Gene Therapy

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

VIENNA – Ibrutinib and obinutuzumab combined with a three-cycle regimen of chemotherapy as a first-line treatment for fit patients with chronic lymphocytic leukemia (CLL) shows progression-free and overall survival rates that are comparable, if not higher, than those commonly reported with six-cycle regimens, new research shows.

“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.

 Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress. 

The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.

For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.

All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.

After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.

At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.

By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.

 One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.

 Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.

“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.

She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.

Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.

And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.

The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.

Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”

“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.

 Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.

“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”

“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said. 

 Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Lisocabtagene maraleucel, a novel chimeric antigen receptor (CAR) T-cell product, evoked a clinical response in patients with relapsed or refractory large B-cell lymphoma in a pilot study presented at the annual meeting of the American Society of Clinical Oncology.

Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.

Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.

In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.

For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.

The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.

“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.

The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.

Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.

“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.

The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.

Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.

The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
 

Addressing an ongoing unmet need

In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”

Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.

“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.

CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”

However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”

An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
 

Liso-cel may fill treatment gap as second-line therapy

The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.

“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.

“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.

“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.

Dr. Till had no relevant financial conflicts to disclose.

The study was funded by Bristol Myers Squibb.

Lisocabtagene maraleucel, a novel chimeric antigen receptor (CAR) T-cell product, evoked a clinical response in patients with relapsed or refractory large B-cell lymphoma in a pilot study presented at the annual meeting of the American Society of Clinical Oncology.

Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.

Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.

In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.

For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.

The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.

“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.

The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.

Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.

“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.

The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.

Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.

The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
 

Addressing an ongoing unmet need

In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”

Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.

“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.

CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”

However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”

An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
 

Liso-cel may fill treatment gap as second-line therapy

The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.

“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.

“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.

“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.

Dr. Till had no relevant financial conflicts to disclose.

The study was funded by Bristol Myers Squibb.

Lisocabtagene maraleucel, a novel chimeric antigen receptor (CAR) T-cell product, evoked a clinical response in patients with relapsed or refractory large B-cell lymphoma in a pilot study presented at the annual meeting of the American Society of Clinical Oncology.

Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.

Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.

In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.

For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.

The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.

“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.

The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.

Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.

“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.

The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.

Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.

The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
 

Addressing an ongoing unmet need

In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”

Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.

“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.

CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”

However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”

An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
 

Liso-cel may fill treatment gap as second-line therapy

The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.

“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.

“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.

“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.

Dr. Till had no relevant financial conflicts to disclose.

The study was funded by Bristol Myers Squibb.

Patients with relapsed or refractory B cell non-Hodgkin lymphoma responded positively to a new therapy based on genome editing in early results from a phase 1 study, according to a news release from manufacturer Caribou Biosciences.

In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.

The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.

The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.

The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m²/day.

Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.

“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.

Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.

Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.

Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.

Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.

In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
 

Study provides solid stepping stone

“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.

“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.

Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.

As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
 

Response and side effects show promise for future research

The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.

Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.

Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.

The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.

Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.

Patients with relapsed or refractory B cell non-Hodgkin lymphoma responded positively to a new therapy based on genome editing in early results from a phase 1 study, according to a news release from manufacturer Caribou Biosciences.

In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.

The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.

The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.

The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m²/day.

Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.

“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.

Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.

Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.

Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.

Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.

In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
 

Study provides solid stepping stone

“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.

“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.

Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.

As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
 

Response and side effects show promise for future research

The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.

Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.

Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.

The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.

Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.

Patients with relapsed or refractory B cell non-Hodgkin lymphoma responded positively to a new therapy based on genome editing in early results from a phase 1 study, according to a news release from manufacturer Caribou Biosciences.

In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.

The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.

The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.

The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m²/day.

Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.

“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.

Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.

Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.

Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.

Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.

In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
 

Study provides solid stepping stone

“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.

“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.

Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.

As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
 

Response and side effects show promise for future research

The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.

Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.

Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.

The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.

Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.

A weekly subcutaneous dose of teclistamab resulted in high response rates among adults with relapsed or refractory multiple myeloma, based on data from 165 patients in the MajesTEC-1 study presented at the annual meeting of the American Society of Clinical Oncology.

“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.

Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.

After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.

The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.

The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.

“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.

The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.

A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.

A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).

The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.

Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.

 “The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”

However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.

As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
 

Be ready to manage infections

Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.

Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.

A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.

He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.

Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.

The study was funded by Janssen Research and Development.

Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.

A weekly subcutaneous dose of teclistamab resulted in high response rates among adults with relapsed or refractory multiple myeloma, based on data from 165 patients in the MajesTEC-1 study presented at the annual meeting of the American Society of Clinical Oncology.

“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.

Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.

After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.

The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.

The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.

“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.

The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.

A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.

A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).

The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.

Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.

 “The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”

However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.

As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
 

Be ready to manage infections

Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.

Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.

A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.

He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.

Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.

The study was funded by Janssen Research and Development.

Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.

A weekly subcutaneous dose of teclistamab resulted in high response rates among adults with relapsed or refractory multiple myeloma, based on data from 165 patients in the MajesTEC-1 study presented at the annual meeting of the American Society of Clinical Oncology.

“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.

Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.

After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.

The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.

The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.

“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.

The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.

A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.

A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).

The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.

Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.

 “The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”

However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.

As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
 

Be ready to manage infections

Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.

Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.

A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.

He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.

Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.

The study was funded by Janssen Research and Development.

Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.

The largest trial to date in mantle cell lymphoma shows that adding the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) to standard of care treatment improves progression-free survival (PFS) by 50%.

The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.

After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.

Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.

“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.

He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.

These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.

She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
 

Some lymphoma experts not impressed

The study got pushback from several lymphoma experts commenting on Twitter.

Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity. 

“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.

“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread. 

“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
 

Potential for first-line use

Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate. 

These new data could lead to approval for first-line use of the drug.

“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.” 

Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.

He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.

Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.

At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.

Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.

The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.

At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).

Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”

Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.

He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.

The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”

Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.

In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.

He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.

The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.

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

The largest trial to date in mantle cell lymphoma shows that adding the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) to standard of care treatment improves progression-free survival (PFS) by 50%.

The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.

After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.

Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.

“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.

He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.

These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.

She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
 

Some lymphoma experts not impressed

The study got pushback from several lymphoma experts commenting on Twitter.

Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity. 

“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.

“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread. 

“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
 

Potential for first-line use

Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate. 

These new data could lead to approval for first-line use of the drug.

“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.” 

Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.

He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.

Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.

At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.

Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.

The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.

At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).

Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”

Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.

He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.

The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”

Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.

In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.

He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.

The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.

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

The largest trial to date in mantle cell lymphoma shows that adding the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) to standard of care treatment improves progression-free survival (PFS) by 50%.

The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.

After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.

Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.

“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.

He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.

These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.

She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
 

Some lymphoma experts not impressed

The study got pushback from several lymphoma experts commenting on Twitter.

Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity. 

“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.

“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread. 

“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
 

Potential for first-line use

Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate. 

These new data could lead to approval for first-line use of the drug.

“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.” 

Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.

He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.

Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.

At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.

Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.

The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.

At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).

Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”

Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.

He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.

The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”

Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.

In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.

He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.

The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.

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