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Frontline myeloma treatments: ASCT vs. CAR T
“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.
Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.
Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.
Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.
Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.
Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.
“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.
A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”
Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.
“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.
Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.
Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.
Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.
Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.
Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.
“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.
A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”
Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.
“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.
Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.
Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.
Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.
Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.
Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.
“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.
A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”
Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.
AT LLM CONGRESS 2023
Dispelling clinicians’ misconceptions about sickle cell disease
Affecting more than 20 million people globally and 100,000 people nationwide, SCD is the most common inherited blood disorder in the United States. It occurs largely but not exclusively among people of African descent.
Patients with SCD develop crescent-shaped or “sickled” red blood cells that, unlike normally round cells, can potentially block blood flow and thus cause a host of problems ranging from a risk of stroke or infections to sometimes severe pain crises, called vaso-occlusive episodes.
To help ward off such complications, some key preventative measures and an array of therapies have become available in recent years: Newborn screening and prophylaxis, including the introduction of pneumococcal vaccines, have substantially reduced rates of invasive pneumococcal infection, which previously accounted for 32% of all causes of death in patients with SCD under the age of 20.
And while hydroxyurea was the only medication from 1998 to 2017 to alleviate acute pain episodes in SCD, newer options have become available in recent years, with l-glutamine, voxelotor, and crizanlizumab gaining FDA approval to further help prevent the episodes.
However, studies show that many if not most patients fail to receive adequate treatment, with one recent report indicating that, between 2016 and 2020, hydroxyurea was prescribed to fewer than 25% of patients with SCD, and fewer than 4% of people with the disease who experience chronic pain episodes had prescriptions for the newer FDA-approved drugs.
Myths and truths
To help clarify some common misconceptions that contribute to the problems, Lewis Hsu, MD, PhD, chief medical officer of the Sickle Cell Disease Association of America, detailed some of the most prevalent and persistent myths among clinicians about SCD:
Pain level
Myths: Firstly, that sickle cell pain is not that bad, and patients therefore don’t really need opioid pain treatment, and secondly, that sickle cell pain is measurable by lab tests, such as the number of sickled red blood cells on a blood smear, reticulocytes, or hemoglobin level.
Truths: “Sickle cell vaso-occlusive pain can be very severe – a 10 on a scale of 10 – but the pain is usually only known by subjective report,” said Dr. Hsu, a pediatric hematologist who serves as director of the Sickle Cell Center and professor of pediatrics for the University of Illinois at Chicago.
“No lab test can be used to measure pain,” he said. “Other lab tests can be abnormal, and some have statistical correlation with lifetime severity of disease course, but the lab tests are not for determination of acute level of pain or absence of pain.”
Blacks only
Myth: SCD only affects Black people.
Truth: People who have sickle cell disease from many ethnic backgrounds and skin colors.
“Around the Mediterranean, there are sickle cell patients from Greece, Turkey, Italy, and Spain. Some are blond and blue-eyed. People in India and Pakistan have sickle cell disease,” Dr. Hsu explained.
In addition, “people from the Arabian Peninsula have sickle cell disease; some Malaysians have sickle cell disease; one child who is about third generation in Hong Kong has sickle cell disease.”
Parental link
Myth: Sickle cell disease only occurs in individuals both of whose parents have the sickle gene.
Truth: “There are types of sickle cell disease [involving] a sickle cell gene from one parent and a gene for hemoglobin C from the other parent,” Dr. Hsu noted. “Others inherited one sickle gene [from one parent] and inherited from the other parent a gene for beta thalassemia. Others involve an inherited sickle gene and hemoglobin E; others have inherited one sickle gene and inherited a gene for hemoglobin D-Punjab, while others have sickle and hemoglobin O-Arab.”
Effects beyond pain
Myth: A person who is not having sickle cell pain is otherwise not significantly affected by their disease.
Truth: “Organs can be damaged silently every day,” Dr. Hsu said. “Kidney failure, retina damage, and pulmonary hypertension are the most notable of organ systems that can suffer damage for a long time without symptoms, then develop symptoms when it is too late to intervene.”
“For this reason, individuals with sickle cell disease should have regular expert care for health maintenance that is disease specific,” Dr. Hsu added.
Consult guidelines
One final concern is a basic failure to utilize critical information sources and guidelines, especially by primary care providers and/or other nonspecialists from whom patients with SCD may often seek treatment. “Awareness of these guidelines is low,” Dr. Hsu said.
Key resources that can be helpful include evidence-based guidelines developed by an expert panel of the National Heart, Lung, and Blood Institute, and the American Society of Hematology has a Pocket Guide app on management of sickle cell disease.
Another key resource being highlighted in September, which is National Sickle Cell Disease Awareness Month, is the NHLBI’s comprehensive website, providing information ranging from fact sheets on the disease and treatments to social media resources and inspiring stories of people with SCD.
“We are trying to bring more sickle cell information and case studies into medical school curricula, nursing curricula, social workers and community health workers awareness, [and] apps and online guidelines are proliferating,” Dr. Hsu says.
He goes on to say, “We need more recognition and resources from insurance providers that quality care for sickle cell disease is measured and rewarded.”
Dr. Hsu coauthored “Hope and Destiny: The Patient and Parent’s Guide to Sickle Cell Disease and Sickle Cell Trait.” He reported relationships with Novartis, Emmaus, Forma Therapeutic, Dupont/Nemours Children’s Hospital, Hilton Publishing, Asklepion, Bayer, CRISPR/Vertex, Cyclerion, Pfizer, and Aruvant.
Affecting more than 20 million people globally and 100,000 people nationwide, SCD is the most common inherited blood disorder in the United States. It occurs largely but not exclusively among people of African descent.
Patients with SCD develop crescent-shaped or “sickled” red blood cells that, unlike normally round cells, can potentially block blood flow and thus cause a host of problems ranging from a risk of stroke or infections to sometimes severe pain crises, called vaso-occlusive episodes.
To help ward off such complications, some key preventative measures and an array of therapies have become available in recent years: Newborn screening and prophylaxis, including the introduction of pneumococcal vaccines, have substantially reduced rates of invasive pneumococcal infection, which previously accounted for 32% of all causes of death in patients with SCD under the age of 20.
And while hydroxyurea was the only medication from 1998 to 2017 to alleviate acute pain episodes in SCD, newer options have become available in recent years, with l-glutamine, voxelotor, and crizanlizumab gaining FDA approval to further help prevent the episodes.
However, studies show that many if not most patients fail to receive adequate treatment, with one recent report indicating that, between 2016 and 2020, hydroxyurea was prescribed to fewer than 25% of patients with SCD, and fewer than 4% of people with the disease who experience chronic pain episodes had prescriptions for the newer FDA-approved drugs.
Myths and truths
To help clarify some common misconceptions that contribute to the problems, Lewis Hsu, MD, PhD, chief medical officer of the Sickle Cell Disease Association of America, detailed some of the most prevalent and persistent myths among clinicians about SCD:
Pain level
Myths: Firstly, that sickle cell pain is not that bad, and patients therefore don’t really need opioid pain treatment, and secondly, that sickle cell pain is measurable by lab tests, such as the number of sickled red blood cells on a blood smear, reticulocytes, or hemoglobin level.
Truths: “Sickle cell vaso-occlusive pain can be very severe – a 10 on a scale of 10 – but the pain is usually only known by subjective report,” said Dr. Hsu, a pediatric hematologist who serves as director of the Sickle Cell Center and professor of pediatrics for the University of Illinois at Chicago.
“No lab test can be used to measure pain,” he said. “Other lab tests can be abnormal, and some have statistical correlation with lifetime severity of disease course, but the lab tests are not for determination of acute level of pain or absence of pain.”
Blacks only
Myth: SCD only affects Black people.
Truth: People who have sickle cell disease from many ethnic backgrounds and skin colors.
“Around the Mediterranean, there are sickle cell patients from Greece, Turkey, Italy, and Spain. Some are blond and blue-eyed. People in India and Pakistan have sickle cell disease,” Dr. Hsu explained.
In addition, “people from the Arabian Peninsula have sickle cell disease; some Malaysians have sickle cell disease; one child who is about third generation in Hong Kong has sickle cell disease.”
Parental link
Myth: Sickle cell disease only occurs in individuals both of whose parents have the sickle gene.
Truth: “There are types of sickle cell disease [involving] a sickle cell gene from one parent and a gene for hemoglobin C from the other parent,” Dr. Hsu noted. “Others inherited one sickle gene [from one parent] and inherited from the other parent a gene for beta thalassemia. Others involve an inherited sickle gene and hemoglobin E; others have inherited one sickle gene and inherited a gene for hemoglobin D-Punjab, while others have sickle and hemoglobin O-Arab.”
Effects beyond pain
Myth: A person who is not having sickle cell pain is otherwise not significantly affected by their disease.
Truth: “Organs can be damaged silently every day,” Dr. Hsu said. “Kidney failure, retina damage, and pulmonary hypertension are the most notable of organ systems that can suffer damage for a long time without symptoms, then develop symptoms when it is too late to intervene.”
“For this reason, individuals with sickle cell disease should have regular expert care for health maintenance that is disease specific,” Dr. Hsu added.
Consult guidelines
One final concern is a basic failure to utilize critical information sources and guidelines, especially by primary care providers and/or other nonspecialists from whom patients with SCD may often seek treatment. “Awareness of these guidelines is low,” Dr. Hsu said.
Key resources that can be helpful include evidence-based guidelines developed by an expert panel of the National Heart, Lung, and Blood Institute, and the American Society of Hematology has a Pocket Guide app on management of sickle cell disease.
Another key resource being highlighted in September, which is National Sickle Cell Disease Awareness Month, is the NHLBI’s comprehensive website, providing information ranging from fact sheets on the disease and treatments to social media resources and inspiring stories of people with SCD.
“We are trying to bring more sickle cell information and case studies into medical school curricula, nursing curricula, social workers and community health workers awareness, [and] apps and online guidelines are proliferating,” Dr. Hsu says.
He goes on to say, “We need more recognition and resources from insurance providers that quality care for sickle cell disease is measured and rewarded.”
Dr. Hsu coauthored “Hope and Destiny: The Patient and Parent’s Guide to Sickle Cell Disease and Sickle Cell Trait.” He reported relationships with Novartis, Emmaus, Forma Therapeutic, Dupont/Nemours Children’s Hospital, Hilton Publishing, Asklepion, Bayer, CRISPR/Vertex, Cyclerion, Pfizer, and Aruvant.
Affecting more than 20 million people globally and 100,000 people nationwide, SCD is the most common inherited blood disorder in the United States. It occurs largely but not exclusively among people of African descent.
Patients with SCD develop crescent-shaped or “sickled” red blood cells that, unlike normally round cells, can potentially block blood flow and thus cause a host of problems ranging from a risk of stroke or infections to sometimes severe pain crises, called vaso-occlusive episodes.
To help ward off such complications, some key preventative measures and an array of therapies have become available in recent years: Newborn screening and prophylaxis, including the introduction of pneumococcal vaccines, have substantially reduced rates of invasive pneumococcal infection, which previously accounted for 32% of all causes of death in patients with SCD under the age of 20.
And while hydroxyurea was the only medication from 1998 to 2017 to alleviate acute pain episodes in SCD, newer options have become available in recent years, with l-glutamine, voxelotor, and crizanlizumab gaining FDA approval to further help prevent the episodes.
However, studies show that many if not most patients fail to receive adequate treatment, with one recent report indicating that, between 2016 and 2020, hydroxyurea was prescribed to fewer than 25% of patients with SCD, and fewer than 4% of people with the disease who experience chronic pain episodes had prescriptions for the newer FDA-approved drugs.
Myths and truths
To help clarify some common misconceptions that contribute to the problems, Lewis Hsu, MD, PhD, chief medical officer of the Sickle Cell Disease Association of America, detailed some of the most prevalent and persistent myths among clinicians about SCD:
Pain level
Myths: Firstly, that sickle cell pain is not that bad, and patients therefore don’t really need opioid pain treatment, and secondly, that sickle cell pain is measurable by lab tests, such as the number of sickled red blood cells on a blood smear, reticulocytes, or hemoglobin level.
Truths: “Sickle cell vaso-occlusive pain can be very severe – a 10 on a scale of 10 – but the pain is usually only known by subjective report,” said Dr. Hsu, a pediatric hematologist who serves as director of the Sickle Cell Center and professor of pediatrics for the University of Illinois at Chicago.
“No lab test can be used to measure pain,” he said. “Other lab tests can be abnormal, and some have statistical correlation with lifetime severity of disease course, but the lab tests are not for determination of acute level of pain or absence of pain.”
Blacks only
Myth: SCD only affects Black people.
Truth: People who have sickle cell disease from many ethnic backgrounds and skin colors.
“Around the Mediterranean, there are sickle cell patients from Greece, Turkey, Italy, and Spain. Some are blond and blue-eyed. People in India and Pakistan have sickle cell disease,” Dr. Hsu explained.
In addition, “people from the Arabian Peninsula have sickle cell disease; some Malaysians have sickle cell disease; one child who is about third generation in Hong Kong has sickle cell disease.”
Parental link
Myth: Sickle cell disease only occurs in individuals both of whose parents have the sickle gene.
Truth: “There are types of sickle cell disease [involving] a sickle cell gene from one parent and a gene for hemoglobin C from the other parent,” Dr. Hsu noted. “Others inherited one sickle gene [from one parent] and inherited from the other parent a gene for beta thalassemia. Others involve an inherited sickle gene and hemoglobin E; others have inherited one sickle gene and inherited a gene for hemoglobin D-Punjab, while others have sickle and hemoglobin O-Arab.”
Effects beyond pain
Myth: A person who is not having sickle cell pain is otherwise not significantly affected by their disease.
Truth: “Organs can be damaged silently every day,” Dr. Hsu said. “Kidney failure, retina damage, and pulmonary hypertension are the most notable of organ systems that can suffer damage for a long time without symptoms, then develop symptoms when it is too late to intervene.”
“For this reason, individuals with sickle cell disease should have regular expert care for health maintenance that is disease specific,” Dr. Hsu added.
Consult guidelines
One final concern is a basic failure to utilize critical information sources and guidelines, especially by primary care providers and/or other nonspecialists from whom patients with SCD may often seek treatment. “Awareness of these guidelines is low,” Dr. Hsu said.
Key resources that can be helpful include evidence-based guidelines developed by an expert panel of the National Heart, Lung, and Blood Institute, and the American Society of Hematology has a Pocket Guide app on management of sickle cell disease.
Another key resource being highlighted in September, which is National Sickle Cell Disease Awareness Month, is the NHLBI’s comprehensive website, providing information ranging from fact sheets on the disease and treatments to social media resources and inspiring stories of people with SCD.
“We are trying to bring more sickle cell information and case studies into medical school curricula, nursing curricula, social workers and community health workers awareness, [and] apps and online guidelines are proliferating,” Dr. Hsu says.
He goes on to say, “We need more recognition and resources from insurance providers that quality care for sickle cell disease is measured and rewarded.”
Dr. Hsu coauthored “Hope and Destiny: The Patient and Parent’s Guide to Sickle Cell Disease and Sickle Cell Trait.” He reported relationships with Novartis, Emmaus, Forma Therapeutic, Dupont/Nemours Children’s Hospital, Hilton Publishing, Asklepion, Bayer, CRISPR/Vertex, Cyclerion, Pfizer, and Aruvant.
FDA approves motixafortide for stem cell mobilization in myeloma
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
Is additional treatment needed, pretransplant, for r/r AML?
This critically important question was debated at the annual meeting of the Society of Hematologic Oncology, held in Houston and online.
Johannes Schetelig, MD, argued in favor of proceeding to transplant, even without a complete remission.
“In the past, I’ve told many patients with relapsed or refractory AML that we do need to induce a [complete remission] prior to transplantation,” said Dr. Schetelig, from the Clinical Trials Unit at DKMS in Dresden, Germany. “But is it true?”
According to findings from a recent randomized trial, it may not be. The trial, led by Dr. Schetelig, found that patients with AML who received immediate allogeneic transplant without first having achieved a complete response following induction therapy did just as well as those who received intensive salvage induction therapy to establish remission before transplant.
If this finding holds, it “completely upends” how experts have traditionally approached patients with AML, Mikkael A. Sekeres, MD, of the University of Miami said at a conference press briefing last year.
The phase 3 ASAP trial, presented at last year’s American Society of Hematology meeting, included patients with AML who had had a poor response or who had experienced a relapse after first induction therapy. Patients were randomly assigned to a remission-induction strategy prior to allogeneic stem cell transplant (alloHCT) or a disease-control approach of watchful waiting followed by sequential conditioning and alloHCT. The primary endpoint was treatment success, defined as a complete response at day 56 following alloHCT.
In an intention-to-treat analysis, 83.5% of patients in the disease-control group and 81% in the remission-induction group achieved treatment success. Similarly, in the per-protocol analysis, 84.1% and 81.3%, respectively, achieved a complete response at day 56 after alloHCT. After a median follow-up of 4 years, there were no differences in leukemia-free survival or overall survival between the two groups.
Another advantage to forgoing an intensive salvage induction regimen: Patients in the disease-control arm experienced significantly fewer severe adverse events (23% vs. 64% in the remission induction arm) and spent a mean of 27 fewer days in the hospital prior to transplantation.
At last year’s press briefing, Dr. Schetelig said his team did not expect that a complete response on day 56 after transplantation would translate into “equal long-term benefit” for these groups. “This is what I was really astonished about,” he said.
Delving further into the findings, Dr. Schetelig explained that in the remission-induction arm patients who had had a complete response prior to transplantation demonstrated significantly better overall survival at 4 years than those who had not had a complete response at that point: 60% vs. 40%.
The study also revealed that in the disease-control arm, for patients under watchful waiting who did not need low-dose cytarabine and mitoxantrone for disease control, overall survival outcomes were similar to those of patients in the remission-induction arm who achieved a complete response.
These findings suggest that patients who can be bridged with watchful waiting may have a more favorable disease biology, and chemosensitivity could just be a biomarker for disease biology. In other words, “AML biology matters for transplant outcome and not tumor load,” Dr. Schetelig explained.
A recent study that found that having minimal residual disease (MRD) prior to transplant “had no independent effect on leukemia-free survival” supports this idea, he added.
Overall, Dr. Schetelig concluded that data from the ASAP trial suggest that watchful waiting prior to alloHCT represents “an alternative” for some patients.
Counterpoint: Aim for complete remission
Ronald B. Walter, MD, PhD, argued the counterpoint: that residual disease before transplantation is associated with worse posttransplant outcomes and represents a meaningful pretransplant therapeutic target.
The goal of intensifying treatment for patients with residual disease is to erase disease vestiges prior to transplantation.
“The idea is that by doing so you might optimize the benefit-to-risk ratio and ultimately improve outcomes,” said Dr. Walter, of the translational science and therapeutics division at the Fred Hutchinson Cancer Research Center in Seattle.
Several reports support this view that patients who are MRD negative at the time of transplant have significantly better survival outcomes than patients with residual disease who undergo transplant.
A 2016 study from Dr. Walter and colleagues at Fred Hutchinson, for instance, found that 3-year overall survival was significantly higher among patients with no MRD who underwent myeloablative alloHCT: 73% vs. 26% of those in MRD-positive morphologic remission and 23% of patients with active AML.
Another study, published the year before by a different research team, also revealed that “adult patients with AML in morphologic [complete remission] but with detectable MRD who undergo alloHCT have poor outcomes, which approximates those who undergo transplantation with active disease,” the authors of the 2015 study wrote in a commentary highlighting findings from both studies.
Still, providing intensive therapy prior to transplant comes with drawbacks, Dr. Walter noted. These downsides include potential toxicity from more intense therapy, which may prevent further therapy with curative intent, as well as the possibility that deintensifying therapy could lead to difficult-to-treat relapse.
It may, however, be possible to reduce the intensity of therapy before transplant and still achieve good outcomes after transplant, though the data remain mixed.
One trial found that a reduced-intensity conditioning regimen was associated with a greater risk of relapse post transplant and worse overall survival, compared with standard myeloablative conditioning.
However, another recent trial in which patients with AML or high-risk myelodysplastic syndrome were randomly assigned to either a reduced-intensity conditioning regimen or an intensified version of that regimen prior to transplant demonstrated no difference in relapse rates and overall survival, regardless of patients’ MRD status prior to transplant.
“To me, it’s still key to go into transplant with as little disease as possible,” Dr. Walter said. How much value there is in targeted treatment to further reduce disease burden prior to transplant “will really require further careful study,” he said.
The ASAP trial was sponsored by DKMS. Dr. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Walter reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
This critically important question was debated at the annual meeting of the Society of Hematologic Oncology, held in Houston and online.
Johannes Schetelig, MD, argued in favor of proceeding to transplant, even without a complete remission.
“In the past, I’ve told many patients with relapsed or refractory AML that we do need to induce a [complete remission] prior to transplantation,” said Dr. Schetelig, from the Clinical Trials Unit at DKMS in Dresden, Germany. “But is it true?”
According to findings from a recent randomized trial, it may not be. The trial, led by Dr. Schetelig, found that patients with AML who received immediate allogeneic transplant without first having achieved a complete response following induction therapy did just as well as those who received intensive salvage induction therapy to establish remission before transplant.
If this finding holds, it “completely upends” how experts have traditionally approached patients with AML, Mikkael A. Sekeres, MD, of the University of Miami said at a conference press briefing last year.
The phase 3 ASAP trial, presented at last year’s American Society of Hematology meeting, included patients with AML who had had a poor response or who had experienced a relapse after first induction therapy. Patients were randomly assigned to a remission-induction strategy prior to allogeneic stem cell transplant (alloHCT) or a disease-control approach of watchful waiting followed by sequential conditioning and alloHCT. The primary endpoint was treatment success, defined as a complete response at day 56 following alloHCT.
In an intention-to-treat analysis, 83.5% of patients in the disease-control group and 81% in the remission-induction group achieved treatment success. Similarly, in the per-protocol analysis, 84.1% and 81.3%, respectively, achieved a complete response at day 56 after alloHCT. After a median follow-up of 4 years, there were no differences in leukemia-free survival or overall survival between the two groups.
Another advantage to forgoing an intensive salvage induction regimen: Patients in the disease-control arm experienced significantly fewer severe adverse events (23% vs. 64% in the remission induction arm) and spent a mean of 27 fewer days in the hospital prior to transplantation.
At last year’s press briefing, Dr. Schetelig said his team did not expect that a complete response on day 56 after transplantation would translate into “equal long-term benefit” for these groups. “This is what I was really astonished about,” he said.
Delving further into the findings, Dr. Schetelig explained that in the remission-induction arm patients who had had a complete response prior to transplantation demonstrated significantly better overall survival at 4 years than those who had not had a complete response at that point: 60% vs. 40%.
The study also revealed that in the disease-control arm, for patients under watchful waiting who did not need low-dose cytarabine and mitoxantrone for disease control, overall survival outcomes were similar to those of patients in the remission-induction arm who achieved a complete response.
These findings suggest that patients who can be bridged with watchful waiting may have a more favorable disease biology, and chemosensitivity could just be a biomarker for disease biology. In other words, “AML biology matters for transplant outcome and not tumor load,” Dr. Schetelig explained.
A recent study that found that having minimal residual disease (MRD) prior to transplant “had no independent effect on leukemia-free survival” supports this idea, he added.
Overall, Dr. Schetelig concluded that data from the ASAP trial suggest that watchful waiting prior to alloHCT represents “an alternative” for some patients.
Counterpoint: Aim for complete remission
Ronald B. Walter, MD, PhD, argued the counterpoint: that residual disease before transplantation is associated with worse posttransplant outcomes and represents a meaningful pretransplant therapeutic target.
The goal of intensifying treatment for patients with residual disease is to erase disease vestiges prior to transplantation.
“The idea is that by doing so you might optimize the benefit-to-risk ratio and ultimately improve outcomes,” said Dr. Walter, of the translational science and therapeutics division at the Fred Hutchinson Cancer Research Center in Seattle.
Several reports support this view that patients who are MRD negative at the time of transplant have significantly better survival outcomes than patients with residual disease who undergo transplant.
A 2016 study from Dr. Walter and colleagues at Fred Hutchinson, for instance, found that 3-year overall survival was significantly higher among patients with no MRD who underwent myeloablative alloHCT: 73% vs. 26% of those in MRD-positive morphologic remission and 23% of patients with active AML.
Another study, published the year before by a different research team, also revealed that “adult patients with AML in morphologic [complete remission] but with detectable MRD who undergo alloHCT have poor outcomes, which approximates those who undergo transplantation with active disease,” the authors of the 2015 study wrote in a commentary highlighting findings from both studies.
Still, providing intensive therapy prior to transplant comes with drawbacks, Dr. Walter noted. These downsides include potential toxicity from more intense therapy, which may prevent further therapy with curative intent, as well as the possibility that deintensifying therapy could lead to difficult-to-treat relapse.
It may, however, be possible to reduce the intensity of therapy before transplant and still achieve good outcomes after transplant, though the data remain mixed.
One trial found that a reduced-intensity conditioning regimen was associated with a greater risk of relapse post transplant and worse overall survival, compared with standard myeloablative conditioning.
However, another recent trial in which patients with AML or high-risk myelodysplastic syndrome were randomly assigned to either a reduced-intensity conditioning regimen or an intensified version of that regimen prior to transplant demonstrated no difference in relapse rates and overall survival, regardless of patients’ MRD status prior to transplant.
“To me, it’s still key to go into transplant with as little disease as possible,” Dr. Walter said. How much value there is in targeted treatment to further reduce disease burden prior to transplant “will really require further careful study,” he said.
The ASAP trial was sponsored by DKMS. Dr. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Walter reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
This critically important question was debated at the annual meeting of the Society of Hematologic Oncology, held in Houston and online.
Johannes Schetelig, MD, argued in favor of proceeding to transplant, even without a complete remission.
“In the past, I’ve told many patients with relapsed or refractory AML that we do need to induce a [complete remission] prior to transplantation,” said Dr. Schetelig, from the Clinical Trials Unit at DKMS in Dresden, Germany. “But is it true?”
According to findings from a recent randomized trial, it may not be. The trial, led by Dr. Schetelig, found that patients with AML who received immediate allogeneic transplant without first having achieved a complete response following induction therapy did just as well as those who received intensive salvage induction therapy to establish remission before transplant.
If this finding holds, it “completely upends” how experts have traditionally approached patients with AML, Mikkael A. Sekeres, MD, of the University of Miami said at a conference press briefing last year.
The phase 3 ASAP trial, presented at last year’s American Society of Hematology meeting, included patients with AML who had had a poor response or who had experienced a relapse after first induction therapy. Patients were randomly assigned to a remission-induction strategy prior to allogeneic stem cell transplant (alloHCT) or a disease-control approach of watchful waiting followed by sequential conditioning and alloHCT. The primary endpoint was treatment success, defined as a complete response at day 56 following alloHCT.
In an intention-to-treat analysis, 83.5% of patients in the disease-control group and 81% in the remission-induction group achieved treatment success. Similarly, in the per-protocol analysis, 84.1% and 81.3%, respectively, achieved a complete response at day 56 after alloHCT. After a median follow-up of 4 years, there were no differences in leukemia-free survival or overall survival between the two groups.
Another advantage to forgoing an intensive salvage induction regimen: Patients in the disease-control arm experienced significantly fewer severe adverse events (23% vs. 64% in the remission induction arm) and spent a mean of 27 fewer days in the hospital prior to transplantation.
At last year’s press briefing, Dr. Schetelig said his team did not expect that a complete response on day 56 after transplantation would translate into “equal long-term benefit” for these groups. “This is what I was really astonished about,” he said.
Delving further into the findings, Dr. Schetelig explained that in the remission-induction arm patients who had had a complete response prior to transplantation demonstrated significantly better overall survival at 4 years than those who had not had a complete response at that point: 60% vs. 40%.
The study also revealed that in the disease-control arm, for patients under watchful waiting who did not need low-dose cytarabine and mitoxantrone for disease control, overall survival outcomes were similar to those of patients in the remission-induction arm who achieved a complete response.
These findings suggest that patients who can be bridged with watchful waiting may have a more favorable disease biology, and chemosensitivity could just be a biomarker for disease biology. In other words, “AML biology matters for transplant outcome and not tumor load,” Dr. Schetelig explained.
A recent study that found that having minimal residual disease (MRD) prior to transplant “had no independent effect on leukemia-free survival” supports this idea, he added.
Overall, Dr. Schetelig concluded that data from the ASAP trial suggest that watchful waiting prior to alloHCT represents “an alternative” for some patients.
Counterpoint: Aim for complete remission
Ronald B. Walter, MD, PhD, argued the counterpoint: that residual disease before transplantation is associated with worse posttransplant outcomes and represents a meaningful pretransplant therapeutic target.
The goal of intensifying treatment for patients with residual disease is to erase disease vestiges prior to transplantation.
“The idea is that by doing so you might optimize the benefit-to-risk ratio and ultimately improve outcomes,” said Dr. Walter, of the translational science and therapeutics division at the Fred Hutchinson Cancer Research Center in Seattle.
Several reports support this view that patients who are MRD negative at the time of transplant have significantly better survival outcomes than patients with residual disease who undergo transplant.
A 2016 study from Dr. Walter and colleagues at Fred Hutchinson, for instance, found that 3-year overall survival was significantly higher among patients with no MRD who underwent myeloablative alloHCT: 73% vs. 26% of those in MRD-positive morphologic remission and 23% of patients with active AML.
Another study, published the year before by a different research team, also revealed that “adult patients with AML in morphologic [complete remission] but with detectable MRD who undergo alloHCT have poor outcomes, which approximates those who undergo transplantation with active disease,” the authors of the 2015 study wrote in a commentary highlighting findings from both studies.
Still, providing intensive therapy prior to transplant comes with drawbacks, Dr. Walter noted. These downsides include potential toxicity from more intense therapy, which may prevent further therapy with curative intent, as well as the possibility that deintensifying therapy could lead to difficult-to-treat relapse.
It may, however, be possible to reduce the intensity of therapy before transplant and still achieve good outcomes after transplant, though the data remain mixed.
One trial found that a reduced-intensity conditioning regimen was associated with a greater risk of relapse post transplant and worse overall survival, compared with standard myeloablative conditioning.
However, another recent trial in which patients with AML or high-risk myelodysplastic syndrome were randomly assigned to either a reduced-intensity conditioning regimen or an intensified version of that regimen prior to transplant demonstrated no difference in relapse rates and overall survival, regardless of patients’ MRD status prior to transplant.
“To me, it’s still key to go into transplant with as little disease as possible,” Dr. Walter said. How much value there is in targeted treatment to further reduce disease burden prior to transplant “will really require further careful study,” he said.
The ASAP trial was sponsored by DKMS. Dr. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Walter reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM SOHO 2023
‘Promising’ new txs for most common adult leukemia
The rapid rise of chimeric antigen receptor T (CAR T-cell) therapy has allowed hematologists to make great strides in treating aggressive cases of multiple myeloma and several types of lymphoma and leukemia. But patients with chronic lymphocytic leukemia (CLL), the most common leukemia in adults, have been left out.
“These are the two immunotherapies that have the most potential right now,” said Ohio State University, Columbus, hematologist Kerry A. Rogers, MD, in an interview. She went on to say that these treatments could be a boon for patients with CLL who don’t respond well to targeted therapy drugs or are so young that those medications may not retain effectiveness throughout the patients’ lifespans.
As the American Cancer Society explains, CAR T therapy is a way to get T cells “to fight cancer by changing them in the lab so they can find and destroy cancer cells.” The cells are then returned to the patient.
As the National Cancer Institute says, “If all goes as planned, the CAR T cells will continue to multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.”
According to Dr. Rogers, CAR T therapy is less toxic than stem cell transplantation, a related treatment. That means older people can better tolerate it, including many CLL patients in their late 60s and beyond, she said. (Side effects of CAR T therapy include cytokine release syndrome, nervous system impairment, and weakening of the immune system.)
Thus far, CAR T therapy has been approved by the U.S. Food and Drug Administration to treat lymphomas, some forms of leukemia, and multiple myeloma. “Despite the excitement around these therapies, they lead to long-term survival in fewer than half of the patients treated,” cautions the National Cancer Institute, which also notes their high cost: more than $450,000 in one case.
CAR T therapy is not FDA-approved for CLL. “There are many reasons why CAR T is less effective in patients with CLL versus other lymphomas,” said Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in an interview. “For one, many patients with heavily pretreated CLL – prior to any use of CAR T – have mutations that are known to be difficult to treat. Dysfunctional T cells are also common in patients with CLL, and there’s often a lower number of available T-cells to manufacture.”
The results of a phase 1/2 trial released in August 2023 offered new insight about CAR T for CLL. In the open-label trial reported in The Lancet, 117 U.S. patients with CLL or small lymphocytic lymphoma underwent a form of CAR T therapy called lisocabtagene maraleucel after failing treatment with two lines of therapy, including a Bruton´s tyrosine kinase inhibitor. Among 49 patients at a specific dose, “the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18%,” the researchers reported. A total of 51 patients in the entire study died.
The rate of undetectable minimal residual disease blood was 64%. That rate is impressive, said University of Texas MD Anderson Cancer Center leukemia specialist Nitin Jain, MD, in an interview. It’s not nearly as high as researchers have seen in other disease settings, but it’s “a good, good thing for these patients. We’ll have to see in the longer follow-up how these patients fare 2, 3, or 4 years down the line.”
Dr. Rogers, the Ohio physician, said doctors had hoped durable benefit in the Lancet study would be more impressive. An important factor limiting its value may be the aggressiveness of the disease in patients who have already failed several treatments, she said. “The efficacy of CAR T might be improved by giving it as an earlier line of therapy before the CLL has become this aggressive. But it’s difficult to propose that you should use this before a Bruton´s tyrosine kinase inhibitor or venetoclax because it’s expensive and difficult.”
What’s next for CART T research in CLL? Understanding the best timing for treatment will be key, Dr. Rogers said.
The Leukemia & Lymphoma Society’s Dr. Greenberger predicted that “we will begin to see CAR T explored in CLL patients whose disease has a high risk of failing approved agents, such as Bruton´s tyrosine kinase and B cell lymphoma 2 inhibitors. However, CLL patients may still receive prior therapy with more effective Bruton’s tyrosine kinase or B cell lymphoma 2 inhibitors in the future before using CAR T. This will likely be heightened as more Bruton´s tyrosine kinase inhibitors become generic in the next 5 to 10 years and, hopefully, less expensive than CAR T therapy.”
In the big picture, he said, “treatment of CLL with CAR T is possible, but still needs significant improvements if it is to become a mainline therapy in the future.”
CAR T therapy remains available via clinical trials, and Dr. Rogers said it is “currently an important option for patients whose CLL has become resistant to standard targeted agents. We can certainly expect to extend someone’s expected survival by years if they have a favorable response.” She acknowledged that the cost is quite high, but noted that targeted therapies are also expensive, especially over the long term. They can run to $10,000-$20,000 a month. Bispecific antibodies are also being explored as potential therapy for CLL. “They’re really exciting,” Dr. Rogers said, with the potential to spur responses similar to those from CAR T therapy.
A 2022 review described these drugs as “molecules that combine antibody-directed therapies with cellular mediated immunotherapy.” The FDA explains that “by targeting two antigens or epitopes, they can cause multiple physiological or antitumor responses, which may be independent or connected.”
According to Dr. Greenberger, many bispecifics are in clinical trials now. However, “in the context of CLL, actually, the data is actually very, very limited. The development is just starting, and there are phase 1 and phase 2 trials ongoing.”
But data from lymphoma trials are encouraging, he said, and bispecifics “are actually looking as good as CAR T in some settings.”
Regimens can be a challenge for patients taking bispecifics, Dr. Greenberger said. “Repeat dosing with a step-up dosing approach to start is typically required when treating lymphoma.”
On the other hand, Dr. Rogers noted that antibody treatment can be easier for hematologists to arrange than CAR T therapy and stem cell transplants. “From an administrative side, there’s not as many things you need to have set up. So it’s able to be administered in a wider variety of settings,” she said,
Bispecific side effects include cytokine release syndrome and neurotoxicity as well as infusion reactions, Dr. Greenberger said, adding that “I would not exclude cost as a challenge.”
According to Formulary Watch, the bispecific Columvi (glofitamab-gxbm), which recently gained FDA approval to treat diffuse large B-cell lymphoma, is estimated to cost $350,000 for an 8.5-month round of treatment. Reuters reported that the bispecific Talvey (talquetamab-tgvs), which just received FDA approval to treat multiple myeloma, is estimated to cost $270,000-$360,000 for 6-8 months of treatment.
For now, bispecific trials “are mostly now reserved for patients with CLL who become resistant to our current standard targeted agents,” Dr. Rogers said. “It’s a little unclear if you can do CAR T therapy first and then bispecifics, or bispecifics and then CAR T therapy.”
What’s coming next for bispecifics? “On the horizon is better ease of administration, which is already being addressed by subcutaneous dosing for some bispecifics in lymphomas,” Dr. Greenberger said. “There’s also the possibility of combining bispecifics with conventional therapy.”
Dr. Rogers discloses ties with Genentech, AbbVie, Novartis, AstraZeneca, Janssen, Pharmacyclics, Beigene, and LOXO@Lilly. Dr. Greenberger discloses employment with the Leukemia & Lymphoma Society, which supports academic grants and a venture philanthropy via the Therapy Acceleration Program.
Dr. Jain reports ties with Pharmacyclics, AbbVie, Genentech, AstraZeneca, Pfizer, and numerous other disclosures.
The rapid rise of chimeric antigen receptor T (CAR T-cell) therapy has allowed hematologists to make great strides in treating aggressive cases of multiple myeloma and several types of lymphoma and leukemia. But patients with chronic lymphocytic leukemia (CLL), the most common leukemia in adults, have been left out.
“These are the two immunotherapies that have the most potential right now,” said Ohio State University, Columbus, hematologist Kerry A. Rogers, MD, in an interview. She went on to say that these treatments could be a boon for patients with CLL who don’t respond well to targeted therapy drugs or are so young that those medications may not retain effectiveness throughout the patients’ lifespans.
As the American Cancer Society explains, CAR T therapy is a way to get T cells “to fight cancer by changing them in the lab so they can find and destroy cancer cells.” The cells are then returned to the patient.
As the National Cancer Institute says, “If all goes as planned, the CAR T cells will continue to multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.”
According to Dr. Rogers, CAR T therapy is less toxic than stem cell transplantation, a related treatment. That means older people can better tolerate it, including many CLL patients in their late 60s and beyond, she said. (Side effects of CAR T therapy include cytokine release syndrome, nervous system impairment, and weakening of the immune system.)
Thus far, CAR T therapy has been approved by the U.S. Food and Drug Administration to treat lymphomas, some forms of leukemia, and multiple myeloma. “Despite the excitement around these therapies, they lead to long-term survival in fewer than half of the patients treated,” cautions the National Cancer Institute, which also notes their high cost: more than $450,000 in one case.
CAR T therapy is not FDA-approved for CLL. “There are many reasons why CAR T is less effective in patients with CLL versus other lymphomas,” said Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in an interview. “For one, many patients with heavily pretreated CLL – prior to any use of CAR T – have mutations that are known to be difficult to treat. Dysfunctional T cells are also common in patients with CLL, and there’s often a lower number of available T-cells to manufacture.”
The results of a phase 1/2 trial released in August 2023 offered new insight about CAR T for CLL. In the open-label trial reported in The Lancet, 117 U.S. patients with CLL or small lymphocytic lymphoma underwent a form of CAR T therapy called lisocabtagene maraleucel after failing treatment with two lines of therapy, including a Bruton´s tyrosine kinase inhibitor. Among 49 patients at a specific dose, “the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18%,” the researchers reported. A total of 51 patients in the entire study died.
The rate of undetectable minimal residual disease blood was 64%. That rate is impressive, said University of Texas MD Anderson Cancer Center leukemia specialist Nitin Jain, MD, in an interview. It’s not nearly as high as researchers have seen in other disease settings, but it’s “a good, good thing for these patients. We’ll have to see in the longer follow-up how these patients fare 2, 3, or 4 years down the line.”
Dr. Rogers, the Ohio physician, said doctors had hoped durable benefit in the Lancet study would be more impressive. An important factor limiting its value may be the aggressiveness of the disease in patients who have already failed several treatments, she said. “The efficacy of CAR T might be improved by giving it as an earlier line of therapy before the CLL has become this aggressive. But it’s difficult to propose that you should use this before a Bruton´s tyrosine kinase inhibitor or venetoclax because it’s expensive and difficult.”
What’s next for CART T research in CLL? Understanding the best timing for treatment will be key, Dr. Rogers said.
The Leukemia & Lymphoma Society’s Dr. Greenberger predicted that “we will begin to see CAR T explored in CLL patients whose disease has a high risk of failing approved agents, such as Bruton´s tyrosine kinase and B cell lymphoma 2 inhibitors. However, CLL patients may still receive prior therapy with more effective Bruton’s tyrosine kinase or B cell lymphoma 2 inhibitors in the future before using CAR T. This will likely be heightened as more Bruton´s tyrosine kinase inhibitors become generic in the next 5 to 10 years and, hopefully, less expensive than CAR T therapy.”
In the big picture, he said, “treatment of CLL with CAR T is possible, but still needs significant improvements if it is to become a mainline therapy in the future.”
CAR T therapy remains available via clinical trials, and Dr. Rogers said it is “currently an important option for patients whose CLL has become resistant to standard targeted agents. We can certainly expect to extend someone’s expected survival by years if they have a favorable response.” She acknowledged that the cost is quite high, but noted that targeted therapies are also expensive, especially over the long term. They can run to $10,000-$20,000 a month. Bispecific antibodies are also being explored as potential therapy for CLL. “They’re really exciting,” Dr. Rogers said, with the potential to spur responses similar to those from CAR T therapy.
A 2022 review described these drugs as “molecules that combine antibody-directed therapies with cellular mediated immunotherapy.” The FDA explains that “by targeting two antigens or epitopes, they can cause multiple physiological or antitumor responses, which may be independent or connected.”
According to Dr. Greenberger, many bispecifics are in clinical trials now. However, “in the context of CLL, actually, the data is actually very, very limited. The development is just starting, and there are phase 1 and phase 2 trials ongoing.”
But data from lymphoma trials are encouraging, he said, and bispecifics “are actually looking as good as CAR T in some settings.”
Regimens can be a challenge for patients taking bispecifics, Dr. Greenberger said. “Repeat dosing with a step-up dosing approach to start is typically required when treating lymphoma.”
On the other hand, Dr. Rogers noted that antibody treatment can be easier for hematologists to arrange than CAR T therapy and stem cell transplants. “From an administrative side, there’s not as many things you need to have set up. So it’s able to be administered in a wider variety of settings,” she said,
Bispecific side effects include cytokine release syndrome and neurotoxicity as well as infusion reactions, Dr. Greenberger said, adding that “I would not exclude cost as a challenge.”
According to Formulary Watch, the bispecific Columvi (glofitamab-gxbm), which recently gained FDA approval to treat diffuse large B-cell lymphoma, is estimated to cost $350,000 for an 8.5-month round of treatment. Reuters reported that the bispecific Talvey (talquetamab-tgvs), which just received FDA approval to treat multiple myeloma, is estimated to cost $270,000-$360,000 for 6-8 months of treatment.
For now, bispecific trials “are mostly now reserved for patients with CLL who become resistant to our current standard targeted agents,” Dr. Rogers said. “It’s a little unclear if you can do CAR T therapy first and then bispecifics, or bispecifics and then CAR T therapy.”
What’s coming next for bispecifics? “On the horizon is better ease of administration, which is already being addressed by subcutaneous dosing for some bispecifics in lymphomas,” Dr. Greenberger said. “There’s also the possibility of combining bispecifics with conventional therapy.”
Dr. Rogers discloses ties with Genentech, AbbVie, Novartis, AstraZeneca, Janssen, Pharmacyclics, Beigene, and LOXO@Lilly. Dr. Greenberger discloses employment with the Leukemia & Lymphoma Society, which supports academic grants and a venture philanthropy via the Therapy Acceleration Program.
Dr. Jain reports ties with Pharmacyclics, AbbVie, Genentech, AstraZeneca, Pfizer, and numerous other disclosures.
The rapid rise of chimeric antigen receptor T (CAR T-cell) therapy has allowed hematologists to make great strides in treating aggressive cases of multiple myeloma and several types of lymphoma and leukemia. But patients with chronic lymphocytic leukemia (CLL), the most common leukemia in adults, have been left out.
“These are the two immunotherapies that have the most potential right now,” said Ohio State University, Columbus, hematologist Kerry A. Rogers, MD, in an interview. She went on to say that these treatments could be a boon for patients with CLL who don’t respond well to targeted therapy drugs or are so young that those medications may not retain effectiveness throughout the patients’ lifespans.
As the American Cancer Society explains, CAR T therapy is a way to get T cells “to fight cancer by changing them in the lab so they can find and destroy cancer cells.” The cells are then returned to the patient.
As the National Cancer Institute says, “If all goes as planned, the CAR T cells will continue to multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.”
According to Dr. Rogers, CAR T therapy is less toxic than stem cell transplantation, a related treatment. That means older people can better tolerate it, including many CLL patients in their late 60s and beyond, she said. (Side effects of CAR T therapy include cytokine release syndrome, nervous system impairment, and weakening of the immune system.)
Thus far, CAR T therapy has been approved by the U.S. Food and Drug Administration to treat lymphomas, some forms of leukemia, and multiple myeloma. “Despite the excitement around these therapies, they lead to long-term survival in fewer than half of the patients treated,” cautions the National Cancer Institute, which also notes their high cost: more than $450,000 in one case.
CAR T therapy is not FDA-approved for CLL. “There are many reasons why CAR T is less effective in patients with CLL versus other lymphomas,” said Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in an interview. “For one, many patients with heavily pretreated CLL – prior to any use of CAR T – have mutations that are known to be difficult to treat. Dysfunctional T cells are also common in patients with CLL, and there’s often a lower number of available T-cells to manufacture.”
The results of a phase 1/2 trial released in August 2023 offered new insight about CAR T for CLL. In the open-label trial reported in The Lancet, 117 U.S. patients with CLL or small lymphocytic lymphoma underwent a form of CAR T therapy called lisocabtagene maraleucel after failing treatment with two lines of therapy, including a Bruton´s tyrosine kinase inhibitor. Among 49 patients at a specific dose, “the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18%,” the researchers reported. A total of 51 patients in the entire study died.
The rate of undetectable minimal residual disease blood was 64%. That rate is impressive, said University of Texas MD Anderson Cancer Center leukemia specialist Nitin Jain, MD, in an interview. It’s not nearly as high as researchers have seen in other disease settings, but it’s “a good, good thing for these patients. We’ll have to see in the longer follow-up how these patients fare 2, 3, or 4 years down the line.”
Dr. Rogers, the Ohio physician, said doctors had hoped durable benefit in the Lancet study would be more impressive. An important factor limiting its value may be the aggressiveness of the disease in patients who have already failed several treatments, she said. “The efficacy of CAR T might be improved by giving it as an earlier line of therapy before the CLL has become this aggressive. But it’s difficult to propose that you should use this before a Bruton´s tyrosine kinase inhibitor or venetoclax because it’s expensive and difficult.”
What’s next for CART T research in CLL? Understanding the best timing for treatment will be key, Dr. Rogers said.
The Leukemia & Lymphoma Society’s Dr. Greenberger predicted that “we will begin to see CAR T explored in CLL patients whose disease has a high risk of failing approved agents, such as Bruton´s tyrosine kinase and B cell lymphoma 2 inhibitors. However, CLL patients may still receive prior therapy with more effective Bruton’s tyrosine kinase or B cell lymphoma 2 inhibitors in the future before using CAR T. This will likely be heightened as more Bruton´s tyrosine kinase inhibitors become generic in the next 5 to 10 years and, hopefully, less expensive than CAR T therapy.”
In the big picture, he said, “treatment of CLL with CAR T is possible, but still needs significant improvements if it is to become a mainline therapy in the future.”
CAR T therapy remains available via clinical trials, and Dr. Rogers said it is “currently an important option for patients whose CLL has become resistant to standard targeted agents. We can certainly expect to extend someone’s expected survival by years if they have a favorable response.” She acknowledged that the cost is quite high, but noted that targeted therapies are also expensive, especially over the long term. They can run to $10,000-$20,000 a month. Bispecific antibodies are also being explored as potential therapy for CLL. “They’re really exciting,” Dr. Rogers said, with the potential to spur responses similar to those from CAR T therapy.
A 2022 review described these drugs as “molecules that combine antibody-directed therapies with cellular mediated immunotherapy.” The FDA explains that “by targeting two antigens or epitopes, they can cause multiple physiological or antitumor responses, which may be independent or connected.”
According to Dr. Greenberger, many bispecifics are in clinical trials now. However, “in the context of CLL, actually, the data is actually very, very limited. The development is just starting, and there are phase 1 and phase 2 trials ongoing.”
But data from lymphoma trials are encouraging, he said, and bispecifics “are actually looking as good as CAR T in some settings.”
Regimens can be a challenge for patients taking bispecifics, Dr. Greenberger said. “Repeat dosing with a step-up dosing approach to start is typically required when treating lymphoma.”
On the other hand, Dr. Rogers noted that antibody treatment can be easier for hematologists to arrange than CAR T therapy and stem cell transplants. “From an administrative side, there’s not as many things you need to have set up. So it’s able to be administered in a wider variety of settings,” she said,
Bispecific side effects include cytokine release syndrome and neurotoxicity as well as infusion reactions, Dr. Greenberger said, adding that “I would not exclude cost as a challenge.”
According to Formulary Watch, the bispecific Columvi (glofitamab-gxbm), which recently gained FDA approval to treat diffuse large B-cell lymphoma, is estimated to cost $350,000 for an 8.5-month round of treatment. Reuters reported that the bispecific Talvey (talquetamab-tgvs), which just received FDA approval to treat multiple myeloma, is estimated to cost $270,000-$360,000 for 6-8 months of treatment.
For now, bispecific trials “are mostly now reserved for patients with CLL who become resistant to our current standard targeted agents,” Dr. Rogers said. “It’s a little unclear if you can do CAR T therapy first and then bispecifics, or bispecifics and then CAR T therapy.”
What’s coming next for bispecifics? “On the horizon is better ease of administration, which is already being addressed by subcutaneous dosing for some bispecifics in lymphomas,” Dr. Greenberger said. “There’s also the possibility of combining bispecifics with conventional therapy.”
Dr. Rogers discloses ties with Genentech, AbbVie, Novartis, AstraZeneca, Janssen, Pharmacyclics, Beigene, and LOXO@Lilly. Dr. Greenberger discloses employment with the Leukemia & Lymphoma Society, which supports academic grants and a venture philanthropy via the Therapy Acceleration Program.
Dr. Jain reports ties with Pharmacyclics, AbbVie, Genentech, AstraZeneca, Pfizer, and numerous other disclosures.
SCD, beta-thalassemia: CRISPR-based gene therapy `transformative’
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.
The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.
In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”
“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.
Burden is high; current curative options have caveats
Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.
The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.
With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.
A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.
Gene therapy
Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.
The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.
While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.
“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.
Phase 3 trial interim results
In investigating exa-cel for beta-thalassemia, the ongoing CLIMB THAL-111 has enrolled 48 patients with a mean baseline age of 20, with 16 between the ages of 12 and 18. Of the patients, 28 (58.3%) had severe genotypes of disease.
Among 27 patients who were evaluable for the study endpoints of the current interim analysis, 24 (88.9%), achieved the primary endpoint of maintaining a weighted average hemoglobin of at least 9 g/dL without the need for a transfusion for at least 12 months (P < .0001).
Patients who achieved the transfusion independence for at least 12 months remained transfusion-free for a mean duration of 20.5 months, with a range of 12.1-40.7 months.
Of 3 patients who did not achieve the 12-month transfusion-free endpoint, substantial reductions in transfusion volume were nevertheless achieved, of 70.3%, 79.6%, and 95.5%, among the 3.
And for the CLIMB SCD-121 trial of SCD, 35 participants have been dosed with exa-cel; in the primary efficacy set of 17 patients, 16 of the 17 (94.1%) achieved the primary endpoint of having no severe vaso-occlusive crises for at least 12 months (P < .0001).
All patients, however, achieved the secondary endpoint of being free from in-patient hospitalizations for severe vaso-occlusive crises for at least 12 months (P < .0001).
Patients who achieved freedom from vaso-occlusive crises for at least 12 months remained free of the events for a mean of 18.7 months, ranging from 13.1 months to 36.5 months.
Durability, patient-reported outcomes favorable
Importantly, in both studies, hemoglobin levels, as well as levels of the edited BCL11A alleles in bone marrow CD34+ and peripheral blood nucleated cells, showed sustained stability over time, indicating durable editing of the cells, Dr. Locatelli said.
In terms of patient-reported quality-of-life, measures significantly improved during both trials at 24 months of follow-up, with significant improvements on the EuroQol visual analog scale, Functional Assessment of Cancer Therapy–General, and the Bone Marrow Transplantation Subscale.
Safety results were consistent with those observed with myeloablative busulfan-based conditioning regimen and autologous transplantation procedures, with adverse events that were manageable.
In the beta-thalassemia study, two patients experienced serious adverse events that were determined to be related to exa-cel, including one patient having symptoms in the context of hemophagocytic lymphohistiocytosis.
For the other patient, the serious adverse events consisted of delayed engraftment and thrombocytopenia, each also considered related to busulfan. None of the patients with SCD had serious adverse events related to exa-cel.
All serious adverse events were resolved, with no reports of deaths, study discontinuations, or malignancies.
Potentially first ever CRISPR-based FDA approval
While CRISPR-CAS9 gene editing is being investigated in multiple other trials in humans for various disorders, to date none have received FDA approval, which would make an approval for exa-cel a landmark development.
The therapy is currently under review, and Dr. Frangoul said the FDA has stated that a decision on the indication for SCD is expected by Dec. 8, 2023, and for beta-thalassemia, by March 2024.
Commenting on the research, Raffaella Colombatti, MD, a pediatric hematologist-oncologist and assistant professor of pediatrics at the University of Padova (Italy), underscored the need for a better curative alternative.
“Unfortunately, the other curative option, bone marrow transplant, is not available for all candidates due to the lack of suitable donors,” Dr. Colombatti said in an interview.
“And, although there are promising results from alternative donors and new conditioning regimens, a further option for selected patients with sickle cell disease and thalassemia utilizing gene therapy and gene editing is needed.”
Caveats regarding gene therapy for the two diseases that still need consideration include: “long-term safety results are still not available and eligibility criteria still needs to be explored outside clinical trials,” she said.
Furthermore, “costs and sustainability are also an issue,” Dr. Colombatti added.
The price of gene therapy is not cheap. With beti-cel priced at more than $2 million for the treatment, its manufacturer, Bluebird Bio, has reportedly already indicated that it will not pursue marketing in Europe because of unfavorable reimbursement policies, and a similar high price is anticipated for exa-cel.
Overall, however, the findings bode well for groundbreaking improvements in treatment of the two red blood cell disorders, Michael J. Eckrich, MD, MPH, medical director of pediatric stem cell transplant & cellular therapy at Atrium Health Levine Children’s Hospital Cancer and Blood Disorders in Charlotte, N.C., said in an interview.
“I do think that this is transformative therapy and will change our approach for patients with severe sickle cell disease in need of transplant,” said Dr. Eckrich, who has also been an investigator on the research of exa-cel for sickle cell disease.
“It might not be hard to imagine, that with the progress in gene therapies and gene editing, that allogeneic transplant will soon become obsolete for patients with sickle cell disease and beta-thalassemia.”
Dr. Locatelli is on the advisory board for Vertex Pharma and the speaker’s bureau for BluebirdBio. Dr. Frangoul and Dr. Colombatti are or have been consultants for Vertex Pharma.
FROM EHA 2023
ESMO helps hematologists assess new cancer drugs
It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.
Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.
On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.
The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.
The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.
To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.
Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.
The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.
ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.
It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.
Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.
On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.
The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.
The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.
To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.
Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.
The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.
ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.
It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.
Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.
On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.
The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.
The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.
To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.
Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.
The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.
ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.
FROM ANNALS OF ONCOLOGY
Huge underuse of germline testing for cancer patients
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.
The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.
The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.
“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.
“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”
Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.
The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.
“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.
They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.
“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.
At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.
The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.
Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.
“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.
One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.
“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.
Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
Details of the study
Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.
It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.
She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”
However, “little is known about genetic testing use and results,” Dr. Kurian noted.
The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.
The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.
The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.
Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.
Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.
Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.
Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.
The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.
By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.
The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.
Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.
There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.
However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.
The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).
With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).
Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.
She also noted that the SEER registries do not collect data on family history or tumor sequencing.
The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
Women hematologists advance MM research, give back
Inspired in childhood to study medicine, Dr. Madduri chose to specialize in oncology after losing a grandparent to cancer. After moving to the United States as a fifth grader, she went back to India every summer. While visiting as a college student, Dr. Madduri found her grandmother pale, with symptoms such as blood in the stool. Diagnosed with stage IV colon cancer, the grandmother died 6 months later.
“I realized I really wanted to be an oncologist because I wanted to see what I could have done to help my grandma,” Dr. Madduri said in an interview.
Today, as a senior medical director at Janssen Oncology, Dr. Madduri joins her colleague Lisa Kallenbach, MD, and others on a team of hematologist oncologists who are working to advance the treatment of multiple myeloma with chimeric antigen receptor (CAR) T-cell therapy. She and Dr. Kallenbach also mentor other blood cancer specialists through a company-sponsored Women in Hematology program.
Dr. Kallenbach, group medical director at the firm, had also long wanted to become a doctor. Unlike Dr. Madduri, however, Dr. Kallenbach took a “long and winding road” and didn’t start med school until age 30.
Put off by college premed requirements, Dr. Kallenbach majored in anthropology and suppressed her desire to study medicine while she got a master’s degree in public administration, worked in public health, and volunteered with the Peace Corps. Ultimately, she decided to do a postbaccalaureate program, entered Brown University in Providence, R.I., and loved it.
“No one in my family was a doctor, so it was all very mystical to me,” she said. “It wasn’t until I worked for a doctor where it was demystified, and I thought, ‘Ah, they’re not any smarter. They just work really hard, and I can work hard. I always do.’”
Time for a change
Hard work brought both Dr. Kallenbach and Dr. Madduri to Janssen at roughly the same time, for similar reasons.
Dr. Madduri had been a junior faculty member at Mount Sinai, where she followed her mentor’s advice and fought hard to become principal investigator of the CARTITUDE-1 trial, which she presented at the annual meetings of the American Society of Hematology in 2019 and 2020. This research led to the Food and Drug Administration’s approval of the CAR T therapy Carvykti for multiple myeloma. Dr. Madduri also launched the CAR T program at Mount Sinai and quickly gained prominence in her field, despite being the hospital’s youngest faculty member for myeloma. But when the pandemic hit, she decided to try something different.
“I was helping one person at a time as a physician, but [Janssen] gave me the opportunity to help people in a much broader sense,” said Dr. Madduri, who joined the firm in April 2021. “I’m now the one designing the trials and looking at what the needs are in myeloma.”
“Janssen’s CAR T product [Carvykti] revolutionized the space because after a one-time treatment, patients are in a deep and durable remission and living much longer,” she said. Furthermore, Janssen offered Dr. Madduri the chance to design the trials toward that long-held goal.
“I want to be part of the team where they’re really dedicated to curing myeloma,” Dr. Madduri said. And she continues to see patients as an adjunct assistant professor at Stanford (Calif.) University, where she did a blood & marrow transplantation fellowship.
Dr. Kallenbach was also drawn to Janssen because of her pandemic experiences – and the promise of broader opportunities, including a better work-life balance. One patient at a time, she was treating a variety of hematologic disorders and malignancies. Although she enjoyed it, she just needed a change.
“It had been 9 months of COVID, and it was just a really busy time and stressful,” Dr. Kallenbach said. When a friend shared the Janssen job posting, she took it as a sign. “I thought, I could really make an impact here. Now I’ve gone from treating one patient at a time to treating tons of patients and helping to get this drug [Carvykti] to patients who can really use it.”
A cancer field with potential
While it was Dr. Madduri’s grandmother’s illness that drew her to study oncology, she chose not to work on the colon cancer that killed her grandmother. It felt too personal, and she didn’t foresee being able to help patients in the ways she wanted. Instead of sending them to hospice when treatment options ran out, Dr. Madduri saw the myeloma landscape advancing rapidly, with more drugs becoming available.
“What really interests me is that this field is going somewhere, and we can potentially find something to cure these patients,” Dr. Madduri said. “There’s great need, but there’s rapid advancement happening as well. I wanted to go into something where I could really make a difference and help these patients that I couldn’t help before.”
She’s currently managing CARTITUDE-6, a head-to-head frontline trial testing CAR T-cell therapy (Carvykti) in patients eligible for transplant. “Right now the standard of care is transplant, so there’s a lot of excitement” with the idea of replacing transplant with CAR T in newly diagnosed patients, something that’s never been done. Dr. Madduri hopes this will move patients into deeper remission and eventually help pave the path to a cure. “We have to change the landscape. We have to push the boundaries, right?”
Similarly, Dr. Kallenbach was drawn to myeloma because of the rush of new therapies.
“From the time I was training to the time I was practicing, the treatments completely changed,” she said. “That’s always exciting when you’re making that much progress on a disease, to see these enormous changes. Now you’re actually seeing people who’ve had tons of prior therapies have responses that I’ve just never seen before.”
Dr. Kallenbach also found fulfillment through patient care. “People really connect with their oncologist, and that relationship is really special,” she said. “The other thing is that you really learn from cancer patients how to live your life, like what’s important. People’s priorities become very clear.”
Importance of mentorship
Both women credit part of their success to finding excellent mentors early on, and both are paying it forward by mentoring other women in their field.
Dr. Madduri met her mentor, Sundar Jagannath, MBBS, when he interviewed her at Icahn School of Medicine’s Tisch Cancer Institute in New York, where he’s director of the multiple myeloma program and the Myeloma Center of Excellence. Noting her enthusiasm and excellent training, Dr. Jagannath recruited Dr. Madduri and quickly discovered her organizational skills. When she expressed interest in running the CAR T program, he let her run with it, while advising her on how to ensure that she got respect and credit for her work.
“You have to do your part, but if you don’t have the right mentor telling you, it’d be really hard for someone who’s just starting out to know what to do,” Dr. Madduri said.
Dr. Jagannath’s guidance paid off. “When she made the ASH presentation, everybody was impressed,” he said. “She captured the attention of my peers who have been in the field for a long time, so she immediately made a national splash.”
Just a few years out of her own fellowship, Dr. Madduri had already begun mentoring other fellows. Through Women in Hematology, she helps gather data about the roles women play in her field and how to further their advancement. “The myeloma field is slowly starting to shift” toward more gender balance, she said – progress she feels happy to support.
Dr. Kallenbach’s mentoring is less formal, yet it makes a deep impact on those she takes under her wing. Her mentees are mostly the students she’s met on the Bryn Mawr College campus where she walks her two Labradors. That’s how she met Louise Breen, who, after a postbaccalaureate there, just graduated from University of Pennsylvania, Philadelphia, and is headed for residency at Mass General Hospital, Boston.
Dr. Breen said her mentor’s greatest gift has been “showing many of us that it’s possible to do it and what life could look like.” While fostering students’ self-confidence as they wrangle with imposter syndrome, Dr. Kallenbach has also demonstrated what a work-life balance in medicine can look like. She learned that from her own mentor, Hedy Smith, MD, PhD, now clinical director of inpatient hematology/oncology at MedStar Washington Hospital Center, and previously an associate professor at Tufts Medical Center.
Dr. Kallenbach quickly made an impression on Dr. Smith by coming to her door in tears one day.
“She was so devastated at the additions I made in her notes,” recalled Dr. Smith. “She felt that she had presented me with this less-than-adequate document. ... I told her, ‘this really says the world about who you are, who you’re going to become in oncology.’ I was struck by her character, a dedication to her work, and her desire to perfect it.”
Three years later, Dr. Smith remembers Dr. Kallenbach coming to her office with a big smile and saying: “Look at this. You didn’t make any changes.” Then Dr. Smith knew that her mentee was ready for the next chapter of her career.
They have kept in touch, with Dr. Kallenbach periodically calling to discuss a difficult case or to plan to meet up at conferences. “It always puts a smile on my face because this person who was once my student has now undergone this metamorphosis, and here we are, now truly equals and colleagues attending the meetings together,” Dr. Smith remarked.
Dr. Kallenbach feels grateful about finding a strong female mentor early in her medical career, especially given some of the everyday sexism she has encountered. A male colleague at a conference once expressed shock that she was practicing medicine full time while also being a mother. Dr. Kallenbach hasn’t encountered such attitudes while working in the pharmaceutical industry.
“I feel more valued as a doctor now than I ever did in practice,” she said. While before, she felt respected, “here, I feel like your expertise is valued, and you can actually help shape programs and inform how doctors practice.”
Dr. Madduri, too, feels like she’s where she’s supposed to be. “I went into the field because I really wanted to help people and make a difference,” she said. “I’m doing everything that I wanted to do.”
Inspired in childhood to study medicine, Dr. Madduri chose to specialize in oncology after losing a grandparent to cancer. After moving to the United States as a fifth grader, she went back to India every summer. While visiting as a college student, Dr. Madduri found her grandmother pale, with symptoms such as blood in the stool. Diagnosed with stage IV colon cancer, the grandmother died 6 months later.
“I realized I really wanted to be an oncologist because I wanted to see what I could have done to help my grandma,” Dr. Madduri said in an interview.
Today, as a senior medical director at Janssen Oncology, Dr. Madduri joins her colleague Lisa Kallenbach, MD, and others on a team of hematologist oncologists who are working to advance the treatment of multiple myeloma with chimeric antigen receptor (CAR) T-cell therapy. She and Dr. Kallenbach also mentor other blood cancer specialists through a company-sponsored Women in Hematology program.
Dr. Kallenbach, group medical director at the firm, had also long wanted to become a doctor. Unlike Dr. Madduri, however, Dr. Kallenbach took a “long and winding road” and didn’t start med school until age 30.
Put off by college premed requirements, Dr. Kallenbach majored in anthropology and suppressed her desire to study medicine while she got a master’s degree in public administration, worked in public health, and volunteered with the Peace Corps. Ultimately, she decided to do a postbaccalaureate program, entered Brown University in Providence, R.I., and loved it.
“No one in my family was a doctor, so it was all very mystical to me,” she said. “It wasn’t until I worked for a doctor where it was demystified, and I thought, ‘Ah, they’re not any smarter. They just work really hard, and I can work hard. I always do.’”
Time for a change
Hard work brought both Dr. Kallenbach and Dr. Madduri to Janssen at roughly the same time, for similar reasons.
Dr. Madduri had been a junior faculty member at Mount Sinai, where she followed her mentor’s advice and fought hard to become principal investigator of the CARTITUDE-1 trial, which she presented at the annual meetings of the American Society of Hematology in 2019 and 2020. This research led to the Food and Drug Administration’s approval of the CAR T therapy Carvykti for multiple myeloma. Dr. Madduri also launched the CAR T program at Mount Sinai and quickly gained prominence in her field, despite being the hospital’s youngest faculty member for myeloma. But when the pandemic hit, she decided to try something different.
“I was helping one person at a time as a physician, but [Janssen] gave me the opportunity to help people in a much broader sense,” said Dr. Madduri, who joined the firm in April 2021. “I’m now the one designing the trials and looking at what the needs are in myeloma.”
“Janssen’s CAR T product [Carvykti] revolutionized the space because after a one-time treatment, patients are in a deep and durable remission and living much longer,” she said. Furthermore, Janssen offered Dr. Madduri the chance to design the trials toward that long-held goal.
“I want to be part of the team where they’re really dedicated to curing myeloma,” Dr. Madduri said. And she continues to see patients as an adjunct assistant professor at Stanford (Calif.) University, where she did a blood & marrow transplantation fellowship.
Dr. Kallenbach was also drawn to Janssen because of her pandemic experiences – and the promise of broader opportunities, including a better work-life balance. One patient at a time, she was treating a variety of hematologic disorders and malignancies. Although she enjoyed it, she just needed a change.
“It had been 9 months of COVID, and it was just a really busy time and stressful,” Dr. Kallenbach said. When a friend shared the Janssen job posting, she took it as a sign. “I thought, I could really make an impact here. Now I’ve gone from treating one patient at a time to treating tons of patients and helping to get this drug [Carvykti] to patients who can really use it.”
A cancer field with potential
While it was Dr. Madduri’s grandmother’s illness that drew her to study oncology, she chose not to work on the colon cancer that killed her grandmother. It felt too personal, and she didn’t foresee being able to help patients in the ways she wanted. Instead of sending them to hospice when treatment options ran out, Dr. Madduri saw the myeloma landscape advancing rapidly, with more drugs becoming available.
“What really interests me is that this field is going somewhere, and we can potentially find something to cure these patients,” Dr. Madduri said. “There’s great need, but there’s rapid advancement happening as well. I wanted to go into something where I could really make a difference and help these patients that I couldn’t help before.”
She’s currently managing CARTITUDE-6, a head-to-head frontline trial testing CAR T-cell therapy (Carvykti) in patients eligible for transplant. “Right now the standard of care is transplant, so there’s a lot of excitement” with the idea of replacing transplant with CAR T in newly diagnosed patients, something that’s never been done. Dr. Madduri hopes this will move patients into deeper remission and eventually help pave the path to a cure. “We have to change the landscape. We have to push the boundaries, right?”
Similarly, Dr. Kallenbach was drawn to myeloma because of the rush of new therapies.
“From the time I was training to the time I was practicing, the treatments completely changed,” she said. “That’s always exciting when you’re making that much progress on a disease, to see these enormous changes. Now you’re actually seeing people who’ve had tons of prior therapies have responses that I’ve just never seen before.”
Dr. Kallenbach also found fulfillment through patient care. “People really connect with their oncologist, and that relationship is really special,” she said. “The other thing is that you really learn from cancer patients how to live your life, like what’s important. People’s priorities become very clear.”
Importance of mentorship
Both women credit part of their success to finding excellent mentors early on, and both are paying it forward by mentoring other women in their field.
Dr. Madduri met her mentor, Sundar Jagannath, MBBS, when he interviewed her at Icahn School of Medicine’s Tisch Cancer Institute in New York, where he’s director of the multiple myeloma program and the Myeloma Center of Excellence. Noting her enthusiasm and excellent training, Dr. Jagannath recruited Dr. Madduri and quickly discovered her organizational skills. When she expressed interest in running the CAR T program, he let her run with it, while advising her on how to ensure that she got respect and credit for her work.
“You have to do your part, but if you don’t have the right mentor telling you, it’d be really hard for someone who’s just starting out to know what to do,” Dr. Madduri said.
Dr. Jagannath’s guidance paid off. “When she made the ASH presentation, everybody was impressed,” he said. “She captured the attention of my peers who have been in the field for a long time, so she immediately made a national splash.”
Just a few years out of her own fellowship, Dr. Madduri had already begun mentoring other fellows. Through Women in Hematology, she helps gather data about the roles women play in her field and how to further their advancement. “The myeloma field is slowly starting to shift” toward more gender balance, she said – progress she feels happy to support.
Dr. Kallenbach’s mentoring is less formal, yet it makes a deep impact on those she takes under her wing. Her mentees are mostly the students she’s met on the Bryn Mawr College campus where she walks her two Labradors. That’s how she met Louise Breen, who, after a postbaccalaureate there, just graduated from University of Pennsylvania, Philadelphia, and is headed for residency at Mass General Hospital, Boston.
Dr. Breen said her mentor’s greatest gift has been “showing many of us that it’s possible to do it and what life could look like.” While fostering students’ self-confidence as they wrangle with imposter syndrome, Dr. Kallenbach has also demonstrated what a work-life balance in medicine can look like. She learned that from her own mentor, Hedy Smith, MD, PhD, now clinical director of inpatient hematology/oncology at MedStar Washington Hospital Center, and previously an associate professor at Tufts Medical Center.
Dr. Kallenbach quickly made an impression on Dr. Smith by coming to her door in tears one day.
“She was so devastated at the additions I made in her notes,” recalled Dr. Smith. “She felt that she had presented me with this less-than-adequate document. ... I told her, ‘this really says the world about who you are, who you’re going to become in oncology.’ I was struck by her character, a dedication to her work, and her desire to perfect it.”
Three years later, Dr. Smith remembers Dr. Kallenbach coming to her office with a big smile and saying: “Look at this. You didn’t make any changes.” Then Dr. Smith knew that her mentee was ready for the next chapter of her career.
They have kept in touch, with Dr. Kallenbach periodically calling to discuss a difficult case or to plan to meet up at conferences. “It always puts a smile on my face because this person who was once my student has now undergone this metamorphosis, and here we are, now truly equals and colleagues attending the meetings together,” Dr. Smith remarked.
Dr. Kallenbach feels grateful about finding a strong female mentor early in her medical career, especially given some of the everyday sexism she has encountered. A male colleague at a conference once expressed shock that she was practicing medicine full time while also being a mother. Dr. Kallenbach hasn’t encountered such attitudes while working in the pharmaceutical industry.
“I feel more valued as a doctor now than I ever did in practice,” she said. While before, she felt respected, “here, I feel like your expertise is valued, and you can actually help shape programs and inform how doctors practice.”
Dr. Madduri, too, feels like she’s where she’s supposed to be. “I went into the field because I really wanted to help people and make a difference,” she said. “I’m doing everything that I wanted to do.”
Inspired in childhood to study medicine, Dr. Madduri chose to specialize in oncology after losing a grandparent to cancer. After moving to the United States as a fifth grader, she went back to India every summer. While visiting as a college student, Dr. Madduri found her grandmother pale, with symptoms such as blood in the stool. Diagnosed with stage IV colon cancer, the grandmother died 6 months later.
“I realized I really wanted to be an oncologist because I wanted to see what I could have done to help my grandma,” Dr. Madduri said in an interview.
Today, as a senior medical director at Janssen Oncology, Dr. Madduri joins her colleague Lisa Kallenbach, MD, and others on a team of hematologist oncologists who are working to advance the treatment of multiple myeloma with chimeric antigen receptor (CAR) T-cell therapy. She and Dr. Kallenbach also mentor other blood cancer specialists through a company-sponsored Women in Hematology program.
Dr. Kallenbach, group medical director at the firm, had also long wanted to become a doctor. Unlike Dr. Madduri, however, Dr. Kallenbach took a “long and winding road” and didn’t start med school until age 30.
Put off by college premed requirements, Dr. Kallenbach majored in anthropology and suppressed her desire to study medicine while she got a master’s degree in public administration, worked in public health, and volunteered with the Peace Corps. Ultimately, she decided to do a postbaccalaureate program, entered Brown University in Providence, R.I., and loved it.
“No one in my family was a doctor, so it was all very mystical to me,” she said. “It wasn’t until I worked for a doctor where it was demystified, and I thought, ‘Ah, they’re not any smarter. They just work really hard, and I can work hard. I always do.’”
Time for a change
Hard work brought both Dr. Kallenbach and Dr. Madduri to Janssen at roughly the same time, for similar reasons.
Dr. Madduri had been a junior faculty member at Mount Sinai, where she followed her mentor’s advice and fought hard to become principal investigator of the CARTITUDE-1 trial, which she presented at the annual meetings of the American Society of Hematology in 2019 and 2020. This research led to the Food and Drug Administration’s approval of the CAR T therapy Carvykti for multiple myeloma. Dr. Madduri also launched the CAR T program at Mount Sinai and quickly gained prominence in her field, despite being the hospital’s youngest faculty member for myeloma. But when the pandemic hit, she decided to try something different.
“I was helping one person at a time as a physician, but [Janssen] gave me the opportunity to help people in a much broader sense,” said Dr. Madduri, who joined the firm in April 2021. “I’m now the one designing the trials and looking at what the needs are in myeloma.”
“Janssen’s CAR T product [Carvykti] revolutionized the space because after a one-time treatment, patients are in a deep and durable remission and living much longer,” she said. Furthermore, Janssen offered Dr. Madduri the chance to design the trials toward that long-held goal.
“I want to be part of the team where they’re really dedicated to curing myeloma,” Dr. Madduri said. And she continues to see patients as an adjunct assistant professor at Stanford (Calif.) University, where she did a blood & marrow transplantation fellowship.
Dr. Kallenbach was also drawn to Janssen because of her pandemic experiences – and the promise of broader opportunities, including a better work-life balance. One patient at a time, she was treating a variety of hematologic disorders and malignancies. Although she enjoyed it, she just needed a change.
“It had been 9 months of COVID, and it was just a really busy time and stressful,” Dr. Kallenbach said. When a friend shared the Janssen job posting, she took it as a sign. “I thought, I could really make an impact here. Now I’ve gone from treating one patient at a time to treating tons of patients and helping to get this drug [Carvykti] to patients who can really use it.”
A cancer field with potential
While it was Dr. Madduri’s grandmother’s illness that drew her to study oncology, she chose not to work on the colon cancer that killed her grandmother. It felt too personal, and she didn’t foresee being able to help patients in the ways she wanted. Instead of sending them to hospice when treatment options ran out, Dr. Madduri saw the myeloma landscape advancing rapidly, with more drugs becoming available.
“What really interests me is that this field is going somewhere, and we can potentially find something to cure these patients,” Dr. Madduri said. “There’s great need, but there’s rapid advancement happening as well. I wanted to go into something where I could really make a difference and help these patients that I couldn’t help before.”
She’s currently managing CARTITUDE-6, a head-to-head frontline trial testing CAR T-cell therapy (Carvykti) in patients eligible for transplant. “Right now the standard of care is transplant, so there’s a lot of excitement” with the idea of replacing transplant with CAR T in newly diagnosed patients, something that’s never been done. Dr. Madduri hopes this will move patients into deeper remission and eventually help pave the path to a cure. “We have to change the landscape. We have to push the boundaries, right?”
Similarly, Dr. Kallenbach was drawn to myeloma because of the rush of new therapies.
“From the time I was training to the time I was practicing, the treatments completely changed,” she said. “That’s always exciting when you’re making that much progress on a disease, to see these enormous changes. Now you’re actually seeing people who’ve had tons of prior therapies have responses that I’ve just never seen before.”
Dr. Kallenbach also found fulfillment through patient care. “People really connect with their oncologist, and that relationship is really special,” she said. “The other thing is that you really learn from cancer patients how to live your life, like what’s important. People’s priorities become very clear.”
Importance of mentorship
Both women credit part of their success to finding excellent mentors early on, and both are paying it forward by mentoring other women in their field.
Dr. Madduri met her mentor, Sundar Jagannath, MBBS, when he interviewed her at Icahn School of Medicine’s Tisch Cancer Institute in New York, where he’s director of the multiple myeloma program and the Myeloma Center of Excellence. Noting her enthusiasm and excellent training, Dr. Jagannath recruited Dr. Madduri and quickly discovered her organizational skills. When she expressed interest in running the CAR T program, he let her run with it, while advising her on how to ensure that she got respect and credit for her work.
“You have to do your part, but if you don’t have the right mentor telling you, it’d be really hard for someone who’s just starting out to know what to do,” Dr. Madduri said.
Dr. Jagannath’s guidance paid off. “When she made the ASH presentation, everybody was impressed,” he said. “She captured the attention of my peers who have been in the field for a long time, so she immediately made a national splash.”
Just a few years out of her own fellowship, Dr. Madduri had already begun mentoring other fellows. Through Women in Hematology, she helps gather data about the roles women play in her field and how to further their advancement. “The myeloma field is slowly starting to shift” toward more gender balance, she said – progress she feels happy to support.
Dr. Kallenbach’s mentoring is less formal, yet it makes a deep impact on those she takes under her wing. Her mentees are mostly the students she’s met on the Bryn Mawr College campus where she walks her two Labradors. That’s how she met Louise Breen, who, after a postbaccalaureate there, just graduated from University of Pennsylvania, Philadelphia, and is headed for residency at Mass General Hospital, Boston.
Dr. Breen said her mentor’s greatest gift has been “showing many of us that it’s possible to do it and what life could look like.” While fostering students’ self-confidence as they wrangle with imposter syndrome, Dr. Kallenbach has also demonstrated what a work-life balance in medicine can look like. She learned that from her own mentor, Hedy Smith, MD, PhD, now clinical director of inpatient hematology/oncology at MedStar Washington Hospital Center, and previously an associate professor at Tufts Medical Center.
Dr. Kallenbach quickly made an impression on Dr. Smith by coming to her door in tears one day.
“She was so devastated at the additions I made in her notes,” recalled Dr. Smith. “She felt that she had presented me with this less-than-adequate document. ... I told her, ‘this really says the world about who you are, who you’re going to become in oncology.’ I was struck by her character, a dedication to her work, and her desire to perfect it.”
Three years later, Dr. Smith remembers Dr. Kallenbach coming to her office with a big smile and saying: “Look at this. You didn’t make any changes.” Then Dr. Smith knew that her mentee was ready for the next chapter of her career.
They have kept in touch, with Dr. Kallenbach periodically calling to discuss a difficult case or to plan to meet up at conferences. “It always puts a smile on my face because this person who was once my student has now undergone this metamorphosis, and here we are, now truly equals and colleagues attending the meetings together,” Dr. Smith remarked.
Dr. Kallenbach feels grateful about finding a strong female mentor early in her medical career, especially given some of the everyday sexism she has encountered. A male colleague at a conference once expressed shock that she was practicing medicine full time while also being a mother. Dr. Kallenbach hasn’t encountered such attitudes while working in the pharmaceutical industry.
“I feel more valued as a doctor now than I ever did in practice,” she said. While before, she felt respected, “here, I feel like your expertise is valued, and you can actually help shape programs and inform how doctors practice.”
Dr. Madduri, too, feels like she’s where she’s supposed to be. “I went into the field because I really wanted to help people and make a difference,” she said. “I’m doing everything that I wanted to do.”
CAR-T hikes overall survival in relapsed/refractory LBCL
.
The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.
The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.
Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.
“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.
The study was published in the New England Journal of Medicine to coincide with the presentations.
Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).
Study details
Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.
Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.
Significantly, the better PFS appears to have translated into better overall survival (OS).
At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).
The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.
Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.
Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.
The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.
.
The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.
The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.
Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.
“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.
The study was published in the New England Journal of Medicine to coincide with the presentations.
Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).
Study details
Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.
Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.
Significantly, the better PFS appears to have translated into better overall survival (OS).
At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).
The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.
Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.
Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.
The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.
.
The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.
The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.
Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.
“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.
The study was published in the New England Journal of Medicine to coincide with the presentations.
Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).
Study details
Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.
Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.
Significantly, the better PFS appears to have translated into better overall survival (OS).
At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).
The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.
Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.
Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.
The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.
FROM ASCO 2023