Cellular Therapy

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.

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.

The US Food and Drug Administration (FDA) has granted accelerated approval to lisocabtagene maraleucel (Breyanzi, Juno Therapeutics /Bristol Myers Squibb) for adults with relapsed or refractory follicular lymphoma who have received two or more prior lines of systemic therapy.

The approval broadens the use of the CAR T-cell therapy for follicular lymphoma. Previous approval was limited to relapsed/refractory grade 3B disease. Lisocabtagene maraleucel also carries relapsed/refractory B-cell lymphoma and lymphocytic leukemia indications.

The new approval was based on the phase 2 single-arm TRANSCEND FL trial in 94 patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.

Adequate bone marrow function and a performance score of 0-1 were required.

Patients received a single dose 2-7 days after completing lymphodepleting chemotherapy.

The overall response rate was 95.7%. The median duration of response was not reached after a median follow-up of 16.8 months.

The most common nonlaboratory adverse events, occurring in at least 20% of patients, were cytokine release syndrome, headache, musculoskeletal pain, fatigue, constipation, and fever.

Lisocabtagene maraleucel is available only through a Risk Evaluation and Mitigation Strategy program due to the risk for fatal cytokine release syndrome and neurologic toxicities.

A single treatment is almost a half million dollars, according to drugs.com.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted accelerated approval to lisocabtagene maraleucel (Breyanzi, Juno Therapeutics /Bristol Myers Squibb) for adults with relapsed or refractory follicular lymphoma who have received two or more prior lines of systemic therapy.

The approval broadens the use of the CAR T-cell therapy for follicular lymphoma. Previous approval was limited to relapsed/refractory grade 3B disease. Lisocabtagene maraleucel also carries relapsed/refractory B-cell lymphoma and lymphocytic leukemia indications.

The new approval was based on the phase 2 single-arm TRANSCEND FL trial in 94 patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.

Adequate bone marrow function and a performance score of 0-1 were required.

Patients received a single dose 2-7 days after completing lymphodepleting chemotherapy.

The overall response rate was 95.7%. The median duration of response was not reached after a median follow-up of 16.8 months.

The most common nonlaboratory adverse events, occurring in at least 20% of patients, were cytokine release syndrome, headache, musculoskeletal pain, fatigue, constipation, and fever.

Lisocabtagene maraleucel is available only through a Risk Evaluation and Mitigation Strategy program due to the risk for fatal cytokine release syndrome and neurologic toxicities.

A single treatment is almost a half million dollars, according to drugs.com.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted accelerated approval to lisocabtagene maraleucel (Breyanzi, Juno Therapeutics /Bristol Myers Squibb) for adults with relapsed or refractory follicular lymphoma who have received two or more prior lines of systemic therapy.

The approval broadens the use of the CAR T-cell therapy for follicular lymphoma. Previous approval was limited to relapsed/refractory grade 3B disease. Lisocabtagene maraleucel also carries relapsed/refractory B-cell lymphoma and lymphocytic leukemia indications.

The new approval was based on the phase 2 single-arm TRANSCEND FL trial in 94 patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.

Adequate bone marrow function and a performance score of 0-1 were required.

Patients received a single dose 2-7 days after completing lymphodepleting chemotherapy.

The overall response rate was 95.7%. The median duration of response was not reached after a median follow-up of 16.8 months.

The most common nonlaboratory adverse events, occurring in at least 20% of patients, were cytokine release syndrome, headache, musculoskeletal pain, fatigue, constipation, and fever.

Lisocabtagene maraleucel is available only through a Risk Evaluation and Mitigation Strategy program due to the risk for fatal cytokine release syndrome and neurologic toxicities.

A single treatment is almost a half million dollars, according to drugs.com.
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

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.”

Children&#039;s Hospital of Philadelphia

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.”

Children&#039;s Hospital of Philadelphia

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.”

Children&#039;s Hospital of Philadelphia

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.

Key novel genetic signatures in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL) strongly correlate with improved survival outcomes in treatment with the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel).

“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”

The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.

Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.

In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”

Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.

Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.

After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10^-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10^-7) after treatment with axi-cel, compared with those who did not have the signature.

The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”

Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10^-13) and progression-free survival (HR, 7.58; P = 2.70 x 10^-14).

The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.

“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.

Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.

Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.

Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”

“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.

A key caveat is that the results need more validation before they true gain clinical value, he noted.

“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”

Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.

“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.” 

Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.

“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.

“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”

Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.

Key novel genetic signatures in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL) strongly correlate with improved survival outcomes in treatment with the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel).

“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”

The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.

Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.

In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”

Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.

Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.

After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10^-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10^-7) after treatment with axi-cel, compared with those who did not have the signature.

The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”

Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10^-13) and progression-free survival (HR, 7.58; P = 2.70 x 10^-14).

The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.

“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.

Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.

Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.

Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”

“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.

A key caveat is that the results need more validation before they true gain clinical value, he noted.

“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”

Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.

“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.” 

Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.

“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.

“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”

Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.

Key novel genetic signatures in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL) strongly correlate with improved survival outcomes in treatment with the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel).

“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”

The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.

Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.

In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”

Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.

Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.

After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10^-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10^-7) after treatment with axi-cel, compared with those who did not have the signature.

The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”

Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10^-13) and progression-free survival (HR, 7.58; P = 2.70 x 10^-14).

The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.

“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.

Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.

Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.

Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”

“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.

A key caveat is that the results need more validation before they true gain clinical value, he noted.

“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”

Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.

“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.” 

Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.

“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.

“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”

Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.

A novel CD19 chimeric antigen responder (CAR) T-cell therapy administered in exceptionally low doses and designed to reinvigorate exhausted T-cells shows impressive early results in the treatment of patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).

“Our study showed a manageable safety profile in r/r DLBCL/B-ALL, with promising breakthrough efficacy of a 100% complete remission in all dose groups,” said first author Jingjing Ren, MD, PhD, associate director of research and development with Leman Biotech in Shenzhen, China. Dr. Ren presented these findings at the American Association for Cancer Research annual meeting held in San Diego.

While CD19 CAR T-cell therapy has been transformative in the treatment of relapsed B -cell hematological malignancies in recent years, more than half of patients relapse within a year because of inadequate CAR T persistence.

To address the problem, Dr. Ren and her colleagues developed a metabolically armed, interleukin (IL)-10-expressing CAR T-cell product called Meta10-19 for the treatment patients with r/r DLBCL or r/r B-ALL.

According to the authors, the IL-10-expressing CAR T-cells trigger “stem-like memory responses” in various lymphoid organs, which prompt a “robust tumor eradication and durable protection,” and hence, better persistence.

Preclinical studies in mice showed the Meta10-19 CAR T-cells exhibited substantially higher expansion of approximately 100-fold compared with a control CD19 CAR-T product.

Therefore, “we dramatically reduced the dose to approximately 1% to 5% of commercial products for the IL-10-expressing CD19 CAR-T for patients,” coauthor Yugang Guo, PhD, cofounder and president of Leman Biotech said in an interview.

For the ongoing, open-label clinical trial, 12 adult patients with r/r DLBCL or r/r B-ALL and confirmed CD19 expression at a hospital center in China were enrolled between December 2022 and November 2023 and treated in three cohorts, receiving doses that corresponded to 1%, 2.5%, or 5% of the doses of other commercialized CAR-T infusion products.

All patients also underwent lympho-depleting chemotherapy with cyclophosphamide and fludarabine prior to the CAR T-cell infusion.

Six patients had r/r DLBCL and the other six had r/r B-ALL; their median age was 47 and their median time since diagnosis was 1 year.

In the single-arm, intent-to-treat analysis, the treatment induced a complete remission in all 12 patients, as evaluated by PET-CT scan, nuclear magnetic resonance (NMR) spectroscopy, or minimal residual disease assessment of bone marrow.

The median time to best response was 1 month (range 0.5 to 2.2 months).

There were no cases of severe cytokine storm syndrome or neurotoxicity, which are among key limitations with current commercial CAR-T products.

All of the patients continued to have a complete remission at 3 months. Two of the 12 patients, both with B-ALL, experienced relapses, one after 4.7 months and the other at 8 months.

The authors reported that the first treated patient had maintained continuous remission as of 9 months.

In comparison with the much higher full doses of commercial CD19 CAR-T products, only about 50% of patients with DLBCL and 70% of B-ALL patients have been shown to achieve CR at 3 months, the authors reported.

“Our IL-10 expressing CAR-T sustains CR at 3 months post infusion in the context of not following allogeneic hematopoietic stem cell transplant, which suggests IL-10 expressing CAR-T is more resistant to relapse,” Dr. Guo said.

In terms of safety, six patients with DLBCL and four with B-ALL experienced grade 1 cytokine release syndrome (CRS), and two patients with B-ALL developed grade 2 CRS. There were no grade 3 or 4 CRS cases.

One patient with B-ALL developed grade 3 ICANS.

Grade 3-4 cytopenias occurred in most patients, but all were limited to no later than 90 days.

“We observed reduced CRS, with no level 3 or 4, or ICANS,” Dr. Guo said. “There was increased cytopenia, but still manageable, compared with commercial products.”

Of note, the Meta10-19 cells showed efficacy in the extremely low infusion doses even among patients with bulky mass (≥ 7.5 cm) of DLBCL, which is associated with an increased risk of relapse.

One patient had primary central nervous system lymphoma (PCNSL), a rare form of DLBCL that is known to have the worst prognosis of all non-Hodgkin lymphomas.

Due to the unique nature of CNS primary tumors, the CAR T-cell infusion dose was further reduced to 1% of the standard dose for the patient.

The patient maintained complete remission for more than 8 months before relapsing in periphery blood, but not in the CNS, Dr. Guo noted.

“Luckily, this relapse has been easily controlled by chemotherapy, and the patient is maintaining complete remission again now,” Dr. Guo said.
 

Mechanisms?

Dr. Guo noted that the mechanism believed to explain the improvements despite such low doses is that “IL-10-expressing CAR-T exhibits enhanced proliferation, cytotoxicity, and stem-like antitumor memory due to enhanced metabolic activities of oxidative phosphorylation.”

The authors noted that a key major factor limiting accessibility to CAR-T therapies is the lengthy production cycle and high costs; however, the “extremely low doses of 1% to 5% can significantly reduce the production cycle and cost of CAR T-cell therapies, increasing accessibility,” they wrote in a press statement.

Currently, more than 20 patients have achieved a CR overall, and studies with a larger cohort and longer follow-up are ongoing, Dr. Guo reported.

The research team plans to launch further clinical investigation this year into patients with solid tumors.

Commenting on the study, Hongbo Chi, PhD, the Robert G. Webster Endowed Chair in Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, noted that, based on the abstract, “the effects are quite remarkable, considering the therapeutic efficacy observed even at the low dose.

“Results from more patients are needed to fully validate these findings, but the results to date are very encouraging,” he said.

The study was sponsored by Leman Biotech. Dr. Chi had no disclosures to report.

A novel CD19 chimeric antigen responder (CAR) T-cell therapy administered in exceptionally low doses and designed to reinvigorate exhausted T-cells shows impressive early results in the treatment of patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).

“Our study showed a manageable safety profile in r/r DLBCL/B-ALL, with promising breakthrough efficacy of a 100% complete remission in all dose groups,” said first author Jingjing Ren, MD, PhD, associate director of research and development with Leman Biotech in Shenzhen, China. Dr. Ren presented these findings at the American Association for Cancer Research annual meeting held in San Diego.

While CD19 CAR T-cell therapy has been transformative in the treatment of relapsed B -cell hematological malignancies in recent years, more than half of patients relapse within a year because of inadequate CAR T persistence.

To address the problem, Dr. Ren and her colleagues developed a metabolically armed, interleukin (IL)-10-expressing CAR T-cell product called Meta10-19 for the treatment patients with r/r DLBCL or r/r B-ALL.

According to the authors, the IL-10-expressing CAR T-cells trigger “stem-like memory responses” in various lymphoid organs, which prompt a “robust tumor eradication and durable protection,” and hence, better persistence.

Preclinical studies in mice showed the Meta10-19 CAR T-cells exhibited substantially higher expansion of approximately 100-fold compared with a control CD19 CAR-T product.

Therefore, “we dramatically reduced the dose to approximately 1% to 5% of commercial products for the IL-10-expressing CD19 CAR-T for patients,” coauthor Yugang Guo, PhD, cofounder and president of Leman Biotech said in an interview.

For the ongoing, open-label clinical trial, 12 adult patients with r/r DLBCL or r/r B-ALL and confirmed CD19 expression at a hospital center in China were enrolled between December 2022 and November 2023 and treated in three cohorts, receiving doses that corresponded to 1%, 2.5%, or 5% of the doses of other commercialized CAR-T infusion products.

All patients also underwent lympho-depleting chemotherapy with cyclophosphamide and fludarabine prior to the CAR T-cell infusion.

Six patients had r/r DLBCL and the other six had r/r B-ALL; their median age was 47 and their median time since diagnosis was 1 year.

In the single-arm, intent-to-treat analysis, the treatment induced a complete remission in all 12 patients, as evaluated by PET-CT scan, nuclear magnetic resonance (NMR) spectroscopy, or minimal residual disease assessment of bone marrow.

The median time to best response was 1 month (range 0.5 to 2.2 months).

There were no cases of severe cytokine storm syndrome or neurotoxicity, which are among key limitations with current commercial CAR-T products.

All of the patients continued to have a complete remission at 3 months. Two of the 12 patients, both with B-ALL, experienced relapses, one after 4.7 months and the other at 8 months.

The authors reported that the first treated patient had maintained continuous remission as of 9 months.

In comparison with the much higher full doses of commercial CD19 CAR-T products, only about 50% of patients with DLBCL and 70% of B-ALL patients have been shown to achieve CR at 3 months, the authors reported.

“Our IL-10 expressing CAR-T sustains CR at 3 months post infusion in the context of not following allogeneic hematopoietic stem cell transplant, which suggests IL-10 expressing CAR-T is more resistant to relapse,” Dr. Guo said.

In terms of safety, six patients with DLBCL and four with B-ALL experienced grade 1 cytokine release syndrome (CRS), and two patients with B-ALL developed grade 2 CRS. There were no grade 3 or 4 CRS cases.

One patient with B-ALL developed grade 3 ICANS.

Grade 3-4 cytopenias occurred in most patients, but all were limited to no later than 90 days.

“We observed reduced CRS, with no level 3 or 4, or ICANS,” Dr. Guo said. “There was increased cytopenia, but still manageable, compared with commercial products.”

Of note, the Meta10-19 cells showed efficacy in the extremely low infusion doses even among patients with bulky mass (≥ 7.5 cm) of DLBCL, which is associated with an increased risk of relapse.

One patient had primary central nervous system lymphoma (PCNSL), a rare form of DLBCL that is known to have the worst prognosis of all non-Hodgkin lymphomas.

Due to the unique nature of CNS primary tumors, the CAR T-cell infusion dose was further reduced to 1% of the standard dose for the patient.

The patient maintained complete remission for more than 8 months before relapsing in periphery blood, but not in the CNS, Dr. Guo noted.

“Luckily, this relapse has been easily controlled by chemotherapy, and the patient is maintaining complete remission again now,” Dr. Guo said.
 

Mechanisms?

Dr. Guo noted that the mechanism believed to explain the improvements despite such low doses is that “IL-10-expressing CAR-T exhibits enhanced proliferation, cytotoxicity, and stem-like antitumor memory due to enhanced metabolic activities of oxidative phosphorylation.”

The authors noted that a key major factor limiting accessibility to CAR-T therapies is the lengthy production cycle and high costs; however, the “extremely low doses of 1% to 5% can significantly reduce the production cycle and cost of CAR T-cell therapies, increasing accessibility,” they wrote in a press statement.

Currently, more than 20 patients have achieved a CR overall, and studies with a larger cohort and longer follow-up are ongoing, Dr. Guo reported.

The research team plans to launch further clinical investigation this year into patients with solid tumors.

Commenting on the study, Hongbo Chi, PhD, the Robert G. Webster Endowed Chair in Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, noted that, based on the abstract, “the effects are quite remarkable, considering the therapeutic efficacy observed even at the low dose.

“Results from more patients are needed to fully validate these findings, but the results to date are very encouraging,” he said.

The study was sponsored by Leman Biotech. Dr. Chi had no disclosures to report.

A novel CD19 chimeric antigen responder (CAR) T-cell therapy administered in exceptionally low doses and designed to reinvigorate exhausted T-cells shows impressive early results in the treatment of patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).

“Our study showed a manageable safety profile in r/r DLBCL/B-ALL, with promising breakthrough efficacy of a 100% complete remission in all dose groups,” said first author Jingjing Ren, MD, PhD, associate director of research and development with Leman Biotech in Shenzhen, China. Dr. Ren presented these findings at the American Association for Cancer Research annual meeting held in San Diego.

While CD19 CAR T-cell therapy has been transformative in the treatment of relapsed B -cell hematological malignancies in recent years, more than half of patients relapse within a year because of inadequate CAR T persistence.

To address the problem, Dr. Ren and her colleagues developed a metabolically armed, interleukin (IL)-10-expressing CAR T-cell product called Meta10-19 for the treatment patients with r/r DLBCL or r/r B-ALL.

According to the authors, the IL-10-expressing CAR T-cells trigger “stem-like memory responses” in various lymphoid organs, which prompt a “robust tumor eradication and durable protection,” and hence, better persistence.

Preclinical studies in mice showed the Meta10-19 CAR T-cells exhibited substantially higher expansion of approximately 100-fold compared with a control CD19 CAR-T product.

Therefore, “we dramatically reduced the dose to approximately 1% to 5% of commercial products for the IL-10-expressing CD19 CAR-T for patients,” coauthor Yugang Guo, PhD, cofounder and president of Leman Biotech said in an interview.

For the ongoing, open-label clinical trial, 12 adult patients with r/r DLBCL or r/r B-ALL and confirmed CD19 expression at a hospital center in China were enrolled between December 2022 and November 2023 and treated in three cohorts, receiving doses that corresponded to 1%, 2.5%, or 5% of the doses of other commercialized CAR-T infusion products.

All patients also underwent lympho-depleting chemotherapy with cyclophosphamide and fludarabine prior to the CAR T-cell infusion.

Six patients had r/r DLBCL and the other six had r/r B-ALL; their median age was 47 and their median time since diagnosis was 1 year.

In the single-arm, intent-to-treat analysis, the treatment induced a complete remission in all 12 patients, as evaluated by PET-CT scan, nuclear magnetic resonance (NMR) spectroscopy, or minimal residual disease assessment of bone marrow.

The median time to best response was 1 month (range 0.5 to 2.2 months).

There were no cases of severe cytokine storm syndrome or neurotoxicity, which are among key limitations with current commercial CAR-T products.

All of the patients continued to have a complete remission at 3 months. Two of the 12 patients, both with B-ALL, experienced relapses, one after 4.7 months and the other at 8 months.

The authors reported that the first treated patient had maintained continuous remission as of 9 months.

In comparison with the much higher full doses of commercial CD19 CAR-T products, only about 50% of patients with DLBCL and 70% of B-ALL patients have been shown to achieve CR at 3 months, the authors reported.

“Our IL-10 expressing CAR-T sustains CR at 3 months post infusion in the context of not following allogeneic hematopoietic stem cell transplant, which suggests IL-10 expressing CAR-T is more resistant to relapse,” Dr. Guo said.

In terms of safety, six patients with DLBCL and four with B-ALL experienced grade 1 cytokine release syndrome (CRS), and two patients with B-ALL developed grade 2 CRS. There were no grade 3 or 4 CRS cases.

One patient with B-ALL developed grade 3 ICANS.

Grade 3-4 cytopenias occurred in most patients, but all were limited to no later than 90 days.

“We observed reduced CRS, with no level 3 or 4, or ICANS,” Dr. Guo said. “There was increased cytopenia, but still manageable, compared with commercial products.”

Of note, the Meta10-19 cells showed efficacy in the extremely low infusion doses even among patients with bulky mass (≥ 7.5 cm) of DLBCL, which is associated with an increased risk of relapse.

One patient had primary central nervous system lymphoma (PCNSL), a rare form of DLBCL that is known to have the worst prognosis of all non-Hodgkin lymphomas.

Due to the unique nature of CNS primary tumors, the CAR T-cell infusion dose was further reduced to 1% of the standard dose for the patient.

The patient maintained complete remission for more than 8 months before relapsing in periphery blood, but not in the CNS, Dr. Guo noted.

“Luckily, this relapse has been easily controlled by chemotherapy, and the patient is maintaining complete remission again now,” Dr. Guo said.
 

Mechanisms?

Dr. Guo noted that the mechanism believed to explain the improvements despite such low doses is that “IL-10-expressing CAR-T exhibits enhanced proliferation, cytotoxicity, and stem-like antitumor memory due to enhanced metabolic activities of oxidative phosphorylation.”

The authors noted that a key major factor limiting accessibility to CAR-T therapies is the lengthy production cycle and high costs; however, the “extremely low doses of 1% to 5% can significantly reduce the production cycle and cost of CAR T-cell therapies, increasing accessibility,” they wrote in a press statement.

Currently, more than 20 patients have achieved a CR overall, and studies with a larger cohort and longer follow-up are ongoing, Dr. Guo reported.

The research team plans to launch further clinical investigation this year into patients with solid tumors.

Commenting on the study, Hongbo Chi, PhD, the Robert G. Webster Endowed Chair in Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, noted that, based on the abstract, “the effects are quite remarkable, considering the therapeutic efficacy observed even at the low dose.

“Results from more patients are needed to fully validate these findings, but the results to date are very encouraging,” he said.

The study was sponsored by Leman Biotech. Dr. Chi had no disclosures to report.

For patients with relapsed/refractory follicular lymphoma (R/R FL), chimeric antigen responder (CAR) T-cell therapy offers the best chance of survival, despite its high rate of serious side effects and the need to travel to infusion centers. Alternatively, updated chemo+immunotherapy regimens and bispecific antibodies provide less rigorous but effective treatment options for low-risk patients who cannot tolerate or access CAR T.

“CAR T-cells offer patients with relapsed or refractory follicular lymphoma the most durable responses and improved chance of survival beyond all other available therapies. This holds true for a broad range of high-risk disease features in patients with relapsed or refractory FL. Furthermore, it accomplishes this with a single infusion, and a discrete toxicity that is predictable, reversible and manageable,” said Caron Jacobson, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

Presenting at the Great Debates & Updates Hematologic Malignancies conference, held April 5-6 in New York City, Dr. Jacobson argued that more patients with R/R FL should be treated with CAR T.

Dana-Farber Cancer Institute

NY Presbyterian Hospital, Weill Cornell Medicine

For patients with relapsed/refractory follicular lymphoma (R/R FL), chimeric antigen responder (CAR) T-cell therapy offers the best chance of survival, despite its high rate of serious side effects and the need to travel to infusion centers. Alternatively, updated chemo+immunotherapy regimens and bispecific antibodies provide less rigorous but effective treatment options for low-risk patients who cannot tolerate or access CAR T.

“CAR T-cells offer patients with relapsed or refractory follicular lymphoma the most durable responses and improved chance of survival beyond all other available therapies. This holds true for a broad range of high-risk disease features in patients with relapsed or refractory FL. Furthermore, it accomplishes this with a single infusion, and a discrete toxicity that is predictable, reversible and manageable,” said Caron Jacobson, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

Presenting at the Great Debates & Updates Hematologic Malignancies conference, held April 5-6 in New York City, Dr. Jacobson argued that more patients with R/R FL should be treated with CAR T.

Dana-Farber Cancer Institute

NY Presbyterian Hospital, Weill Cornell Medicine

For patients with relapsed/refractory follicular lymphoma (R/R FL), chimeric antigen responder (CAR) T-cell therapy offers the best chance of survival, despite its high rate of serious side effects and the need to travel to infusion centers. Alternatively, updated chemo+immunotherapy regimens and bispecific antibodies provide less rigorous but effective treatment options for low-risk patients who cannot tolerate or access CAR T.

“CAR T-cells offer patients with relapsed or refractory follicular lymphoma the most durable responses and improved chance of survival beyond all other available therapies. This holds true for a broad range of high-risk disease features in patients with relapsed or refractory FL. Furthermore, it accomplishes this with a single infusion, and a discrete toxicity that is predictable, reversible and manageable,” said Caron Jacobson, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

Presenting at the Great Debates & Updates Hematologic Malignancies conference, held April 5-6 in New York City, Dr. Jacobson argued that more patients with R/R FL should be treated with CAR T.

Dana-Farber Cancer Institute

NY Presbyterian Hospital, Weill Cornell Medicine

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

In recent years, innovative use of bispecific antibodies and CAR T-cell therapy has ushered in an era when many patients with relapsed/refractory acute lymphoblastic leukemia (ALL) — who once had prognoses of 6 months or less — now survive for multiple years with the malignancy, and some are cured.

The comparative benefits and limitations of these two treatments for r/r ALL were a topic for discussion at the Great Debates & Updates Hematological Malignancies conference, held April 5-6 in New York City.

“Every single patient with ALL should benefit from bispecific antibodies before getting CAR-T cells, and I want to make the case that everybody should get CAR T as well. But they should get blinatumomab before they get CAR T,” said Elias Jabbour, MD, of the MD Anderson Cancer Center at The University of Texas in Houston, whose presentation focused on the merits of bispecific antibodies.

MD Anderson Cancer Center

His argument was based on data indicating that patients have better chances of long-term remission with the use of bispecific antibodies when they are administered in an earlier round of salvage treatment — and the fact that patients who are not cured with these drugs can still achieve a lower disease burden and perform better on CAR T-cell therapy than those who don’t receive the drugs.

“When blinatumomab is used as a consolidation during the first salvage treatment and spaces out transplantation, 3-year overall survival increases in the relapse setting, deepening responses and reducing the rate of VOD (veno-occlusive disease). The safety and efficacy of CAR T depends on a disease burden. If you have a minimal residual disease (MRD), you have a safer outcome and a better outcome in the long run,” Dr. Jabbour explained.

This point of view is supported by data from the treatment of patients r/r ALL with low intensity chemotherapy + inotuzumab ozogamicin (Besponsa; Pfizer) +/- blinatumomab (Blincyto; Amgen), knows as Mini-HCVD + Ino +/-Blina. Trial members achieved a median overall survival (OS) rate of 17 months, a 3-year survival rate of 42%, and an overall MRD negativity rate of 85%.

Dr. Jabbour noted that blinatumomab has its limitations. Generally, this treatment is administered intravenously every few weeks and can be cumbersome for patients who must travel to an infusion center. However, data from a phase 1b trial of single agent subcutaneous blinatumomab for advanced ALL has demonstrated that this formulation can be effective and can lead to MRD negativity, possibly paving the way for easier administration of the drug.

Aditi Shastri, MD, a leukemia specialist at New York’s Montefiore Medical Center who attended the debate, agreed that the data presented did support Dr. Jabbour’s contention that subcutaneous blinatumomab could make treatment available to even more people with r/r ALL. “It’s easier to administer than the blina pump and could act as a bridge to curative therapies like AlloHSCT,” she said.

Jae Park, MD, a leukemia and cellular therapy specialist at Memorial Sloan Kettering Cancer Center in New York City, argued that CAR T is the most potent therapy for r/r ALL. Dr. Park agreed that inotuzumab and blinatumomab have yielded tremendous progress in the treatment of patients with r/r ALL, but he noted that bispecific antibodies lack some of the advantages of CAR T.

Memorial Sloan Kettering Cancer Center

In recent years, innovative use of bispecific antibodies and CAR T-cell therapy has ushered in an era when many patients with relapsed/refractory acute lymphoblastic leukemia (ALL) — who once had prognoses of 6 months or less — now survive for multiple years with the malignancy, and some are cured.

The comparative benefits and limitations of these two treatments for r/r ALL were a topic for discussion at the Great Debates & Updates Hematological Malignancies conference, held April 5-6 in New York City.

“Every single patient with ALL should benefit from bispecific antibodies before getting CAR-T cells, and I want to make the case that everybody should get CAR T as well. But they should get blinatumomab before they get CAR T,” said Elias Jabbour, MD, of the MD Anderson Cancer Center at The University of Texas in Houston, whose presentation focused on the merits of bispecific antibodies.

MD Anderson Cancer Center

His argument was based on data indicating that patients have better chances of long-term remission with the use of bispecific antibodies when they are administered in an earlier round of salvage treatment — and the fact that patients who are not cured with these drugs can still achieve a lower disease burden and perform better on CAR T-cell therapy than those who don’t receive the drugs.

“When blinatumomab is used as a consolidation during the first salvage treatment and spaces out transplantation, 3-year overall survival increases in the relapse setting, deepening responses and reducing the rate of VOD (veno-occlusive disease). The safety and efficacy of CAR T depends on a disease burden. If you have a minimal residual disease (MRD), you have a safer outcome and a better outcome in the long run,” Dr. Jabbour explained.

This point of view is supported by data from the treatment of patients r/r ALL with low intensity chemotherapy + inotuzumab ozogamicin (Besponsa; Pfizer) +/- blinatumomab (Blincyto; Amgen), knows as Mini-HCVD + Ino +/-Blina. Trial members achieved a median overall survival (OS) rate of 17 months, a 3-year survival rate of 42%, and an overall MRD negativity rate of 85%.

Dr. Jabbour noted that blinatumomab has its limitations. Generally, this treatment is administered intravenously every few weeks and can be cumbersome for patients who must travel to an infusion center. However, data from a phase 1b trial of single agent subcutaneous blinatumomab for advanced ALL has demonstrated that this formulation can be effective and can lead to MRD negativity, possibly paving the way for easier administration of the drug.

Aditi Shastri, MD, a leukemia specialist at New York’s Montefiore Medical Center who attended the debate, agreed that the data presented did support Dr. Jabbour’s contention that subcutaneous blinatumomab could make treatment available to even more people with r/r ALL. “It’s easier to administer than the blina pump and could act as a bridge to curative therapies like AlloHSCT,” she said.

Jae Park, MD, a leukemia and cellular therapy specialist at Memorial Sloan Kettering Cancer Center in New York City, argued that CAR T is the most potent therapy for r/r ALL. Dr. Park agreed that inotuzumab and blinatumomab have yielded tremendous progress in the treatment of patients with r/r ALL, but he noted that bispecific antibodies lack some of the advantages of CAR T.

Memorial Sloan Kettering Cancer Center

In recent years, innovative use of bispecific antibodies and CAR T-cell therapy has ushered in an era when many patients with relapsed/refractory acute lymphoblastic leukemia (ALL) — who once had prognoses of 6 months or less — now survive for multiple years with the malignancy, and some are cured.

The comparative benefits and limitations of these two treatments for r/r ALL were a topic for discussion at the Great Debates & Updates Hematological Malignancies conference, held April 5-6 in New York City.

“Every single patient with ALL should benefit from bispecific antibodies before getting CAR-T cells, and I want to make the case that everybody should get CAR T as well. But they should get blinatumomab before they get CAR T,” said Elias Jabbour, MD, of the MD Anderson Cancer Center at The University of Texas in Houston, whose presentation focused on the merits of bispecific antibodies.

MD Anderson Cancer Center

His argument was based on data indicating that patients have better chances of long-term remission with the use of bispecific antibodies when they are administered in an earlier round of salvage treatment — and the fact that patients who are not cured with these drugs can still achieve a lower disease burden and perform better on CAR T-cell therapy than those who don’t receive the drugs.

“When blinatumomab is used as a consolidation during the first salvage treatment and spaces out transplantation, 3-year overall survival increases in the relapse setting, deepening responses and reducing the rate of VOD (veno-occlusive disease). The safety and efficacy of CAR T depends on a disease burden. If you have a minimal residual disease (MRD), you have a safer outcome and a better outcome in the long run,” Dr. Jabbour explained.

This point of view is supported by data from the treatment of patients r/r ALL with low intensity chemotherapy + inotuzumab ozogamicin (Besponsa; Pfizer) +/- blinatumomab (Blincyto; Amgen), knows as Mini-HCVD + Ino +/-Blina. Trial members achieved a median overall survival (OS) rate of 17 months, a 3-year survival rate of 42%, and an overall MRD negativity rate of 85%.

Dr. Jabbour noted that blinatumomab has its limitations. Generally, this treatment is administered intravenously every few weeks and can be cumbersome for patients who must travel to an infusion center. However, data from a phase 1b trial of single agent subcutaneous blinatumomab for advanced ALL has demonstrated that this formulation can be effective and can lead to MRD negativity, possibly paving the way for easier administration of the drug.

Aditi Shastri, MD, a leukemia specialist at New York’s Montefiore Medical Center who attended the debate, agreed that the data presented did support Dr. Jabbour’s contention that subcutaneous blinatumomab could make treatment available to even more people with r/r ALL. “It’s easier to administer than the blina pump and could act as a bridge to curative therapies like AlloHSCT,” she said.

Jae Park, MD, a leukemia and cellular therapy specialist at Memorial Sloan Kettering Cancer Center in New York City, argued that CAR T is the most potent therapy for r/r ALL. Dr. Park agreed that inotuzumab and blinatumomab have yielded tremendous progress in the treatment of patients with r/r ALL, but he noted that bispecific antibodies lack some of the advantages of CAR T.

Memorial Sloan Kettering Cancer Center