports relationships with Pfizer and Novartis.

A reformulation of the multiple cancer drugs in the combination treatment known as BEACOPP boosted progression free survival vs. the original therapy in adult patients with advanced-stage classical Hodgkin lymphoma, a large, open-label, phase III trial found.

At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”

As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”

Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.

However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.

In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.

In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.

There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.

Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).

Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.

Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.

In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”

Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.

Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.

A reformulation of the multiple cancer drugs in the combination treatment known as BEACOPP boosted progression free survival vs. the original therapy in adult patients with advanced-stage classical Hodgkin lymphoma, a large, open-label, phase III trial found.

At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”

As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”

Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.

However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.

In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.

In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.

There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.

Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).

Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.

Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.

In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”

Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.

Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.

A reformulation of the multiple cancer drugs in the combination treatment known as BEACOPP boosted progression free survival vs. the original therapy in adult patients with advanced-stage classical Hodgkin lymphoma, a large, open-label, phase III trial found.

At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”

As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”

Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.

However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.

In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.

In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.

There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.

Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).

Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.

Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.

In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”

Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.

Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.

The topic of head and neck cancer is especially timely since the disease is evolving. A hematologist/oncologist with the Association of VA Hematology/Oncology (AVAHO) told colleagues that specialists are grappling with how to de-escalate treatment.

Molly Tokaz, MD, of Veterans Affairs Puget Sound Health Care and the University of Washington said tobacco is fading as a cause as fewer people smoke, and that human papillomavirus (HPV) is triggering more cases. HPV-positive patients have better prognoses, raising the prospect that their treatment could be adjusted.

“Instead of increasing the amount of therapy we're giving, we’re trying to peel it back,” she said. “If they’re going to respond no matter what we do, why are we going in with these huge weapons of mass destruction if we can get the same results with something more like a light infantry?”

Tokaz spoke about deescalating therapy at a May 2024 regional AVAHO meeting in Seattle that was focused on head and neck cancer. She elaborated on her presentation in an interview with Federal Practitioner. according to Tokaz, 90% of head and neck cancers are mucosal squamous cell carcinomas (SCC). HPV is associated specifically with nasopharyngeal cancer, which is distinct from SCC, and oropharyngeal cancer, which has been linked to better prognoses.

HPV-positive head and neck cancer is a unique entity with its own epidemiology, clinical prognosis, and treatment. “Patients tend to be younger without the same number of comorbid conditions,” Tokaz said. “Some of them are never smokers or light smokers. So, it's a different demographic than we’ve seen traditionally.”

The bad news is that HPV-associated head and neck cancer numbers are on the rise. Fortunately, outcomes tend to be better for the HPV-positive forms.

As for therapy for head and neck cancer, immunotherapy and targeted therapy play smaller roles than in some other cancers because the form tends to be diagnosed in early stages before metastases appear. Surgery, chemotherapy, and radiation remain the major treatments. According to Tokaz’s presentation, surgery, or radiation—often with minimal adjuvant chemotherapy—can be appropriate for the earliest stage I and II cases of head and neck SCC. (She noted that HPV-positive oropharyngeal squamous cell carcinoma has its own staging system.)

Stage I and II cases make up 15% of new diagnoses and have a 5-year survival rate of > 70%. “In the earliest days, our main role was to make radiation work better and reduce it while adding a minimum amount of toxicity mutations,” she said. “Chemotherapy can help, but it’s only demonstrated improvement in overall survival in patients with positive surgical margins and extracapsular extension.”

In Stage III, IVA, and IVB cases, which make up 70% of new diagnoses, chemotherapy plus radiation is recommended. Five-year survival drops to 30% to 50%. Finally, 10% of new diagnoses are Stage IVC, which is incurable and median survival is < 1 year.

Since HPV-positive patients generally have better prognoses, oncologists are considering how to adjust their treatment. However, Tokaz notes that clinical trials have not shown a benefit from less intensive treatment in these patients. “At this point, we still treat them the same way as HPV-negative patients. But it's an ongoing area of research.”

Researchers are also exploring how to optimize regimens in patients ineligible for treatment with the chemotherapy agent cisplatin. “These folks have been traditionally excluded from clinical trials because they’re sicker,” Tokaz explained. “Researchers normally want the fittest and the best patients [in trials]. If you give a drug to someone with a lot of other comorbid conditions, they might not do as well with it, and it makes your drug look bad.”

Figuring out how to treat these patients is an especially urgent task in head and neck cancer because so many patients are frail and have comorbidities. More globally, Tokaz said the rise of HPV-related head and neck cancer highlights the importance of HPV vaccination, which is crucial for preventing cervical and anal cancer in addition to head and neck cancer. “HPV vaccination for children and young adults is crucial.”

Molly Tokaz, MD, reported no relevant financial relationships.

The topic of head and neck cancer is especially timely since the disease is evolving. A hematologist/oncologist with the Association of VA Hematology/Oncology (AVAHO) told colleagues that specialists are grappling with how to de-escalate treatment.

Molly Tokaz, MD, of Veterans Affairs Puget Sound Health Care and the University of Washington said tobacco is fading as a cause as fewer people smoke, and that human papillomavirus (HPV) is triggering more cases. HPV-positive patients have better prognoses, raising the prospect that their treatment could be adjusted.

“Instead of increasing the amount of therapy we're giving, we’re trying to peel it back,” she said. “If they’re going to respond no matter what we do, why are we going in with these huge weapons of mass destruction if we can get the same results with something more like a light infantry?”

Tokaz spoke about deescalating therapy at a May 2024 regional AVAHO meeting in Seattle that was focused on head and neck cancer. She elaborated on her presentation in an interview with Federal Practitioner. according to Tokaz, 90% of head and neck cancers are mucosal squamous cell carcinomas (SCC). HPV is associated specifically with nasopharyngeal cancer, which is distinct from SCC, and oropharyngeal cancer, which has been linked to better prognoses.

HPV-positive head and neck cancer is a unique entity with its own epidemiology, clinical prognosis, and treatment. “Patients tend to be younger without the same number of comorbid conditions,” Tokaz said. “Some of them are never smokers or light smokers. So, it's a different demographic than we’ve seen traditionally.”

The bad news is that HPV-associated head and neck cancer numbers are on the rise. Fortunately, outcomes tend to be better for the HPV-positive forms.

As for therapy for head and neck cancer, immunotherapy and targeted therapy play smaller roles than in some other cancers because the form tends to be diagnosed in early stages before metastases appear. Surgery, chemotherapy, and radiation remain the major treatments. According to Tokaz’s presentation, surgery, or radiation—often with minimal adjuvant chemotherapy—can be appropriate for the earliest stage I and II cases of head and neck SCC. (She noted that HPV-positive oropharyngeal squamous cell carcinoma has its own staging system.)

Stage I and II cases make up 15% of new diagnoses and have a 5-year survival rate of > 70%. “In the earliest days, our main role was to make radiation work better and reduce it while adding a minimum amount of toxicity mutations,” she said. “Chemotherapy can help, but it’s only demonstrated improvement in overall survival in patients with positive surgical margins and extracapsular extension.”

In Stage III, IVA, and IVB cases, which make up 70% of new diagnoses, chemotherapy plus radiation is recommended. Five-year survival drops to 30% to 50%. Finally, 10% of new diagnoses are Stage IVC, which is incurable and median survival is < 1 year.

Since HPV-positive patients generally have better prognoses, oncologists are considering how to adjust their treatment. However, Tokaz notes that clinical trials have not shown a benefit from less intensive treatment in these patients. “At this point, we still treat them the same way as HPV-negative patients. But it's an ongoing area of research.”

Researchers are also exploring how to optimize regimens in patients ineligible for treatment with the chemotherapy agent cisplatin. “These folks have been traditionally excluded from clinical trials because they’re sicker,” Tokaz explained. “Researchers normally want the fittest and the best patients [in trials]. If you give a drug to someone with a lot of other comorbid conditions, they might not do as well with it, and it makes your drug look bad.”

Figuring out how to treat these patients is an especially urgent task in head and neck cancer because so many patients are frail and have comorbidities. More globally, Tokaz said the rise of HPV-related head and neck cancer highlights the importance of HPV vaccination, which is crucial for preventing cervical and anal cancer in addition to head and neck cancer. “HPV vaccination for children and young adults is crucial.”

Molly Tokaz, MD, reported no relevant financial relationships.

The topic of head and neck cancer is especially timely since the disease is evolving. A hematologist/oncologist with the Association of VA Hematology/Oncology (AVAHO) told colleagues that specialists are grappling with how to de-escalate treatment.

Molly Tokaz, MD, of Veterans Affairs Puget Sound Health Care and the University of Washington said tobacco is fading as a cause as fewer people smoke, and that human papillomavirus (HPV) is triggering more cases. HPV-positive patients have better prognoses, raising the prospect that their treatment could be adjusted.

“Instead of increasing the amount of therapy we're giving, we’re trying to peel it back,” she said. “If they’re going to respond no matter what we do, why are we going in with these huge weapons of mass destruction if we can get the same results with something more like a light infantry?”

Tokaz spoke about deescalating therapy at a May 2024 regional AVAHO meeting in Seattle that was focused on head and neck cancer. She elaborated on her presentation in an interview with Federal Practitioner. according to Tokaz, 90% of head and neck cancers are mucosal squamous cell carcinomas (SCC). HPV is associated specifically with nasopharyngeal cancer, which is distinct from SCC, and oropharyngeal cancer, which has been linked to better prognoses.

HPV-positive head and neck cancer is a unique entity with its own epidemiology, clinical prognosis, and treatment. “Patients tend to be younger without the same number of comorbid conditions,” Tokaz said. “Some of them are never smokers or light smokers. So, it's a different demographic than we’ve seen traditionally.”

The bad news is that HPV-associated head and neck cancer numbers are on the rise. Fortunately, outcomes tend to be better for the HPV-positive forms.

As for therapy for head and neck cancer, immunotherapy and targeted therapy play smaller roles than in some other cancers because the form tends to be diagnosed in early stages before metastases appear. Surgery, chemotherapy, and radiation remain the major treatments. According to Tokaz’s presentation, surgery, or radiation—often with minimal adjuvant chemotherapy—can be appropriate for the earliest stage I and II cases of head and neck SCC. (She noted that HPV-positive oropharyngeal squamous cell carcinoma has its own staging system.)

Stage I and II cases make up 15% of new diagnoses and have a 5-year survival rate of > 70%. “In the earliest days, our main role was to make radiation work better and reduce it while adding a minimum amount of toxicity mutations,” she said. “Chemotherapy can help, but it’s only demonstrated improvement in overall survival in patients with positive surgical margins and extracapsular extension.”

In Stage III, IVA, and IVB cases, which make up 70% of new diagnoses, chemotherapy plus radiation is recommended. Five-year survival drops to 30% to 50%. Finally, 10% of new diagnoses are Stage IVC, which is incurable and median survival is < 1 year.

Since HPV-positive patients generally have better prognoses, oncologists are considering how to adjust their treatment. However, Tokaz notes that clinical trials have not shown a benefit from less intensive treatment in these patients. “At this point, we still treat them the same way as HPV-negative patients. But it's an ongoing area of research.”

Researchers are also exploring how to optimize regimens in patients ineligible for treatment with the chemotherapy agent cisplatin. “These folks have been traditionally excluded from clinical trials because they’re sicker,” Tokaz explained. “Researchers normally want the fittest and the best patients [in trials]. If you give a drug to someone with a lot of other comorbid conditions, they might not do as well with it, and it makes your drug look bad.”

Figuring out how to treat these patients is an especially urgent task in head and neck cancer because so many patients are frail and have comorbidities. More globally, Tokaz said the rise of HPV-related head and neck cancer highlights the importance of HPV vaccination, which is crucial for preventing cervical and anal cancer in addition to head and neck cancer. “HPV vaccination for children and young adults is crucial.”

Molly Tokaz, MD, reported no relevant financial relationships.

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

From India to Brazil, researchers around the world are experimenting with ways to simplify the complex production of chimeric antigen receptor (CAR) T cells and lower the treatment’s sky-high costs.

In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.

At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.

“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”

However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.

A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.

“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.

Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
 

Harnessing the Power of T-Cells

Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.

Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.

These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”

As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”

In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”

The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
 

Treatment: Individual, Complex, and Costly

Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.

“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”

Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”

Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”

Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
 

Taking Gene Therapy In-House

As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.

“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”

167902_Kadauke_Stephan_PA_web.jpg

India: Big Hopes for Homegrown Technology

In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.

Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.

In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.

Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.

According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
 

A US-Brazil Partnership Holds Promise

Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.

“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”

According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.

The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.

Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.

From India to Brazil, researchers around the world are experimenting with ways to simplify the complex production of chimeric antigen receptor (CAR) T cells and lower the treatment’s sky-high costs.

In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.

At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.

“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”

However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.

A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.

“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.

Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
 

Harnessing the Power of T-Cells

Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.

Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.

These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”

As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”

In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”

The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
 

Treatment: Individual, Complex, and Costly

Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.

“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”

Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”

Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”

Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
 

Taking Gene Therapy In-House

As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.

“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”

167902_Kadauke_Stephan_PA_web.jpg

India: Big Hopes for Homegrown Technology

In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.

Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.

In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.

Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.

According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
 

A US-Brazil Partnership Holds Promise

Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.

“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”

According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.

The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.

Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.

From India to Brazil, researchers around the world are experimenting with ways to simplify the complex production of chimeric antigen receptor (CAR) T cells and lower the treatment’s sky-high costs.

In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.

At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.

“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”

However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.

A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.

“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.

Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
 

Harnessing the Power of T-Cells

Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.

Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.

These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”

As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”

In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”

The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
 

Treatment: Individual, Complex, and Costly

Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.

“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”

Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”

Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”

Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
 

Taking Gene Therapy In-House

As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.

“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”

167902_Kadauke_Stephan_PA_web.jpg

India: Big Hopes for Homegrown Technology

In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.

Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.

In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.

Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.

According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
 

A US-Brazil Partnership Holds Promise

Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.

“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”

According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.

The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.

Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.