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First Denosumab Biosimilar Approved in Two Different Formulations
The US Food and Drug Administration (FDA) has approved the first biosimilar to denosumab, denosumab-bddz (Wyost/Jubbonti).
The biosimilar was also granted interchangeability status, which allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Sandoz announced the approval on March 5, 2024. The lower dosage of denosumab-bddz, marketed as Jubbonti, was also approved by Health Canada in February.
The FDA approval “is based on robust clinical studies and accompanied by labeling with safety warnings,” according to the press release. Like the reference products Prolia and Xgeva, denosumab-bddz is approved for two indications at separate doses.
Wyost (120-mg/1.7-mL injection) is approved to:
- Prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors
- Treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity
- Treat hypercalcemia of cancer that is refractory to bisphosphonate therapy
Jubbonti (60-mg/1-mL injection) is approved to:
- Treat postmenopausal women with osteoporosis who are at high risk for fracture
- Increase bone mass in men with osteoporosis who are at high risk for fracture
- Treat glucocorticoid-induced osteoporosis in men and women who are at high risk for fracture
- Increase bone mass in men who are at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer
- Increase bone mass in women who are at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer.
Both doses are contraindicated for hypocalcemia and known clinically significant hypersensitivity to denosumab products. Exposure to denosumab products during pregnancy can cause fetal harm, so women of reproductive potential should be advised to use effective contraception during therapy and for at least 5 months after the last dose of denosumab-bddz.
Sandoz did not provide information on US launch details, citing “ongoing patent litigation around these products.”
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved the first biosimilar to denosumab, denosumab-bddz (Wyost/Jubbonti).
The biosimilar was also granted interchangeability status, which allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Sandoz announced the approval on March 5, 2024. The lower dosage of denosumab-bddz, marketed as Jubbonti, was also approved by Health Canada in February.
The FDA approval “is based on robust clinical studies and accompanied by labeling with safety warnings,” according to the press release. Like the reference products Prolia and Xgeva, denosumab-bddz is approved for two indications at separate doses.
Wyost (120-mg/1.7-mL injection) is approved to:
- Prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors
- Treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity
- Treat hypercalcemia of cancer that is refractory to bisphosphonate therapy
Jubbonti (60-mg/1-mL injection) is approved to:
- Treat postmenopausal women with osteoporosis who are at high risk for fracture
- Increase bone mass in men with osteoporosis who are at high risk for fracture
- Treat glucocorticoid-induced osteoporosis in men and women who are at high risk for fracture
- Increase bone mass in men who are at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer
- Increase bone mass in women who are at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer.
Both doses are contraindicated for hypocalcemia and known clinically significant hypersensitivity to denosumab products. Exposure to denosumab products during pregnancy can cause fetal harm, so women of reproductive potential should be advised to use effective contraception during therapy and for at least 5 months after the last dose of denosumab-bddz.
Sandoz did not provide information on US launch details, citing “ongoing patent litigation around these products.”
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved the first biosimilar to denosumab, denosumab-bddz (Wyost/Jubbonti).
The biosimilar was also granted interchangeability status, which allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Sandoz announced the approval on March 5, 2024. The lower dosage of denosumab-bddz, marketed as Jubbonti, was also approved by Health Canada in February.
The FDA approval “is based on robust clinical studies and accompanied by labeling with safety warnings,” according to the press release. Like the reference products Prolia and Xgeva, denosumab-bddz is approved for two indications at separate doses.
Wyost (120-mg/1.7-mL injection) is approved to:
- Prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors
- Treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity
- Treat hypercalcemia of cancer that is refractory to bisphosphonate therapy
Jubbonti (60-mg/1-mL injection) is approved to:
- Treat postmenopausal women with osteoporosis who are at high risk for fracture
- Increase bone mass in men with osteoporosis who are at high risk for fracture
- Treat glucocorticoid-induced osteoporosis in men and women who are at high risk for fracture
- Increase bone mass in men who are at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer
- Increase bone mass in women who are at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer.
Both doses are contraindicated for hypocalcemia and known clinically significant hypersensitivity to denosumab products. Exposure to denosumab products during pregnancy can cause fetal harm, so women of reproductive potential should be advised to use effective contraception during therapy and for at least 5 months after the last dose of denosumab-bddz.
Sandoz did not provide information on US launch details, citing “ongoing patent litigation around these products.”
A version of this article appeared on Medscape.com.
Can Changes to Chemo Regimens Improve Drug Tolerability in Older Patients?
TOPLINE:
Treatment modifications, such as dose reductions, schedule changes, or use of less toxic regimens, can improve how well older patients with advanced cancer and aging-related conditions tolerate chemotherapy regimens.
METHODOLOGY:
- Older patients are underrepresented in clinical trials, which means the reported risks associated with standard-of-care regimens typically reflect outcomes in younger, healthier patients. This underrepresentation in clinical trials has also led to uncertainties about the safety of standard chemotherapy regimens in older patients who often have other health conditions to manage, alongside cancer.
- In this secondary analysis, researchers evaluated the association between primary treatment modifications to standard-of-care chemotherapy regimens and treatment tolerability.
- The trial included 609 patients aged ≥ 70 years who had advanced cancer alongside at least one age-related condition, such as impaired cognition, and planned to start a new palliative chemotherapy regimen in the community oncology setting. The most common cancer types were gastrointestinal cancer (37.4%) and lung cancer (28.6%).
- The primary outcome was grade 3-5 adverse events within 3 months of chemotherapy initiation.
- Secondary outcomes included patient-reported functional decline and combined adverse outcomes, which incorporated clinician-rated toxic effects, patient-reported functional decline, and 6-month overall survival.
TAKEAWAY:
- Overall, 281 patients (46.1%) received a primary treatment modification, most often a dose reduction (71.9%) or a scheduling change (11.7%).
- Patients who received primary treatment modifications had a 15% lower risk for grades 3-5 adverse effects (relative risk [RR], 0.85) and a 20% lower risk for patient-reported functional decline (RR, 0.80) than those who received standard treatment.
- Patients receiving treatment modifications had 32% lower risk for a worse combined adverse outcome (odds ratio, 0.68).
- Cancer type may matter as well. When looking at outcomes by cancer type, patients with gastrointestinal cancers who received a primary treatment modification had a lower risk for toxic effects (RR, 0.82), whereas patients with lung cancer did not (RR, 1.03; 95% CI, 0.88-1.20).
IN PRACTICE:
These findings “can help oncologists to choose the optimal drug regimen, select a safe and effective initial dose, and undertake appropriate monitoring strategies to manage the clinical care of older people with advanced cancer,” the authors said.
SOURCE:
This study, led by Mostafa R. Mohamed from University of Rochester, New York, was published February 15 in JAMA Network Open.
LIMITATIONS:
Residual confounding may be present. Extremely healthy older patients may have been excluded due to study criteria, limiting generalizability. There may be variation in toxicities due to inclusion of patients with multiple heterogeneous cancer.
DISCLOSURES:
This work was supported by the National Cancer Institute and the University of Rochester, New York. The authors disclosed financial relationships outside this work.
A version of this article first appeared on Medscape.com.
TOPLINE:
Treatment modifications, such as dose reductions, schedule changes, or use of less toxic regimens, can improve how well older patients with advanced cancer and aging-related conditions tolerate chemotherapy regimens.
METHODOLOGY:
- Older patients are underrepresented in clinical trials, which means the reported risks associated with standard-of-care regimens typically reflect outcomes in younger, healthier patients. This underrepresentation in clinical trials has also led to uncertainties about the safety of standard chemotherapy regimens in older patients who often have other health conditions to manage, alongside cancer.
- In this secondary analysis, researchers evaluated the association between primary treatment modifications to standard-of-care chemotherapy regimens and treatment tolerability.
- The trial included 609 patients aged ≥ 70 years who had advanced cancer alongside at least one age-related condition, such as impaired cognition, and planned to start a new palliative chemotherapy regimen in the community oncology setting. The most common cancer types were gastrointestinal cancer (37.4%) and lung cancer (28.6%).
- The primary outcome was grade 3-5 adverse events within 3 months of chemotherapy initiation.
- Secondary outcomes included patient-reported functional decline and combined adverse outcomes, which incorporated clinician-rated toxic effects, patient-reported functional decline, and 6-month overall survival.
TAKEAWAY:
- Overall, 281 patients (46.1%) received a primary treatment modification, most often a dose reduction (71.9%) or a scheduling change (11.7%).
- Patients who received primary treatment modifications had a 15% lower risk for grades 3-5 adverse effects (relative risk [RR], 0.85) and a 20% lower risk for patient-reported functional decline (RR, 0.80) than those who received standard treatment.
- Patients receiving treatment modifications had 32% lower risk for a worse combined adverse outcome (odds ratio, 0.68).
- Cancer type may matter as well. When looking at outcomes by cancer type, patients with gastrointestinal cancers who received a primary treatment modification had a lower risk for toxic effects (RR, 0.82), whereas patients with lung cancer did not (RR, 1.03; 95% CI, 0.88-1.20).
IN PRACTICE:
These findings “can help oncologists to choose the optimal drug regimen, select a safe and effective initial dose, and undertake appropriate monitoring strategies to manage the clinical care of older people with advanced cancer,” the authors said.
SOURCE:
This study, led by Mostafa R. Mohamed from University of Rochester, New York, was published February 15 in JAMA Network Open.
LIMITATIONS:
Residual confounding may be present. Extremely healthy older patients may have been excluded due to study criteria, limiting generalizability. There may be variation in toxicities due to inclusion of patients with multiple heterogeneous cancer.
DISCLOSURES:
This work was supported by the National Cancer Institute and the University of Rochester, New York. The authors disclosed financial relationships outside this work.
A version of this article first appeared on Medscape.com.
TOPLINE:
Treatment modifications, such as dose reductions, schedule changes, or use of less toxic regimens, can improve how well older patients with advanced cancer and aging-related conditions tolerate chemotherapy regimens.
METHODOLOGY:
- Older patients are underrepresented in clinical trials, which means the reported risks associated with standard-of-care regimens typically reflect outcomes in younger, healthier patients. This underrepresentation in clinical trials has also led to uncertainties about the safety of standard chemotherapy regimens in older patients who often have other health conditions to manage, alongside cancer.
- In this secondary analysis, researchers evaluated the association between primary treatment modifications to standard-of-care chemotherapy regimens and treatment tolerability.
- The trial included 609 patients aged ≥ 70 years who had advanced cancer alongside at least one age-related condition, such as impaired cognition, and planned to start a new palliative chemotherapy regimen in the community oncology setting. The most common cancer types were gastrointestinal cancer (37.4%) and lung cancer (28.6%).
- The primary outcome was grade 3-5 adverse events within 3 months of chemotherapy initiation.
- Secondary outcomes included patient-reported functional decline and combined adverse outcomes, which incorporated clinician-rated toxic effects, patient-reported functional decline, and 6-month overall survival.
TAKEAWAY:
- Overall, 281 patients (46.1%) received a primary treatment modification, most often a dose reduction (71.9%) or a scheduling change (11.7%).
- Patients who received primary treatment modifications had a 15% lower risk for grades 3-5 adverse effects (relative risk [RR], 0.85) and a 20% lower risk for patient-reported functional decline (RR, 0.80) than those who received standard treatment.
- Patients receiving treatment modifications had 32% lower risk for a worse combined adverse outcome (odds ratio, 0.68).
- Cancer type may matter as well. When looking at outcomes by cancer type, patients with gastrointestinal cancers who received a primary treatment modification had a lower risk for toxic effects (RR, 0.82), whereas patients with lung cancer did not (RR, 1.03; 95% CI, 0.88-1.20).
IN PRACTICE:
These findings “can help oncologists to choose the optimal drug regimen, select a safe and effective initial dose, and undertake appropriate monitoring strategies to manage the clinical care of older people with advanced cancer,” the authors said.
SOURCE:
This study, led by Mostafa R. Mohamed from University of Rochester, New York, was published February 15 in JAMA Network Open.
LIMITATIONS:
Residual confounding may be present. Extremely healthy older patients may have been excluded due to study criteria, limiting generalizability. There may be variation in toxicities due to inclusion of patients with multiple heterogeneous cancer.
DISCLOSURES:
This work was supported by the National Cancer Institute and the University of Rochester, New York. The authors disclosed financial relationships outside this work.
A version of this article first appeared on Medscape.com.
Patient-Reported Outcomes Predict Mortality in Cutaneous Chronic GVHD
. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.
“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.
Symptoms and QOL
The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.
Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).
Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.
Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.
Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”
A growing population
Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.
With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”
Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”
Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.
“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”
In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.
Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.
Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.
If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”
The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.
. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.
“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.
Symptoms and QOL
The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.
Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).
Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.
Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.
Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”
A growing population
Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.
With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”
Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”
Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.
“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”
In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.
Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.
Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.
If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”
The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.
. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.
“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.
Symptoms and QOL
The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.
Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).
Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.
Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.
Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”
A growing population
Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.
With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”
Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”
Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.
“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”
In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.
Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.
Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.
If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”
The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.
FROM JAMA DERMATOLOGY
FDA Removes Harmful Chemicals From Food Packaging
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.
In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.
PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
Endocrine Society Report Sounds the Alarm About PFAS and Others
The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.
“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.
The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.
At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”
Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”
While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.
Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.
Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.
“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
New Data on Four Classes of EDCs
Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.
The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.
Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.
Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.
The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’
Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.
The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”
The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.
A version of this article appeared on Medscape.com.
B-ALL: CAR-T Outperforms Novel Therapies
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
“This is the first time there is a real-world comparison of CAR-T cell therapy versus other treatments in the era of other novel therapies such as inotuzumab or tyrosine kinase inhibitors (TKIs),” said first author Alexandros Rampotas, MD, of the University College London Hospital NHS Foundation Trust. “The study was looking retrospectively at patients treated in the UK, but the results should be applicable to most countries where similar treatments are available.”
Dr. Rampotas presented the research at the 6th European CAR T-cell Meeting jointly sponsored by the Society for Blood and Marrow Transplantation and the European Hematology Association.
Outcomes when patients with B-ALL relapse after allo-HCT treatment are generally very poor, and while the advent of CAR T-cell therapy has provided significant improvements, additional novel targeted therapies have also joined the field to further improve outcomes.
With no prior studies directly comparing outcomes between the various treatment options in a real-world setting, Dr. Rampotas and colleagues conducted a retrospective analysis of posttransplant relapsed B-ALL cases at six major transplant centers in the United Kingdom between 2010 and 2022.
Of 93 patients with sufficient data for the analysis, 17 had been treated with CAR T-cell therapy: 4 with UCART19, 1 with CD22 CAR T-cell, and 12 with the CD19-directed CAR T-cell products tisagenlecleucel (Kymriah) or obecabtagene autoleucel (obe-cel).
Among the remaining 75 patients who received non-CAR T-cell therapies, 24 received TKIs, 11 received blinatumumab, 12 received inotuzumab, 10 received intensive chemotherapy, 3 received intensive chemotherapy and TKI therapy, 14 received palliative/supportive regimens and 1 had a second allo-HCT following relapse from the first.
The median time from relapse to treatment was 2.8 months in the CAR T-cell therapy group, and 0.32 months for those receiving non-CAR T-cell therapies.
“The 2.8-month time-to-treat is quite expected as CAR T-cells can take a while to manufacture and be infused,” Dr. Rampotas noted. “This also comes with the bias that the patients who did receive them were likely fitter and could wait for that long.”
Patients receiving CAR T-cell therapy were also younger (median age 26 versus 47 in the non-CAR T-cell group) but the CAR T-cell group had higher risk disease and had a median of 2 prior lines of therapy versus 1 in the non-CAR T-cell group.
With a median follow-up of 24.8 months, patients receiving CAR T-cell therapy had significantly better rates of overall survival (OS), with 31 months compared with the non-CAR T-cell therapy OS of just 6.4 months (P = .0147).
The patients treated with CAR T-cell therapy also had improved progression-free survival (PFS) over the non-CAR T-cell patients (16.7 vs 3.7 months; P = .0001).
The superior outcomes in the CAR T-cell group remained consistent after exclusion of patients who received palliative approaches.
“In the realm of numerous innovative therapies for B-ALL, CAR Ts have now, for the first time, exhibited superior outcomes over alternative approaches in posttransplant relapsed B-ALL in the real world,” the authors reported. “The clear superior PFS and OS should encourage the use of more CAR T-cell therapies for this challenging cohort, while further improvements are imperative to enhance outcomes.”
In the meantime, “patients who relapse post transplant with B-ALL should be referred for CAR-T cell therapy as it is a superior treatment to other available options,” Dr. Rampotas said.
Dr. Rampotas discloses receiving conference fees from Gilead.
FROM THE 6TH EUROPEAN CAR T-CELL MEETING
‘There’s Nothing Left to Try’: Oncologists on Managing Grief
Dr. Lewis was well acquainted with cancer grief long before he became an oncologist. Dr. Lewis’ father died of a rare, hereditary cancer syndrome when he was only 14. The condition, which causes tumors to grow in the endocrine glands, can be hard to identify and, if found late, deadly.
In some ways, Dr. Lewis’ career caring for patients with advanced cancers was born out of that first loss. He centered his practice around helping patients diagnosed at late stages, like his father.
But that comes at a cost. Many patients will die.
Dr. Lewis’ encounter with his colleague led him to inventory his practice. He found that well over half of his patients died within 2 years following their advanced cancer diagnosis.
To stave off the grief of so many losses, Dr. Lewis became an eternal optimist in the clinic, in search of the Hail Mary chemotherapy, any way to eke out a few more months only to be ambushed by grief when a patient did finally pass.
At funerals — which he made every effort to attend — Dr. Lewis couldn’t help but think, “If I had done my job better, none of us with be here.” His grief started to mingle with this sense of guilt.
It became a cycle: Denial shrouded in optimism, grief, then a toxic guilt. The pattern became untenable for his colleagues. And his partner finally called him out.
Few medical specialties draw physicians as close to their patients as oncology. The long courses of treatment-spanning years can foster an intimacy that is comforting for patients and fulfilling for physicians. But that closeness can also set doctors up for an acute grief when the end of life comes.
Experts agree that no amount of training in medical school prepares an oncologist to navigate the grief that comes with losing patients. Five oncologists spoke with this news organization about the boundaries they rely on to sustain their careers.
Don’t Go to Funerals
Don Dizon, MD, who specializes in women’s cancers, established an essential boundary 20 years ago: Never go to funerals. In his early days at Memorial Sloan Kettering Cancer Center, the death of each patient dealt him a crushing blow. He’d go to the funerals in search of closure, but that only added to the weight of his grief.
“When I started in oncology, I just remember the most tragic cases were the ones I was taking care of,” recalled Dr. Dizon, now director of the Pelvic Malignancies Program at Lifespan Cancer Institute in Lincoln, Rhode Island.
Dr. Dizon recalled one young mother who was diagnosed with ovarian cancer. She responded to treatment, but it was short-lived, and her cancer progressed, he said. Multiple treatments followed, but none were effective. Eventually, Dr. Dizon had to tell her that “there’s nothing left to try.”
At her funeral, watching her grieving husband with their daughter who had just started to walk, Dr. Dizon was overwhelmed with despair.
“When you have to do this multiple times a year,” the grief becomes untenable, he said. Sensing the difficulty I was having as a new attending, “my boss stopped sending me patients because he knew I was in trouble emotionally.”
That’s when Dr. Dizon started looking for other ways to get closure.
Today, he tries to say his goodbyes before a patient dies. After the final treatment or before hospice, Dr. Dizon has a parting conversation with his patients to express the privilege of caring for them and all he learned from them. These talks help him and his patient connect in their last moments together.
The Price of Wildly Happy Days
Molly Taylor, MD, MS, a pediatric oncologist in Seattle, sees the deeply sad days as the price an oncologist pays to be witness to the “wildly happy ones.”
Dr. Taylor has gone to patients’ funerals, has even been asked to speak at them, but she has also attended patients’ weddings.
To some degree, doctors get good at compartmentalizing, and they become accustomed to tragedy, she said. But there are some patients who stick with you, “and that is a whole other level of grief,” Dr. Taylor said.
Several years into her practice, one of Dr. Taylor’s patients, someone who reminded her of her own child, died. The death came as a surprise, and the finality of it took her breath away, she said. The sadness only deepened as days went by. “I felt that mother’s grief and still do,” she said.
The patient’s funeral was one of the most difficult moments in her career as an oncologist. Even weeks later, she caught herself picturing the family huddled together that day.
Taking long walks, commiserating with colleagues who get it, and watching the occasional cat video can help take the immediate sting away. But the pain of losing a patient can be long lasting and processing that grief can be a lonely endeavor.
“We need space to recognize grief for all providers, all the people that touch these patients’ lives — the nurses, the translators, the cleaning staff,” Dr. Taylor said. Otherwise, you start to believe you’re the only one feeling the weight of the loss.
While it doesn’t make the losses any less poignant, Dr. Taylor finds solace in the good moments: Patient graduations and weddings, survivors who now volunteer at the hospital, and a patient who had a baby of her own this past year. If facing grief daily has taught Dr. Taylor anything, it is to not let the good moments pass unnoticed.
Towing the Line
Ten years ago, Tina Rizack, MD, walked into the ICU to see a young mother holding her 6-year-old daughter. The mother had necrotizing fasciitis that had gone undiagnosed.
As Dr. Rizack stood in the doorway watching the embrace, she saw a grim future: A child without her mother. This realization hit too close to home, she said. “I still think about that case.”
In her training, Dr. Rizack, now medical director of hematology/oncology at St. Anne’s in Fall River, Massachusetts, worked with a social worker who taught her how to deal with these tough cases — most importantly, how to not take them home with her.
Over the years, Dr. Rizack learned how to build and sustain a firm barrier between work and outside work.
She doesn’t go to funerals or give out her cell phone number. If charts need to be done, she prefers to stay late at the clinic instead of bringing them home.
And she invests in the simple moments that help her detach from the day-to-day in the clinic — rooting for her kids at their games, carving out time for family meals most days, and having relaxed movie nights on the couch.
“It’s hard sometimes,” she said. But “I really do need the line.” Because without it, she can’t show up for her patients the way she wants and needs to.
Establishing the work-life boundary means that when at work, Dr. Rizack can be all in for her patients. Even after her patients’ treatment ends, she makes sure to check on them at home or in hospice. For her, sticking with patients over the long term offers some closure.
“I want to love work, and if I’m there all the time, I’m not going to love it,” she said.
Trading Funerals for the Bedside
Like many other oncologists, Charles Blanke, MD, finds that going to patients’ funerals makes the loss seem more profound. Being at the bedside when they die is not as painful, he said. In fact, being there when his patients die offers him some comfort. He rarely misses a patient’s death because now Dr. Blanke’s patients can schedule their departure.
An oncologist at the Knight Cancer Institute in Portland, Oregon, Dr. Blanke specializes in end-of-life care with an emphasis on death with dignity, also known as medical aid in dying. He admits it’s not a role every physician is comfortable with.
“If you’re paralyzed by grief, you can’t do this for a living,” he said. But he’s able to do the work because he genuinely feels he’s helping patients get “the relief they so strongly desire” in their last moments.
When cancer care can’t give them the life they wanted, he can give them control over when and how they die. And the ability to honor their last wishes offers him some closure as well.
“You know what kind of end they have. You know it was peaceful. You see them achieve the thing that was the most important to them,” he said.
Despite this process, he still encounters some circumstances utterly heart-wrenching — the very young patients who have advanced disease. Some of these patients choose to die because they can’t afford to continue treatment. Others don’t have a support system. In these instances, Dr. Blanke is often the only one in the room.
Believe it or not, he said, the paperwork — and there’s a lot of it in his line of work — helps remind Dr. Blanke that patients’ last wishes are being honored.
Making Changes
After Dr. Lewis was confronted by his partner, he began to face the shortcomings of his own coping strategies. His practice hired a social worker to help staff process difficult experiences. After the loss of every patient, the practice comes together to share and process the loss.
For him, funerals remain helpful, providing a sort of solace, so he continues to go when he can. But how to grieve is something each doctor has to figure out, he said.
Deaths still hit hard, especially the ones he doesn’t see coming. The patients who remind him of his dad can also be hard. They restart a cycle of grief from his teenage years.
The difference now is he has space to voice those concerns and someone objective to help his process.
“It’s a privilege to prepare [patients for death] and help them build their legacy,” he said. But it’s also an unrelenting challenge to navigate that grief, he said.
Still, the grief lets Dr. Lewis know he’s still engaged.
“The day I don’t feel something is probably the day I need to take a break or walk away.”
A version of this article appeared on Medscape.com.
Dr. Lewis was well acquainted with cancer grief long before he became an oncologist. Dr. Lewis’ father died of a rare, hereditary cancer syndrome when he was only 14. The condition, which causes tumors to grow in the endocrine glands, can be hard to identify and, if found late, deadly.
In some ways, Dr. Lewis’ career caring for patients with advanced cancers was born out of that first loss. He centered his practice around helping patients diagnosed at late stages, like his father.
But that comes at a cost. Many patients will die.
Dr. Lewis’ encounter with his colleague led him to inventory his practice. He found that well over half of his patients died within 2 years following their advanced cancer diagnosis.
To stave off the grief of so many losses, Dr. Lewis became an eternal optimist in the clinic, in search of the Hail Mary chemotherapy, any way to eke out a few more months only to be ambushed by grief when a patient did finally pass.
At funerals — which he made every effort to attend — Dr. Lewis couldn’t help but think, “If I had done my job better, none of us with be here.” His grief started to mingle with this sense of guilt.
It became a cycle: Denial shrouded in optimism, grief, then a toxic guilt. The pattern became untenable for his colleagues. And his partner finally called him out.
Few medical specialties draw physicians as close to their patients as oncology. The long courses of treatment-spanning years can foster an intimacy that is comforting for patients and fulfilling for physicians. But that closeness can also set doctors up for an acute grief when the end of life comes.
Experts agree that no amount of training in medical school prepares an oncologist to navigate the grief that comes with losing patients. Five oncologists spoke with this news organization about the boundaries they rely on to sustain their careers.
Don’t Go to Funerals
Don Dizon, MD, who specializes in women’s cancers, established an essential boundary 20 years ago: Never go to funerals. In his early days at Memorial Sloan Kettering Cancer Center, the death of each patient dealt him a crushing blow. He’d go to the funerals in search of closure, but that only added to the weight of his grief.
“When I started in oncology, I just remember the most tragic cases were the ones I was taking care of,” recalled Dr. Dizon, now director of the Pelvic Malignancies Program at Lifespan Cancer Institute in Lincoln, Rhode Island.
Dr. Dizon recalled one young mother who was diagnosed with ovarian cancer. She responded to treatment, but it was short-lived, and her cancer progressed, he said. Multiple treatments followed, but none were effective. Eventually, Dr. Dizon had to tell her that “there’s nothing left to try.”
At her funeral, watching her grieving husband with their daughter who had just started to walk, Dr. Dizon was overwhelmed with despair.
“When you have to do this multiple times a year,” the grief becomes untenable, he said. Sensing the difficulty I was having as a new attending, “my boss stopped sending me patients because he knew I was in trouble emotionally.”
That’s when Dr. Dizon started looking for other ways to get closure.
Today, he tries to say his goodbyes before a patient dies. After the final treatment or before hospice, Dr. Dizon has a parting conversation with his patients to express the privilege of caring for them and all he learned from them. These talks help him and his patient connect in their last moments together.
The Price of Wildly Happy Days
Molly Taylor, MD, MS, a pediatric oncologist in Seattle, sees the deeply sad days as the price an oncologist pays to be witness to the “wildly happy ones.”
Dr. Taylor has gone to patients’ funerals, has even been asked to speak at them, but she has also attended patients’ weddings.
To some degree, doctors get good at compartmentalizing, and they become accustomed to tragedy, she said. But there are some patients who stick with you, “and that is a whole other level of grief,” Dr. Taylor said.
Several years into her practice, one of Dr. Taylor’s patients, someone who reminded her of her own child, died. The death came as a surprise, and the finality of it took her breath away, she said. The sadness only deepened as days went by. “I felt that mother’s grief and still do,” she said.
The patient’s funeral was one of the most difficult moments in her career as an oncologist. Even weeks later, she caught herself picturing the family huddled together that day.
Taking long walks, commiserating with colleagues who get it, and watching the occasional cat video can help take the immediate sting away. But the pain of losing a patient can be long lasting and processing that grief can be a lonely endeavor.
“We need space to recognize grief for all providers, all the people that touch these patients’ lives — the nurses, the translators, the cleaning staff,” Dr. Taylor said. Otherwise, you start to believe you’re the only one feeling the weight of the loss.
While it doesn’t make the losses any less poignant, Dr. Taylor finds solace in the good moments: Patient graduations and weddings, survivors who now volunteer at the hospital, and a patient who had a baby of her own this past year. If facing grief daily has taught Dr. Taylor anything, it is to not let the good moments pass unnoticed.
Towing the Line
Ten years ago, Tina Rizack, MD, walked into the ICU to see a young mother holding her 6-year-old daughter. The mother had necrotizing fasciitis that had gone undiagnosed.
As Dr. Rizack stood in the doorway watching the embrace, she saw a grim future: A child without her mother. This realization hit too close to home, she said. “I still think about that case.”
In her training, Dr. Rizack, now medical director of hematology/oncology at St. Anne’s in Fall River, Massachusetts, worked with a social worker who taught her how to deal with these tough cases — most importantly, how to not take them home with her.
Over the years, Dr. Rizack learned how to build and sustain a firm barrier between work and outside work.
She doesn’t go to funerals or give out her cell phone number. If charts need to be done, she prefers to stay late at the clinic instead of bringing them home.
And she invests in the simple moments that help her detach from the day-to-day in the clinic — rooting for her kids at their games, carving out time for family meals most days, and having relaxed movie nights on the couch.
“It’s hard sometimes,” she said. But “I really do need the line.” Because without it, she can’t show up for her patients the way she wants and needs to.
Establishing the work-life boundary means that when at work, Dr. Rizack can be all in for her patients. Even after her patients’ treatment ends, she makes sure to check on them at home or in hospice. For her, sticking with patients over the long term offers some closure.
“I want to love work, and if I’m there all the time, I’m not going to love it,” she said.
Trading Funerals for the Bedside
Like many other oncologists, Charles Blanke, MD, finds that going to patients’ funerals makes the loss seem more profound. Being at the bedside when they die is not as painful, he said. In fact, being there when his patients die offers him some comfort. He rarely misses a patient’s death because now Dr. Blanke’s patients can schedule their departure.
An oncologist at the Knight Cancer Institute in Portland, Oregon, Dr. Blanke specializes in end-of-life care with an emphasis on death with dignity, also known as medical aid in dying. He admits it’s not a role every physician is comfortable with.
“If you’re paralyzed by grief, you can’t do this for a living,” he said. But he’s able to do the work because he genuinely feels he’s helping patients get “the relief they so strongly desire” in their last moments.
When cancer care can’t give them the life they wanted, he can give them control over when and how they die. And the ability to honor their last wishes offers him some closure as well.
“You know what kind of end they have. You know it was peaceful. You see them achieve the thing that was the most important to them,” he said.
Despite this process, he still encounters some circumstances utterly heart-wrenching — the very young patients who have advanced disease. Some of these patients choose to die because they can’t afford to continue treatment. Others don’t have a support system. In these instances, Dr. Blanke is often the only one in the room.
Believe it or not, he said, the paperwork — and there’s a lot of it in his line of work — helps remind Dr. Blanke that patients’ last wishes are being honored.
Making Changes
After Dr. Lewis was confronted by his partner, he began to face the shortcomings of his own coping strategies. His practice hired a social worker to help staff process difficult experiences. After the loss of every patient, the practice comes together to share and process the loss.
For him, funerals remain helpful, providing a sort of solace, so he continues to go when he can. But how to grieve is something each doctor has to figure out, he said.
Deaths still hit hard, especially the ones he doesn’t see coming. The patients who remind him of his dad can also be hard. They restart a cycle of grief from his teenage years.
The difference now is he has space to voice those concerns and someone objective to help his process.
“It’s a privilege to prepare [patients for death] and help them build their legacy,” he said. But it’s also an unrelenting challenge to navigate that grief, he said.
Still, the grief lets Dr. Lewis know he’s still engaged.
“The day I don’t feel something is probably the day I need to take a break or walk away.”
A version of this article appeared on Medscape.com.
Dr. Lewis was well acquainted with cancer grief long before he became an oncologist. Dr. Lewis’ father died of a rare, hereditary cancer syndrome when he was only 14. The condition, which causes tumors to grow in the endocrine glands, can be hard to identify and, if found late, deadly.
In some ways, Dr. Lewis’ career caring for patients with advanced cancers was born out of that first loss. He centered his practice around helping patients diagnosed at late stages, like his father.
But that comes at a cost. Many patients will die.
Dr. Lewis’ encounter with his colleague led him to inventory his practice. He found that well over half of his patients died within 2 years following their advanced cancer diagnosis.
To stave off the grief of so many losses, Dr. Lewis became an eternal optimist in the clinic, in search of the Hail Mary chemotherapy, any way to eke out a few more months only to be ambushed by grief when a patient did finally pass.
At funerals — which he made every effort to attend — Dr. Lewis couldn’t help but think, “If I had done my job better, none of us with be here.” His grief started to mingle with this sense of guilt.
It became a cycle: Denial shrouded in optimism, grief, then a toxic guilt. The pattern became untenable for his colleagues. And his partner finally called him out.
Few medical specialties draw physicians as close to their patients as oncology. The long courses of treatment-spanning years can foster an intimacy that is comforting for patients and fulfilling for physicians. But that closeness can also set doctors up for an acute grief when the end of life comes.
Experts agree that no amount of training in medical school prepares an oncologist to navigate the grief that comes with losing patients. Five oncologists spoke with this news organization about the boundaries they rely on to sustain their careers.
Don’t Go to Funerals
Don Dizon, MD, who specializes in women’s cancers, established an essential boundary 20 years ago: Never go to funerals. In his early days at Memorial Sloan Kettering Cancer Center, the death of each patient dealt him a crushing blow. He’d go to the funerals in search of closure, but that only added to the weight of his grief.
“When I started in oncology, I just remember the most tragic cases were the ones I was taking care of,” recalled Dr. Dizon, now director of the Pelvic Malignancies Program at Lifespan Cancer Institute in Lincoln, Rhode Island.
Dr. Dizon recalled one young mother who was diagnosed with ovarian cancer. She responded to treatment, but it was short-lived, and her cancer progressed, he said. Multiple treatments followed, but none were effective. Eventually, Dr. Dizon had to tell her that “there’s nothing left to try.”
At her funeral, watching her grieving husband with their daughter who had just started to walk, Dr. Dizon was overwhelmed with despair.
“When you have to do this multiple times a year,” the grief becomes untenable, he said. Sensing the difficulty I was having as a new attending, “my boss stopped sending me patients because he knew I was in trouble emotionally.”
That’s when Dr. Dizon started looking for other ways to get closure.
Today, he tries to say his goodbyes before a patient dies. After the final treatment or before hospice, Dr. Dizon has a parting conversation with his patients to express the privilege of caring for them and all he learned from them. These talks help him and his patient connect in their last moments together.
The Price of Wildly Happy Days
Molly Taylor, MD, MS, a pediatric oncologist in Seattle, sees the deeply sad days as the price an oncologist pays to be witness to the “wildly happy ones.”
Dr. Taylor has gone to patients’ funerals, has even been asked to speak at them, but she has also attended patients’ weddings.
To some degree, doctors get good at compartmentalizing, and they become accustomed to tragedy, she said. But there are some patients who stick with you, “and that is a whole other level of grief,” Dr. Taylor said.
Several years into her practice, one of Dr. Taylor’s patients, someone who reminded her of her own child, died. The death came as a surprise, and the finality of it took her breath away, she said. The sadness only deepened as days went by. “I felt that mother’s grief and still do,” she said.
The patient’s funeral was one of the most difficult moments in her career as an oncologist. Even weeks later, she caught herself picturing the family huddled together that day.
Taking long walks, commiserating with colleagues who get it, and watching the occasional cat video can help take the immediate sting away. But the pain of losing a patient can be long lasting and processing that grief can be a lonely endeavor.
“We need space to recognize grief for all providers, all the people that touch these patients’ lives — the nurses, the translators, the cleaning staff,” Dr. Taylor said. Otherwise, you start to believe you’re the only one feeling the weight of the loss.
While it doesn’t make the losses any less poignant, Dr. Taylor finds solace in the good moments: Patient graduations and weddings, survivors who now volunteer at the hospital, and a patient who had a baby of her own this past year. If facing grief daily has taught Dr. Taylor anything, it is to not let the good moments pass unnoticed.
Towing the Line
Ten years ago, Tina Rizack, MD, walked into the ICU to see a young mother holding her 6-year-old daughter. The mother had necrotizing fasciitis that had gone undiagnosed.
As Dr. Rizack stood in the doorway watching the embrace, she saw a grim future: A child without her mother. This realization hit too close to home, she said. “I still think about that case.”
In her training, Dr. Rizack, now medical director of hematology/oncology at St. Anne’s in Fall River, Massachusetts, worked with a social worker who taught her how to deal with these tough cases — most importantly, how to not take them home with her.
Over the years, Dr. Rizack learned how to build and sustain a firm barrier between work and outside work.
She doesn’t go to funerals or give out her cell phone number. If charts need to be done, she prefers to stay late at the clinic instead of bringing them home.
And she invests in the simple moments that help her detach from the day-to-day in the clinic — rooting for her kids at their games, carving out time for family meals most days, and having relaxed movie nights on the couch.
“It’s hard sometimes,” she said. But “I really do need the line.” Because without it, she can’t show up for her patients the way she wants and needs to.
Establishing the work-life boundary means that when at work, Dr. Rizack can be all in for her patients. Even after her patients’ treatment ends, she makes sure to check on them at home or in hospice. For her, sticking with patients over the long term offers some closure.
“I want to love work, and if I’m there all the time, I’m not going to love it,” she said.
Trading Funerals for the Bedside
Like many other oncologists, Charles Blanke, MD, finds that going to patients’ funerals makes the loss seem more profound. Being at the bedside when they die is not as painful, he said. In fact, being there when his patients die offers him some comfort. He rarely misses a patient’s death because now Dr. Blanke’s patients can schedule their departure.
An oncologist at the Knight Cancer Institute in Portland, Oregon, Dr. Blanke specializes in end-of-life care with an emphasis on death with dignity, also known as medical aid in dying. He admits it’s not a role every physician is comfortable with.
“If you’re paralyzed by grief, you can’t do this for a living,” he said. But he’s able to do the work because he genuinely feels he’s helping patients get “the relief they so strongly desire” in their last moments.
When cancer care can’t give them the life they wanted, he can give them control over when and how they die. And the ability to honor their last wishes offers him some closure as well.
“You know what kind of end they have. You know it was peaceful. You see them achieve the thing that was the most important to them,” he said.
Despite this process, he still encounters some circumstances utterly heart-wrenching — the very young patients who have advanced disease. Some of these patients choose to die because they can’t afford to continue treatment. Others don’t have a support system. In these instances, Dr. Blanke is often the only one in the room.
Believe it or not, he said, the paperwork — and there’s a lot of it in his line of work — helps remind Dr. Blanke that patients’ last wishes are being honored.
Making Changes
After Dr. Lewis was confronted by his partner, he began to face the shortcomings of his own coping strategies. His practice hired a social worker to help staff process difficult experiences. After the loss of every patient, the practice comes together to share and process the loss.
For him, funerals remain helpful, providing a sort of solace, so he continues to go when he can. But how to grieve is something each doctor has to figure out, he said.
Deaths still hit hard, especially the ones he doesn’t see coming. The patients who remind him of his dad can also be hard. They restart a cycle of grief from his teenage years.
The difference now is he has space to voice those concerns and someone objective to help his process.
“It’s a privilege to prepare [patients for death] and help them build their legacy,” he said. But it’s also an unrelenting challenge to navigate that grief, he said.
Still, the grief lets Dr. Lewis know he’s still engaged.
“The day I don’t feel something is probably the day I need to take a break or walk away.”
A version of this article appeared on Medscape.com.
‘Less is More’ in Myeloma
Among those that intrigue me most are the pioneering “less is more” trials that challenged conventional practices and remain relevant today. One such trial was inspired by a patient’s dissatisfaction with high doses of dexamethasone and its side effects.
Unlike the prevailing norm of frequent high doses, this trial compared a steroid dose administered weekly (as opposed to doses given several days a week). Lo and behold, the lower steroid dosage was associated with significantly better survival rates. At 1-year follow-up, 96% of patients in the lower-dose group were alive, compared with 87% in the higher-dose group.
Another noteworthy “less-is more” trial that I love, spearheaded by an Italian team, also focused on steroid dosage. This trial investigated discontinuing dexamethasone after nine cycles, along with reducing the dose of lenalidomide, versus maintaining long-term treatment without reductions. The findings revealed comparable progression-free survival with reduced toxicity, highlighting the potential benefits of this less-is-more approach.
While these trials are inspirational, a closer examination of myeloma trial history, especially those that led to regulatory approvals, reveals a preponderance of “add-on” trials. You add a potentially effective drug to an existing backbone, and you get an improvement in an outcome such as response rate (shrinking cancer) or duration of remission or progression free survival (amount of time alive and in remission).
Such trials have led to an abundance of effective options. But these same trials have almost always been a comparison of three drugs versus two drugs, and almost never three drugs versus three. And the drugs are often given continuously, especially the “newer” added drug, without a break. As a result, we are left completely unsure of how to sequence our drugs, and whether a finite course of the new drug would be equivalent to administering that new drug forever.
This problem is not unique to myeloma. Yet it is very apparent in myeloma, because we have been lucky to have so many good drugs (or at least “potentially” good drugs) that make it to phase 3 trials.
Unfortunately, the landscape of clinical trials is heavily influenced by the pharmaceutical industry, with limited funding available from alternative sources. As a result, there is a scarcity of trials exploring “less is more” approaches, despite their potential to optimize treatment outcomes and quality of life.
Even government-funded trials run by cooperative groups require industry buy-in or are run by people who have very close contacts and conflicts of interest with industry. We need so many more of these less-is-more trials, but we have limited means to fund them.
These are the kinds of discussions I have with my patients daily. We grapple with questions about the necessity of lifelong (or any) maintenance therapy or the feasibility of treatment breaks for patients with stable disease. While we strive to provide the best care possible, the lack of definitive data often leaves us making tough decisions in the clinic.
I am grateful to those who are working tirelessly to facilitate trials that prioritize quality of life and “less is more” approaches. Your efforts are invaluable. Looking forward, I aspire to contribute to this important work.
Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
Among those that intrigue me most are the pioneering “less is more” trials that challenged conventional practices and remain relevant today. One such trial was inspired by a patient’s dissatisfaction with high doses of dexamethasone and its side effects.
Unlike the prevailing norm of frequent high doses, this trial compared a steroid dose administered weekly (as opposed to doses given several days a week). Lo and behold, the lower steroid dosage was associated with significantly better survival rates. At 1-year follow-up, 96% of patients in the lower-dose group were alive, compared with 87% in the higher-dose group.
Another noteworthy “less-is more” trial that I love, spearheaded by an Italian team, also focused on steroid dosage. This trial investigated discontinuing dexamethasone after nine cycles, along with reducing the dose of lenalidomide, versus maintaining long-term treatment without reductions. The findings revealed comparable progression-free survival with reduced toxicity, highlighting the potential benefits of this less-is-more approach.
While these trials are inspirational, a closer examination of myeloma trial history, especially those that led to regulatory approvals, reveals a preponderance of “add-on” trials. You add a potentially effective drug to an existing backbone, and you get an improvement in an outcome such as response rate (shrinking cancer) or duration of remission or progression free survival (amount of time alive and in remission).
Such trials have led to an abundance of effective options. But these same trials have almost always been a comparison of three drugs versus two drugs, and almost never three drugs versus three. And the drugs are often given continuously, especially the “newer” added drug, without a break. As a result, we are left completely unsure of how to sequence our drugs, and whether a finite course of the new drug would be equivalent to administering that new drug forever.
This problem is not unique to myeloma. Yet it is very apparent in myeloma, because we have been lucky to have so many good drugs (or at least “potentially” good drugs) that make it to phase 3 trials.
Unfortunately, the landscape of clinical trials is heavily influenced by the pharmaceutical industry, with limited funding available from alternative sources. As a result, there is a scarcity of trials exploring “less is more” approaches, despite their potential to optimize treatment outcomes and quality of life.
Even government-funded trials run by cooperative groups require industry buy-in or are run by people who have very close contacts and conflicts of interest with industry. We need so many more of these less-is-more trials, but we have limited means to fund them.
These are the kinds of discussions I have with my patients daily. We grapple with questions about the necessity of lifelong (or any) maintenance therapy or the feasibility of treatment breaks for patients with stable disease. While we strive to provide the best care possible, the lack of definitive data often leaves us making tough decisions in the clinic.
I am grateful to those who are working tirelessly to facilitate trials that prioritize quality of life and “less is more” approaches. Your efforts are invaluable. Looking forward, I aspire to contribute to this important work.
Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
Among those that intrigue me most are the pioneering “less is more” trials that challenged conventional practices and remain relevant today. One such trial was inspired by a patient’s dissatisfaction with high doses of dexamethasone and its side effects.
Unlike the prevailing norm of frequent high doses, this trial compared a steroid dose administered weekly (as opposed to doses given several days a week). Lo and behold, the lower steroid dosage was associated with significantly better survival rates. At 1-year follow-up, 96% of patients in the lower-dose group were alive, compared with 87% in the higher-dose group.
Another noteworthy “less-is more” trial that I love, spearheaded by an Italian team, also focused on steroid dosage. This trial investigated discontinuing dexamethasone after nine cycles, along with reducing the dose of lenalidomide, versus maintaining long-term treatment without reductions. The findings revealed comparable progression-free survival with reduced toxicity, highlighting the potential benefits of this less-is-more approach.
While these trials are inspirational, a closer examination of myeloma trial history, especially those that led to regulatory approvals, reveals a preponderance of “add-on” trials. You add a potentially effective drug to an existing backbone, and you get an improvement in an outcome such as response rate (shrinking cancer) or duration of remission or progression free survival (amount of time alive and in remission).
Such trials have led to an abundance of effective options. But these same trials have almost always been a comparison of three drugs versus two drugs, and almost never three drugs versus three. And the drugs are often given continuously, especially the “newer” added drug, without a break. As a result, we are left completely unsure of how to sequence our drugs, and whether a finite course of the new drug would be equivalent to administering that new drug forever.
This problem is not unique to myeloma. Yet it is very apparent in myeloma, because we have been lucky to have so many good drugs (or at least “potentially” good drugs) that make it to phase 3 trials.
Unfortunately, the landscape of clinical trials is heavily influenced by the pharmaceutical industry, with limited funding available from alternative sources. As a result, there is a scarcity of trials exploring “less is more” approaches, despite their potential to optimize treatment outcomes and quality of life.
Even government-funded trials run by cooperative groups require industry buy-in or are run by people who have very close contacts and conflicts of interest with industry. We need so many more of these less-is-more trials, but we have limited means to fund them.
These are the kinds of discussions I have with my patients daily. We grapple with questions about the necessity of lifelong (or any) maintenance therapy or the feasibility of treatment breaks for patients with stable disease. While we strive to provide the best care possible, the lack of definitive data often leaves us making tough decisions in the clinic.
I am grateful to those who are working tirelessly to facilitate trials that prioritize quality of life and “less is more” approaches. Your efforts are invaluable. Looking forward, I aspire to contribute to this important work.
Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
MM:New Tool Gauges Post–CAR T Relapse Risk
“To our knowledge, this large multicenter study is the first report to identify patients with RRMM at high risk of early relapse after CAR-T,” the authors report in the study, published February 15 in the Journal of Clinical Oncology.
“We saw that early relapse within 5 months from infusion was significantly associated with very poor outcomes, and disease-, treatment-, and inflammation-specific variables were independent predictors of early relapse,” first author Nico Gagelmann, MD, of the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany, explained in presenting the findings at the 6th European CAR T-cell Meeting jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association. CAR-T therapy has revolutionized the treatment of RRMM, with the idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) CAR-T therapies approved for the condition. However, the treatment is far from a cure, with nearly 50% of patients relapsing and having progression of disease within the first year after infusion, prompting a need to better understand the risk factors for who may or may not progress.
With a lack of a universal model to help with those predictions across products and populations, Dr. Gagelmann and colleagues conducted a retrospective observational study utilizing data from 136 patients at seven CAR-T centers in Europe and 133 patients at three centers in the US who had received either commercial or academically produced anti-BCMA CAR-T.
Of the patients, 171 were infused with ide-cel, 38 with cilta-cel, and 60 with an academic CAR-T therapy. The patients had a median age of 63, and extramedullary disease was more common in the US cohort (48%) versus European (35%; P = .04).
Notably, the response rates between the European and US cohorts were similar, despite various differences between the cohorts, including differences in ethnicities and a lower body mass index (BMI) in the European cohort versus US (BMI 25 vs 28, respectively; P < .001). There were also no significant differences in responses between the CAR-T treatments.
The overall response rate was 87% and was comparable between the European and US groups, with complete responses occurring among 48% of patients in Europe and 49% in the US group.
Their measurable residual disease (MRD) negativity rate at any time was 29% and 37%, respectively, and rates of complete response at day 30 were 29% and 26%, respectively. The rate of progression-free survival at 12 months was 40% for the entire cohort, with a rate of 45% in the European group and 34% in the US group (P = .09). Overall survival rates at 12 months were 79% and 65%, respectively (P = .11).
The patients had a median time to relapse of 5 months, and the 5-month incidence of relapse was identical, at 24% in each cohort.
Of those patients, overall survival at 12 months was low, at 30% in the European cohort and 14% in the US group.
“Early relapse within the first 5 months clearly identified patients with poor survival across the cohort,” Dr. Gagelmann said.
Key Risk Factors Identified
Key factors found after multivariate adjustment to be independently predictive of early relapse or progression included extramedullary disease or plasma cell leukemia, being refractory to lenalidomide, having high-risk cytogenetics, and having increased age- and sex-adjusted ferritin at the time of lymphodepletion.
With each of the risk factors valued at 1 point, the MyCARe model ranked scores of 0-1 points as low-risk, 2-3 as intermediate risk, and a score above 4 was considered high-risk.
Based on the model, the risk of early relapse within 5 months among those scored as low risk was 7%, for intermediate risk, 27% (hazard ratio [HR], 3.27 vs low-risk; P < .001), and for high risk, 53% (HR, 7.89 vs low-risk; P < .001), with outcomes overall comparable between the two geographic groups. Importantly, the model maintained utility for patients who did and did not receive salvage therapies; however, “more studies are needed to identify the optimal post–CAR-T approach,” the authors write.
Dr. Gagelmann added that older age was significantly associated with improved progression-free survival in the US cohort, with a 12-month progression-free survival of 27% among patients under 65 versus 43% for those over 65 (P = .03). However, age was not found to be associated with similar outcomes in the European cohort.
The authors note that the MyCARe model outperformed the CAR-HEMATOTOX and more recent disease-specific R2-ISS risk-stratification tools regarding prediction of relapse/progression and progression-free survival.
However, with CAR-HEMATOTOX developed to predict side effects and non-relapse mortality, “our results demonstrate that both scores independently predict different outcomes after anti–BCMA CAR-T in RRMM,” the authors report. Therefore, “they can be used complimentarily to predict complications (CAR-HEMATOTOX) and relapse/progression-free survival (MyCARe model).”
Importantly, the authors add that the tool may help in patient selection for earlier treatment.
“As ide-cel and cilta-cel have shown astonishing efficacy for earlier treatment lines, our model might also be validated for such patients,” the authors note in the study. They conclude that the study provides “the first Euro-American cartography of the efficacy and safety profile of current CAR-T, showing comparable results.”
“We also built the MyCARe model, which can predict early relapse, response, and survival and may facilitate patient selection in this very challenging setting,” the authors report.
Hope for Interventions Based on Patients’ Risk
Commenting on the study, Rahul Banerjee, MD, an assistant professor with the Division of Hematology and Oncology, University of Washington, Seattle, underscored that “we need more cross-border research like this in the myeloma field.”
“Clinically, my hope that this will help us tailor post–CAR-T interventions according to each patient’s risk profile,” he said.
Risk factors such as the presence of extramedullary disease, plasma cell leukemia, or high-risk cytogenetics are expected; however, Dr. Banerjee said the inclusion of increased ferritin before CAR-T was “an interesting new risk factor that we’ve also heard about from our colleagues in the lymphoma space.”
Ferritin perturbations can indicate many things, but high ferritin can be a sign of elevated inflammation at baseline,” he explained. “These patients may have a hyperinflammatory phenotype of their myeloma which can predispose T-cells to exhaustion,” Dr. Banerjee said.
“Exhausted T-cells at collection mean exhausted CAR T-cells at infusion, and so the negative prognostic significance of elevated ferritin — which we don’t always check before CAR-T — makes sense.”
While the authors suggest a potential benefit of the MyCAR3 model in identifying patients who could benefit from other novel therapies at relapse, Dr. Banerjee suggests another possibility. “I’d take this a step further and suggest future studies of this MyCARe model to identify patients who might benefit from post–CAR-T maintenance,” he said.
“The ‘one-and-done’ nature of CAR-T in terms of not requiring further myeloma therapy after infusion is a powerful benefit for patients, but there are some patients who may benefit from low-dose pomalidomide or iberdomide/mezigdomide maintenance to help keep the myeloma at bay and to promote T-cell fitness,” Dr. Banerjee explained. “This risk model may identify patients to prioritize for such types of clinical trials in the future.”
Caveats include that factors beyond the baseline features (used for the risk model) can further influence outcomes,” Dr. Banerjee noted.
“Risk stratification is inherently a dynamic process over time,” he said, questioning, for instance, “what about patients who achieve measurable residual disease negativity [MRD] at day +28 after CAR-T cell? Does the achievement of MRD negativity ‘erase’ a high-risk MyCARe score? We’ll need future studies to tell.”
An overriding take-home message for clinicians should be to simply refer eligible patients to a CAR-T capable center as soon as possible for evaluation.
“In the lymphoma world, they have a nice adage for this: ‘If they recur, you should refer,’ ” he said. “I’d suggest the same here. By no means will we move to CAR-T therapy for every patient at first relapse. However, based on their MyCARe score and other risk factors, there may be patients we prioritize for CAR-T first versus CAR-T with maintenance versus clinical trials.”
Dr. Gagelmann reported relationships with BMS, Pfizer, Stemline, MorphoSys, and Kite. Dr. Banerjee disclosed ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
“To our knowledge, this large multicenter study is the first report to identify patients with RRMM at high risk of early relapse after CAR-T,” the authors report in the study, published February 15 in the Journal of Clinical Oncology.
“We saw that early relapse within 5 months from infusion was significantly associated with very poor outcomes, and disease-, treatment-, and inflammation-specific variables were independent predictors of early relapse,” first author Nico Gagelmann, MD, of the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany, explained in presenting the findings at the 6th European CAR T-cell Meeting jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association. CAR-T therapy has revolutionized the treatment of RRMM, with the idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) CAR-T therapies approved for the condition. However, the treatment is far from a cure, with nearly 50% of patients relapsing and having progression of disease within the first year after infusion, prompting a need to better understand the risk factors for who may or may not progress.
With a lack of a universal model to help with those predictions across products and populations, Dr. Gagelmann and colleagues conducted a retrospective observational study utilizing data from 136 patients at seven CAR-T centers in Europe and 133 patients at three centers in the US who had received either commercial or academically produced anti-BCMA CAR-T.
Of the patients, 171 were infused with ide-cel, 38 with cilta-cel, and 60 with an academic CAR-T therapy. The patients had a median age of 63, and extramedullary disease was more common in the US cohort (48%) versus European (35%; P = .04).
Notably, the response rates between the European and US cohorts were similar, despite various differences between the cohorts, including differences in ethnicities and a lower body mass index (BMI) in the European cohort versus US (BMI 25 vs 28, respectively; P < .001). There were also no significant differences in responses between the CAR-T treatments.
The overall response rate was 87% and was comparable between the European and US groups, with complete responses occurring among 48% of patients in Europe and 49% in the US group.
Their measurable residual disease (MRD) negativity rate at any time was 29% and 37%, respectively, and rates of complete response at day 30 were 29% and 26%, respectively. The rate of progression-free survival at 12 months was 40% for the entire cohort, with a rate of 45% in the European group and 34% in the US group (P = .09). Overall survival rates at 12 months were 79% and 65%, respectively (P = .11).
The patients had a median time to relapse of 5 months, and the 5-month incidence of relapse was identical, at 24% in each cohort.
Of those patients, overall survival at 12 months was low, at 30% in the European cohort and 14% in the US group.
“Early relapse within the first 5 months clearly identified patients with poor survival across the cohort,” Dr. Gagelmann said.
Key Risk Factors Identified
Key factors found after multivariate adjustment to be independently predictive of early relapse or progression included extramedullary disease or plasma cell leukemia, being refractory to lenalidomide, having high-risk cytogenetics, and having increased age- and sex-adjusted ferritin at the time of lymphodepletion.
With each of the risk factors valued at 1 point, the MyCARe model ranked scores of 0-1 points as low-risk, 2-3 as intermediate risk, and a score above 4 was considered high-risk.
Based on the model, the risk of early relapse within 5 months among those scored as low risk was 7%, for intermediate risk, 27% (hazard ratio [HR], 3.27 vs low-risk; P < .001), and for high risk, 53% (HR, 7.89 vs low-risk; P < .001), with outcomes overall comparable between the two geographic groups. Importantly, the model maintained utility for patients who did and did not receive salvage therapies; however, “more studies are needed to identify the optimal post–CAR-T approach,” the authors write.
Dr. Gagelmann added that older age was significantly associated with improved progression-free survival in the US cohort, with a 12-month progression-free survival of 27% among patients under 65 versus 43% for those over 65 (P = .03). However, age was not found to be associated with similar outcomes in the European cohort.
The authors note that the MyCARe model outperformed the CAR-HEMATOTOX and more recent disease-specific R2-ISS risk-stratification tools regarding prediction of relapse/progression and progression-free survival.
However, with CAR-HEMATOTOX developed to predict side effects and non-relapse mortality, “our results demonstrate that both scores independently predict different outcomes after anti–BCMA CAR-T in RRMM,” the authors report. Therefore, “they can be used complimentarily to predict complications (CAR-HEMATOTOX) and relapse/progression-free survival (MyCARe model).”
Importantly, the authors add that the tool may help in patient selection for earlier treatment.
“As ide-cel and cilta-cel have shown astonishing efficacy for earlier treatment lines, our model might also be validated for such patients,” the authors note in the study. They conclude that the study provides “the first Euro-American cartography of the efficacy and safety profile of current CAR-T, showing comparable results.”
“We also built the MyCARe model, which can predict early relapse, response, and survival and may facilitate patient selection in this very challenging setting,” the authors report.
Hope for Interventions Based on Patients’ Risk
Commenting on the study, Rahul Banerjee, MD, an assistant professor with the Division of Hematology and Oncology, University of Washington, Seattle, underscored that “we need more cross-border research like this in the myeloma field.”
“Clinically, my hope that this will help us tailor post–CAR-T interventions according to each patient’s risk profile,” he said.
Risk factors such as the presence of extramedullary disease, plasma cell leukemia, or high-risk cytogenetics are expected; however, Dr. Banerjee said the inclusion of increased ferritin before CAR-T was “an interesting new risk factor that we’ve also heard about from our colleagues in the lymphoma space.”
Ferritin perturbations can indicate many things, but high ferritin can be a sign of elevated inflammation at baseline,” he explained. “These patients may have a hyperinflammatory phenotype of their myeloma which can predispose T-cells to exhaustion,” Dr. Banerjee said.
“Exhausted T-cells at collection mean exhausted CAR T-cells at infusion, and so the negative prognostic significance of elevated ferritin — which we don’t always check before CAR-T — makes sense.”
While the authors suggest a potential benefit of the MyCAR3 model in identifying patients who could benefit from other novel therapies at relapse, Dr. Banerjee suggests another possibility. “I’d take this a step further and suggest future studies of this MyCARe model to identify patients who might benefit from post–CAR-T maintenance,” he said.
“The ‘one-and-done’ nature of CAR-T in terms of not requiring further myeloma therapy after infusion is a powerful benefit for patients, but there are some patients who may benefit from low-dose pomalidomide or iberdomide/mezigdomide maintenance to help keep the myeloma at bay and to promote T-cell fitness,” Dr. Banerjee explained. “This risk model may identify patients to prioritize for such types of clinical trials in the future.”
Caveats include that factors beyond the baseline features (used for the risk model) can further influence outcomes,” Dr. Banerjee noted.
“Risk stratification is inherently a dynamic process over time,” he said, questioning, for instance, “what about patients who achieve measurable residual disease negativity [MRD] at day +28 after CAR-T cell? Does the achievement of MRD negativity ‘erase’ a high-risk MyCARe score? We’ll need future studies to tell.”
An overriding take-home message for clinicians should be to simply refer eligible patients to a CAR-T capable center as soon as possible for evaluation.
“In the lymphoma world, they have a nice adage for this: ‘If they recur, you should refer,’ ” he said. “I’d suggest the same here. By no means will we move to CAR-T therapy for every patient at first relapse. However, based on their MyCARe score and other risk factors, there may be patients we prioritize for CAR-T first versus CAR-T with maintenance versus clinical trials.”
Dr. Gagelmann reported relationships with BMS, Pfizer, Stemline, MorphoSys, and Kite. Dr. Banerjee disclosed ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
“To our knowledge, this large multicenter study is the first report to identify patients with RRMM at high risk of early relapse after CAR-T,” the authors report in the study, published February 15 in the Journal of Clinical Oncology.
“We saw that early relapse within 5 months from infusion was significantly associated with very poor outcomes, and disease-, treatment-, and inflammation-specific variables were independent predictors of early relapse,” first author Nico Gagelmann, MD, of the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany, explained in presenting the findings at the 6th European CAR T-cell Meeting jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association. CAR-T therapy has revolutionized the treatment of RRMM, with the idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) CAR-T therapies approved for the condition. However, the treatment is far from a cure, with nearly 50% of patients relapsing and having progression of disease within the first year after infusion, prompting a need to better understand the risk factors for who may or may not progress.
With a lack of a universal model to help with those predictions across products and populations, Dr. Gagelmann and colleagues conducted a retrospective observational study utilizing data from 136 patients at seven CAR-T centers in Europe and 133 patients at three centers in the US who had received either commercial or academically produced anti-BCMA CAR-T.
Of the patients, 171 were infused with ide-cel, 38 with cilta-cel, and 60 with an academic CAR-T therapy. The patients had a median age of 63, and extramedullary disease was more common in the US cohort (48%) versus European (35%; P = .04).
Notably, the response rates between the European and US cohorts were similar, despite various differences between the cohorts, including differences in ethnicities and a lower body mass index (BMI) in the European cohort versus US (BMI 25 vs 28, respectively; P < .001). There were also no significant differences in responses between the CAR-T treatments.
The overall response rate was 87% and was comparable between the European and US groups, with complete responses occurring among 48% of patients in Europe and 49% in the US group.
Their measurable residual disease (MRD) negativity rate at any time was 29% and 37%, respectively, and rates of complete response at day 30 were 29% and 26%, respectively. The rate of progression-free survival at 12 months was 40% for the entire cohort, with a rate of 45% in the European group and 34% in the US group (P = .09). Overall survival rates at 12 months were 79% and 65%, respectively (P = .11).
The patients had a median time to relapse of 5 months, and the 5-month incidence of relapse was identical, at 24% in each cohort.
Of those patients, overall survival at 12 months was low, at 30% in the European cohort and 14% in the US group.
“Early relapse within the first 5 months clearly identified patients with poor survival across the cohort,” Dr. Gagelmann said.
Key Risk Factors Identified
Key factors found after multivariate adjustment to be independently predictive of early relapse or progression included extramedullary disease or plasma cell leukemia, being refractory to lenalidomide, having high-risk cytogenetics, and having increased age- and sex-adjusted ferritin at the time of lymphodepletion.
With each of the risk factors valued at 1 point, the MyCARe model ranked scores of 0-1 points as low-risk, 2-3 as intermediate risk, and a score above 4 was considered high-risk.
Based on the model, the risk of early relapse within 5 months among those scored as low risk was 7%, for intermediate risk, 27% (hazard ratio [HR], 3.27 vs low-risk; P < .001), and for high risk, 53% (HR, 7.89 vs low-risk; P < .001), with outcomes overall comparable between the two geographic groups. Importantly, the model maintained utility for patients who did and did not receive salvage therapies; however, “more studies are needed to identify the optimal post–CAR-T approach,” the authors write.
Dr. Gagelmann added that older age was significantly associated with improved progression-free survival in the US cohort, with a 12-month progression-free survival of 27% among patients under 65 versus 43% for those over 65 (P = .03). However, age was not found to be associated with similar outcomes in the European cohort.
The authors note that the MyCARe model outperformed the CAR-HEMATOTOX and more recent disease-specific R2-ISS risk-stratification tools regarding prediction of relapse/progression and progression-free survival.
However, with CAR-HEMATOTOX developed to predict side effects and non-relapse mortality, “our results demonstrate that both scores independently predict different outcomes after anti–BCMA CAR-T in RRMM,” the authors report. Therefore, “they can be used complimentarily to predict complications (CAR-HEMATOTOX) and relapse/progression-free survival (MyCARe model).”
Importantly, the authors add that the tool may help in patient selection for earlier treatment.
“As ide-cel and cilta-cel have shown astonishing efficacy for earlier treatment lines, our model might also be validated for such patients,” the authors note in the study. They conclude that the study provides “the first Euro-American cartography of the efficacy and safety profile of current CAR-T, showing comparable results.”
“We also built the MyCARe model, which can predict early relapse, response, and survival and may facilitate patient selection in this very challenging setting,” the authors report.
Hope for Interventions Based on Patients’ Risk
Commenting on the study, Rahul Banerjee, MD, an assistant professor with the Division of Hematology and Oncology, University of Washington, Seattle, underscored that “we need more cross-border research like this in the myeloma field.”
“Clinically, my hope that this will help us tailor post–CAR-T interventions according to each patient’s risk profile,” he said.
Risk factors such as the presence of extramedullary disease, plasma cell leukemia, or high-risk cytogenetics are expected; however, Dr. Banerjee said the inclusion of increased ferritin before CAR-T was “an interesting new risk factor that we’ve also heard about from our colleagues in the lymphoma space.”
Ferritin perturbations can indicate many things, but high ferritin can be a sign of elevated inflammation at baseline,” he explained. “These patients may have a hyperinflammatory phenotype of their myeloma which can predispose T-cells to exhaustion,” Dr. Banerjee said.
“Exhausted T-cells at collection mean exhausted CAR T-cells at infusion, and so the negative prognostic significance of elevated ferritin — which we don’t always check before CAR-T — makes sense.”
While the authors suggest a potential benefit of the MyCAR3 model in identifying patients who could benefit from other novel therapies at relapse, Dr. Banerjee suggests another possibility. “I’d take this a step further and suggest future studies of this MyCARe model to identify patients who might benefit from post–CAR-T maintenance,” he said.
“The ‘one-and-done’ nature of CAR-T in terms of not requiring further myeloma therapy after infusion is a powerful benefit for patients, but there are some patients who may benefit from low-dose pomalidomide or iberdomide/mezigdomide maintenance to help keep the myeloma at bay and to promote T-cell fitness,” Dr. Banerjee explained. “This risk model may identify patients to prioritize for such types of clinical trials in the future.”
Caveats include that factors beyond the baseline features (used for the risk model) can further influence outcomes,” Dr. Banerjee noted.
“Risk stratification is inherently a dynamic process over time,” he said, questioning, for instance, “what about patients who achieve measurable residual disease negativity [MRD] at day +28 after CAR-T cell? Does the achievement of MRD negativity ‘erase’ a high-risk MyCARe score? We’ll need future studies to tell.”
An overriding take-home message for clinicians should be to simply refer eligible patients to a CAR-T capable center as soon as possible for evaluation.
“In the lymphoma world, they have a nice adage for this: ‘If they recur, you should refer,’ ” he said. “I’d suggest the same here. By no means will we move to CAR-T therapy for every patient at first relapse. However, based on their MyCARe score and other risk factors, there may be patients we prioritize for CAR-T first versus CAR-T with maintenance versus clinical trials.”
Dr. Gagelmann reported relationships with BMS, Pfizer, Stemline, MorphoSys, and Kite. Dr. Banerjee disclosed ties with BMS, Caribou Biosciences, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, SparkCures, Novartis, and Pack Health.
FROM THE 6TH EUROPEAN CAR T-CELL MEETING
FDA Withdraws Melflufen Approval, but EMA Still Allows Its Use
But the European Medicines Agency (EMA) still authorizes the drug’s manufacturer Oncopeptides AB to market the drug, also called Pepaxti, in Europe, Iceland, Lichtenstein, Norway, and the United Kingdom.
Amol Akhade, MBBS, who describes himself as a senior consultant medical and hemato oncologist–bone marrow transplant physician on LinkedIn, raised questions about the inconsistencies between the FDA and EMA’s opinions about these drugs. Dr. Akhad, of Suyog Cancer Clinics in India, posted via the following handle @SuyogCancer on X (Twitter):
“How can one drug and one trial data [have] two diagonally different outcomes from two different drug approval agencies?
Melphalan Flufenamide is finally completely withdrawn by @US_FDA
But approval by @EMA_News stays.
How can be one drug be harmful across one side of Atlantic Ocean and becomes safe and useful on the other side of Atlantic Ocean?
Modern day miracle?”
EMA: Pepaxti’s Benefits Exceed Its Risks
The EMA, which could not be reached for comment regarding why the agency was still allowing patients to use the drug, said the following about Pepaxti on its website:
“The European Medicines Agency decided that Pepaxti’s benefits are greater than its risks and it can be authorised for use in the EU. The Agency noted the unmet medical need for patients with multiple myeloma who no longer improve with the available therapies. Despite some limitations in the studies, the results were considered clinically relevant, with the exception of the subgroup of patients who had an autologous stem cell transplant and whose disease progressed within three years of transplantation.
Regarding safety, although side effects, including severe effects, were seen with treatment involving Pepaxti, these were considered acceptable and manageable,” the agency wrote.
“Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Pepaxti have been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Pepaxti are continuously monitored. Suspected side effects reported with Pepaxti are carefully evaluated and any necessary action taken to protect patients,” according to the EMA.
The FDA’s final decision, issued on February 23, 2024, follows its warning in 2021 that meflufen plus dexamethasone exposed patients with multiple myeloma to increased risk for death, and its call for withdrawal of the drug in 2022.
“The grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use,” Peter Marks, MD, PhD, Director of the FDA Center for Biologics Evaluation and Research, wrote in the final decision document.
Oncopeptides AB: Drug ‘Caters to a Large Unmet Need’
David Augustsson, Director of Corporate Affairs, Oncopeptides AB, explained in an interview why he thinks the EMA and FDA’s actions regarding the drug differ from each other.
“The European Medicines Agency had the opinion that the OCEAN study met its primary endpoint by demonstrating superior progression-free survival and it agreed that the potential detriment of overall survival was limited to patients progressing less than 36 months after an autologous stem cell transplant,” he said.“The FDA was not willing to acknowledge the observed clinically relevant differences across patient subgroups in the OCEAN study as confirmed.”
Mr. Augustsson added that this decision will deprive US patients of access to “a drug we believe caters to a large unmet need among elderly multiple myeloma patients with few treatment options left.”
“While we remain confident that we have science on our side we are of course disappointed in the decision [to remove Pepaxto from the US market],” Oncopeptides AB CEO Sofia Heigis said in a statement. “At the same time this is no change to our plans and we will continue to focus all our attention on the commercialization in Europe, progression of our pipeline and rest of world opportunities.”
FDA 'Took Swift Action' to Ensure Users of Pepaxto Were Informed of Risks
In February 2021, the FDA used the Accelerated Approval Program to enable certain patients with multiple myeloma to be treated with the peptide conjugated alkylating drug melflufen plus dexamethasone. Under the program, Oncopeptides was required to conduct the phase III randomized, controlled OCEAN clinical trial.
OCEAN enrolled 495 patients with relapsed/refractory multiple myeloma who had 2 to 4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy. Participants in the multinational study received either melflufen plus dexamethasone or pomalidomide plus dexamethasone until disease progression, unacceptable toxicity, or lack of benefit.
In July 2021, the FDA issued an alert that the study results showed increased risk for death in participants treated with melflufen. In October that year, at FDA request, Oncopeptides removed the drug from the US market but continued to provide it to patients already receiving it. In December 2022, the FDA requested that the company withdraw melflufen’s US marketing authorization.
Responding to questions about the timing of the FDA’s most recent decision about Pepaxto and how the decision will affect patient care in the US, the FDA emailed the following statement to this news organization:
“Since the OCEAN trial results for Pepaxto in 2021, the FDA has responded to safety concerns about Pepaxto by issuing a CDER Alert, communicating concerns to Oncopeptides, holding an Oncologic Drugs Advisory Committee meeting in September 2022, and issuing a letter of notice to Oncopeptides in July 2023, proposing to withdraw Pepaxto (NDA 214383). After receiving the notice, Oncopeptides appealed the withdrawal in August 2023. A meeting was held with the Commissioner’s designee, Dr. Peter Marks, Oncopeptides, and others from FDA in October 2023. Dr. Marks reviewed the record and considered the arguments made on appeal and issued a final decision on February 23, 2024. Prior to reaching a decision, the FDA took swift action to ensure those receiving Pepaxto in the post-confirmatory clinical trial were informed of the risks and that no new patients were enrolled in the trial. We also note that it is our understanding that Pepaxto has not been marketed in the U.S. since October 22, 2021.”
“This is the first time FDA has used the amended procedures for withdrawal of accelerated approval that were enacted in 2023, as part of the Food and Drug Omnibus Report Act of 2022 (FDORA),” the agency wrote in a Feb 23 statement. The agency will also remove melflufen from the Approved Drug Products with Therapeutic Equivalence Evaluations, also called the Orange Book.
But the European Medicines Agency (EMA) still authorizes the drug’s manufacturer Oncopeptides AB to market the drug, also called Pepaxti, in Europe, Iceland, Lichtenstein, Norway, and the United Kingdom.
Amol Akhade, MBBS, who describes himself as a senior consultant medical and hemato oncologist–bone marrow transplant physician on LinkedIn, raised questions about the inconsistencies between the FDA and EMA’s opinions about these drugs. Dr. Akhad, of Suyog Cancer Clinics in India, posted via the following handle @SuyogCancer on X (Twitter):
“How can one drug and one trial data [have] two diagonally different outcomes from two different drug approval agencies?
Melphalan Flufenamide is finally completely withdrawn by @US_FDA
But approval by @EMA_News stays.
How can be one drug be harmful across one side of Atlantic Ocean and becomes safe and useful on the other side of Atlantic Ocean?
Modern day miracle?”
EMA: Pepaxti’s Benefits Exceed Its Risks
The EMA, which could not be reached for comment regarding why the agency was still allowing patients to use the drug, said the following about Pepaxti on its website:
“The European Medicines Agency decided that Pepaxti’s benefits are greater than its risks and it can be authorised for use in the EU. The Agency noted the unmet medical need for patients with multiple myeloma who no longer improve with the available therapies. Despite some limitations in the studies, the results were considered clinically relevant, with the exception of the subgroup of patients who had an autologous stem cell transplant and whose disease progressed within three years of transplantation.
Regarding safety, although side effects, including severe effects, were seen with treatment involving Pepaxti, these were considered acceptable and manageable,” the agency wrote.
“Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Pepaxti have been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Pepaxti are continuously monitored. Suspected side effects reported with Pepaxti are carefully evaluated and any necessary action taken to protect patients,” according to the EMA.
The FDA’s final decision, issued on February 23, 2024, follows its warning in 2021 that meflufen plus dexamethasone exposed patients with multiple myeloma to increased risk for death, and its call for withdrawal of the drug in 2022.
“The grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use,” Peter Marks, MD, PhD, Director of the FDA Center for Biologics Evaluation and Research, wrote in the final decision document.
Oncopeptides AB: Drug ‘Caters to a Large Unmet Need’
David Augustsson, Director of Corporate Affairs, Oncopeptides AB, explained in an interview why he thinks the EMA and FDA’s actions regarding the drug differ from each other.
“The European Medicines Agency had the opinion that the OCEAN study met its primary endpoint by demonstrating superior progression-free survival and it agreed that the potential detriment of overall survival was limited to patients progressing less than 36 months after an autologous stem cell transplant,” he said.“The FDA was not willing to acknowledge the observed clinically relevant differences across patient subgroups in the OCEAN study as confirmed.”
Mr. Augustsson added that this decision will deprive US patients of access to “a drug we believe caters to a large unmet need among elderly multiple myeloma patients with few treatment options left.”
“While we remain confident that we have science on our side we are of course disappointed in the decision [to remove Pepaxto from the US market],” Oncopeptides AB CEO Sofia Heigis said in a statement. “At the same time this is no change to our plans and we will continue to focus all our attention on the commercialization in Europe, progression of our pipeline and rest of world opportunities.”
FDA 'Took Swift Action' to Ensure Users of Pepaxto Were Informed of Risks
In February 2021, the FDA used the Accelerated Approval Program to enable certain patients with multiple myeloma to be treated with the peptide conjugated alkylating drug melflufen plus dexamethasone. Under the program, Oncopeptides was required to conduct the phase III randomized, controlled OCEAN clinical trial.
OCEAN enrolled 495 patients with relapsed/refractory multiple myeloma who had 2 to 4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy. Participants in the multinational study received either melflufen plus dexamethasone or pomalidomide plus dexamethasone until disease progression, unacceptable toxicity, or lack of benefit.
In July 2021, the FDA issued an alert that the study results showed increased risk for death in participants treated with melflufen. In October that year, at FDA request, Oncopeptides removed the drug from the US market but continued to provide it to patients already receiving it. In December 2022, the FDA requested that the company withdraw melflufen’s US marketing authorization.
Responding to questions about the timing of the FDA’s most recent decision about Pepaxto and how the decision will affect patient care in the US, the FDA emailed the following statement to this news organization:
“Since the OCEAN trial results for Pepaxto in 2021, the FDA has responded to safety concerns about Pepaxto by issuing a CDER Alert, communicating concerns to Oncopeptides, holding an Oncologic Drugs Advisory Committee meeting in September 2022, and issuing a letter of notice to Oncopeptides in July 2023, proposing to withdraw Pepaxto (NDA 214383). After receiving the notice, Oncopeptides appealed the withdrawal in August 2023. A meeting was held with the Commissioner’s designee, Dr. Peter Marks, Oncopeptides, and others from FDA in October 2023. Dr. Marks reviewed the record and considered the arguments made on appeal and issued a final decision on February 23, 2024. Prior to reaching a decision, the FDA took swift action to ensure those receiving Pepaxto in the post-confirmatory clinical trial were informed of the risks and that no new patients were enrolled in the trial. We also note that it is our understanding that Pepaxto has not been marketed in the U.S. since October 22, 2021.”
“This is the first time FDA has used the amended procedures for withdrawal of accelerated approval that were enacted in 2023, as part of the Food and Drug Omnibus Report Act of 2022 (FDORA),” the agency wrote in a Feb 23 statement. The agency will also remove melflufen from the Approved Drug Products with Therapeutic Equivalence Evaluations, also called the Orange Book.
But the European Medicines Agency (EMA) still authorizes the drug’s manufacturer Oncopeptides AB to market the drug, also called Pepaxti, in Europe, Iceland, Lichtenstein, Norway, and the United Kingdom.
Amol Akhade, MBBS, who describes himself as a senior consultant medical and hemato oncologist–bone marrow transplant physician on LinkedIn, raised questions about the inconsistencies between the FDA and EMA’s opinions about these drugs. Dr. Akhad, of Suyog Cancer Clinics in India, posted via the following handle @SuyogCancer on X (Twitter):
“How can one drug and one trial data [have] two diagonally different outcomes from two different drug approval agencies?
Melphalan Flufenamide is finally completely withdrawn by @US_FDA
But approval by @EMA_News stays.
How can be one drug be harmful across one side of Atlantic Ocean and becomes safe and useful on the other side of Atlantic Ocean?
Modern day miracle?”
EMA: Pepaxti’s Benefits Exceed Its Risks
The EMA, which could not be reached for comment regarding why the agency was still allowing patients to use the drug, said the following about Pepaxti on its website:
“The European Medicines Agency decided that Pepaxti’s benefits are greater than its risks and it can be authorised for use in the EU. The Agency noted the unmet medical need for patients with multiple myeloma who no longer improve with the available therapies. Despite some limitations in the studies, the results were considered clinically relevant, with the exception of the subgroup of patients who had an autologous stem cell transplant and whose disease progressed within three years of transplantation.
Regarding safety, although side effects, including severe effects, were seen with treatment involving Pepaxti, these were considered acceptable and manageable,” the agency wrote.
“Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Pepaxti have been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Pepaxti are continuously monitored. Suspected side effects reported with Pepaxti are carefully evaluated and any necessary action taken to protect patients,” according to the EMA.
The FDA’s final decision, issued on February 23, 2024, follows its warning in 2021 that meflufen plus dexamethasone exposed patients with multiple myeloma to increased risk for death, and its call for withdrawal of the drug in 2022.
“The grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use,” Peter Marks, MD, PhD, Director of the FDA Center for Biologics Evaluation and Research, wrote in the final decision document.
Oncopeptides AB: Drug ‘Caters to a Large Unmet Need’
David Augustsson, Director of Corporate Affairs, Oncopeptides AB, explained in an interview why he thinks the EMA and FDA’s actions regarding the drug differ from each other.
“The European Medicines Agency had the opinion that the OCEAN study met its primary endpoint by demonstrating superior progression-free survival and it agreed that the potential detriment of overall survival was limited to patients progressing less than 36 months after an autologous stem cell transplant,” he said.“The FDA was not willing to acknowledge the observed clinically relevant differences across patient subgroups in the OCEAN study as confirmed.”
Mr. Augustsson added that this decision will deprive US patients of access to “a drug we believe caters to a large unmet need among elderly multiple myeloma patients with few treatment options left.”
“While we remain confident that we have science on our side we are of course disappointed in the decision [to remove Pepaxto from the US market],” Oncopeptides AB CEO Sofia Heigis said in a statement. “At the same time this is no change to our plans and we will continue to focus all our attention on the commercialization in Europe, progression of our pipeline and rest of world opportunities.”
FDA 'Took Swift Action' to Ensure Users of Pepaxto Were Informed of Risks
In February 2021, the FDA used the Accelerated Approval Program to enable certain patients with multiple myeloma to be treated with the peptide conjugated alkylating drug melflufen plus dexamethasone. Under the program, Oncopeptides was required to conduct the phase III randomized, controlled OCEAN clinical trial.
OCEAN enrolled 495 patients with relapsed/refractory multiple myeloma who had 2 to 4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy. Participants in the multinational study received either melflufen plus dexamethasone or pomalidomide plus dexamethasone until disease progression, unacceptable toxicity, or lack of benefit.
In July 2021, the FDA issued an alert that the study results showed increased risk for death in participants treated with melflufen. In October that year, at FDA request, Oncopeptides removed the drug from the US market but continued to provide it to patients already receiving it. In December 2022, the FDA requested that the company withdraw melflufen’s US marketing authorization.
Responding to questions about the timing of the FDA’s most recent decision about Pepaxto and how the decision will affect patient care in the US, the FDA emailed the following statement to this news organization:
“Since the OCEAN trial results for Pepaxto in 2021, the FDA has responded to safety concerns about Pepaxto by issuing a CDER Alert, communicating concerns to Oncopeptides, holding an Oncologic Drugs Advisory Committee meeting in September 2022, and issuing a letter of notice to Oncopeptides in July 2023, proposing to withdraw Pepaxto (NDA 214383). After receiving the notice, Oncopeptides appealed the withdrawal in August 2023. A meeting was held with the Commissioner’s designee, Dr. Peter Marks, Oncopeptides, and others from FDA in October 2023. Dr. Marks reviewed the record and considered the arguments made on appeal and issued a final decision on February 23, 2024. Prior to reaching a decision, the FDA took swift action to ensure those receiving Pepaxto in the post-confirmatory clinical trial were informed of the risks and that no new patients were enrolled in the trial. We also note that it is our understanding that Pepaxto has not been marketed in the U.S. since October 22, 2021.”
“This is the first time FDA has used the amended procedures for withdrawal of accelerated approval that were enacted in 2023, as part of the Food and Drug Omnibus Report Act of 2022 (FDORA),” the agency wrote in a Feb 23 statement. The agency will also remove melflufen from the Approved Drug Products with Therapeutic Equivalence Evaluations, also called the Orange Book.
New Trials in Leukemia and Lymphoma: Could Your Patient Benefit?
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .
Several clinical trials in leukemia and lymphoma have started enrolling recently. Maybe one of your patients could benefit from taking part?
run by the Center for International Blood and Bone Marrow Transplant Research.
The purpose of the study is to test whether cyclophosphamide, which is given to prevent a dreaded complication of stem cell transplantation called graft-versus-host disease, can be safely reduced without increasing infection or reducing protection. All participants will receive cyclophosphamide on days 3 and 4 post transplant. One group will receive a reduced dose of cyclophosphamide (25 mg/kg per dose), and the other will be given a usual dose (37.5 mg/kg).
Sites in Michigan, Missouri, Oregon, Virginia, and Washington started recruiting for 190 participants in December 2023. Study centers in Florida, Massachusetts, New York, and Wisconsin are also planned. Infection-free survival is the primary endpoint, and overall survival is a secondary measure. Quality of life (QoL) is not recorded. More details at clinicaltrials.gov.
Untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Adults who are newly diagnosed with this type of cancer and have active disease may wish to consider a randomized, open-label, phase 3 trial testing an experimental Bruton tyrosine kinase (BTK) inhibitor, nemtabrutinib (from Merck Sharp & Dohme), against standard-of-care BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).
BTK inhibitors target B-cell proliferation in B-cell cancers such as CLL/SLL and allow for chemotherapy-free treatment of some hematological malignancies. In this study, until disease progression, unacceptable toxicity, or another reason for discontinuation occurs, participants will take daily oral nemtabrutinib, ibrutinib, or acalabrutinib.
The study opened in December 2023 in Pennsylvania, Washington, Taiwan, Israel, and the United Kingdom seeking 1200 participants. The primary outcomes are objective response rate and progression-free survival. Overall survival is a secondary outcome, and QoL is not measured. More details at clinicaltrials.gov.
Relapsed or refractory leukemia with a KMT2A-gene rearrangement (KMT2A-r). Children aged 1 month to younger than 6 years with this diagnosis may be able to join an open-label, nonrandomized, Children’s Oncology Group phase 2 study to determine the most tolerable and/or effective dose of an experimental oral drug called revumenib when added to chemotherapy.
KMT2A-gene alterations are associated with a poor prognosis in leukemia. These alterations cause blood cells to dedifferentiate and start proliferating uncontrollably as leukemia cells. The expression of the damaged KMT2A gene relies on a protein called menin. Revumenib, from Syndax Pharmaceuticals, blocks menin and prevents expression of KMT2A.
Children in the study will receive two different regimens of revumenib in combination with chemotherapy for up to a year, or until disease progression or unacceptable toxicity, and will then be followed for up to 5 years. Trial centers in 12 US states opened their doors in January 2024 looking for 78 participants. Toxicities and minimal residual disease are the primary outcomes; overall survival is a secondary outcome, and QoL is not assessed. More details at clinicaltrials.gov.
Previously untreated follicular lymphoma or diffuse large B-cell lymphoma. Adults with one of these types of lymphoma may be eligible for one of three open-label, randomized, phase 3 trials testing odronextamab (from Regeneron). This bispecific antibody is designed to ‘lock together’ CD20 on cancer cells with CD3-expressing cancer-killing T cells. It has shown anti-lymphoma activity in heavily pretreated patients.
Late in 2023, three phase 3 trials turned the spotlight on treatment-naive patients and started recruiting 2115 participants to assess odronextamab in this setting. The trial OLYMPIA-1 will compare odronextamab with standard-of-care rituximab (Rituxan) plus chemotherapy in follicular lymphoma. OLYMPIA-2 will test the drug in combination with chemotherapy, also in follicular lymphoma. OLYMPIA-3 will evaluate odronextamab plus chemotherapy against rituximab and chemotherapy in people with large B-cell lymphoma.
All study drugs, including odronextamab, will be administered by intravenous infusion, and participants will be followed for up to 5 years. Research centers across eight US states and Australia, Czechia, France, Italy, Poland, Spain, Turkey, and Thailand are currently accepting participants for the three trials. The primary outcomes are various measures of toxicity and complete response at 30 months in the follicular lymphoma studies and toxicity and progression-free survival in large B-cell lymphoma. All three trials are measuring overall survival and QoL as secondary endpoints.
Previously untreated stage II, III, or IV follicular lymphoma. Adults with this type of cancer may be eligible to participate in a randomized, open-label, phase 3 study testing whether an experimental therapy called epcoritamab (from AbbVie) improves disease response and is tolerable when added to standard therapy. For up to 120 weeks, one group of participants will receive a combination of intravenous rituximab and oral lenalidomide (Revlimid), while a second group will also receive subcutaneous injections of epcoritamab. Some participants may be offered investigators’ choice of chemotherapy as well.
Sites across Iowa, Maryland, Missouri, Ohio, Washington, and Montana started welcoming their 900 participants in February 2024. The primary outcome is complete response at 30 months. Overall survival and QoL are secondary outcomes. More details at clinicaltrials.gov.
Relapsed or refractory mantle cell lymphoma. Adults facing one of these clinical scenarios can join an Academic and Community Cancer Research United open label, phase 2 trial examining the effectiveness of combining tafasitamab (Monjuvi), lenalidomide, and venetoclax (Venclexta) for such patients.
Frontline therapy does not cure mantle cell lymphoma, and continued relapses are common. In this situation, treatments can include acalabrutinib, ibrutinib, stem cell transplantation, venetoclax, lenalidomide, and rituximab.
In this study, participants will take venetoclax and lenalidomide daily and receive intravenous tafasitamab every 2 weeks after an initial ramp-up period as per clinic standards. Participants will be followed for 5 years after entering the trial. The Mayo Clinic in Rochester, Minnesota, began recruiting the planned 100 trial participants in January 2024. The primary outcome is objective response rate; overall survival is a secondary outcome, and QoL will not be tracked. More details at clinicaltrials.gov.
All trial information is from the National Institutes of Health US National Library of Medicine (online at clinicaltrials.gov).
A version of this article appeared on Medscape.com .