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Evidence favors lower-dose R-CHOP for fit, very elderly DLBCL patients
A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.
In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
Study characteristics
Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.
Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.
In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.
Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.
Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
MiniCHOP mattered
Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.
In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.
For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m2 on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m2 or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.
One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).
“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.
The authors reported that they received no research funds for the study and that they had no disclosures.
A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.
In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
Study characteristics
Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.
Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.
In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.
Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.
Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
MiniCHOP mattered
Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.
In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.
For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m2 on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m2 or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.
One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).
“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.
The authors reported that they received no research funds for the study and that they had no disclosures.
A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.
In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
Study characteristics
Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.
Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.
In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.
Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.
Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
MiniCHOP mattered
Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.
In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.
For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m2 on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m2 or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.
One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).
“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.
The authors reported that they received no research funds for the study and that they had no disclosures.
FROM CRITICAL REVIEWS IN ONCOLOGY/HEMATOLOGY
Poor survival with COVID in patients who have had HSCT
Among individuals who have received a hematopoietic stem cell transplant (HSCT), often used in the treatment of blood cancers, rates of survival are poor for those who develop COVID-19.
The probability of survival 30 days after being diagnosed with COVID-19 is only 68% for persons who have received an allogeneic HSCT and 67% for autologous HSCT recipients, according to new data from the Center for International Blood and Marrow Transplant Research.
These findings underscore the need for “stringent surveillance and aggressive treatment measures” in this population, Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital, Memphis, and colleagues wrote.
The findings were published online March 1, 2021, in The Lancet Haematology.
The study is “of importance for physicians caring for HSCT recipients worldwide,” Mathieu Leclerc, MD, and Sébastien Maury, MD, Hôpital Henri Mondor, Créteil, France, commented in an accompanying editorial.
Study details
For their study, Dr. Sharma and colleagues analyzed outcomes for all HSCT recipients who developed COVID-19 and whose cases were reported to the CIBMTR. Of 318 such patients, 184 had undergone allogeneic HSCT, and 134 had undergone autologous HSCT.
Overall, about half of these patients (49%) had mild COVID-19.
Severe COVID-19 that required mechanical ventilation developed in 15% and 13% of the allogeneic and autologous HSCT recipients, respectively.
About one-fifth of patients died: 22% and 19% of allogeneic and autologous HSCT recipients, respectively.
Factors associated with greater mortality risk included age of 50 years or older (hazard ratio, 2.53), male sex (HR, 3.53), and development of COVID-19 within 12 months of undergoing HSCT (HR, 2.67).
Among autologous HSCT recipients, lymphoma was associated with higher mortality risk in comparison with a plasma cell disorder or myeloma (HR, 2.41), the authors noted.
“Two important messages can be drawn from the results reported by Sharma and colleagues,” Dr. Leclerc and Dr. Maury wrote in their editorial. “The first is the confirmation that the prognosis of COVID-19 is particularly poor in HSCT recipients, and that its prevention, in the absence of any specific curative treatment with sufficient efficacy, should be at the forefront of concerns.”
The second relates to the risk factors for death among HSCT recipients who develop COVID-19. In addition to previously known risk factors, such as age and gender, the investigators identified transplant-specific factors potentially associated with prognosis – namely, the nearly threefold increase in death among allogeneic HSCT recipients who develop COVID-19 within 12 months of transplant, they explained.
However, the findings are limited by a substantial amount of missing data, short follow-up, and the possibility of selection bias, they noted.
“Further large and well-designed studies with longer follow-up are needed to confirm and refine the results,” the editorialists wrote.
“[A] better understanding of the distinctive features of COVID-19 infection in HSCT recipients will be a necessary and essential step toward improvement of the remarkably poor prognosis observed in this setting,” they added.
The study was funded by the American Society of Hematology; the Leukemia and Lymphoma Society; the National Cancer Institute; the National Heart, Lung and Blood Institute; the National Institute of Allergy and Infectious Diseases; the National Institutes of Health; the Health Resources and Services Administration; and the Office of Naval Research. Dr. Sharma receives support for the conduct of industry-sponsored trials from Vertex Pharmaceuticals, CRISPR Therapeutics, and Novartis and consulting fees from Spotlight Therapeutics. Dr. Leclerc and Dr. Maury disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among individuals who have received a hematopoietic stem cell transplant (HSCT), often used in the treatment of blood cancers, rates of survival are poor for those who develop COVID-19.
The probability of survival 30 days after being diagnosed with COVID-19 is only 68% for persons who have received an allogeneic HSCT and 67% for autologous HSCT recipients, according to new data from the Center for International Blood and Marrow Transplant Research.
These findings underscore the need for “stringent surveillance and aggressive treatment measures” in this population, Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital, Memphis, and colleagues wrote.
The findings were published online March 1, 2021, in The Lancet Haematology.
The study is “of importance for physicians caring for HSCT recipients worldwide,” Mathieu Leclerc, MD, and Sébastien Maury, MD, Hôpital Henri Mondor, Créteil, France, commented in an accompanying editorial.
Study details
For their study, Dr. Sharma and colleagues analyzed outcomes for all HSCT recipients who developed COVID-19 and whose cases were reported to the CIBMTR. Of 318 such patients, 184 had undergone allogeneic HSCT, and 134 had undergone autologous HSCT.
Overall, about half of these patients (49%) had mild COVID-19.
Severe COVID-19 that required mechanical ventilation developed in 15% and 13% of the allogeneic and autologous HSCT recipients, respectively.
About one-fifth of patients died: 22% and 19% of allogeneic and autologous HSCT recipients, respectively.
Factors associated with greater mortality risk included age of 50 years or older (hazard ratio, 2.53), male sex (HR, 3.53), and development of COVID-19 within 12 months of undergoing HSCT (HR, 2.67).
Among autologous HSCT recipients, lymphoma was associated with higher mortality risk in comparison with a plasma cell disorder or myeloma (HR, 2.41), the authors noted.
“Two important messages can be drawn from the results reported by Sharma and colleagues,” Dr. Leclerc and Dr. Maury wrote in their editorial. “The first is the confirmation that the prognosis of COVID-19 is particularly poor in HSCT recipients, and that its prevention, in the absence of any specific curative treatment with sufficient efficacy, should be at the forefront of concerns.”
The second relates to the risk factors for death among HSCT recipients who develop COVID-19. In addition to previously known risk factors, such as age and gender, the investigators identified transplant-specific factors potentially associated with prognosis – namely, the nearly threefold increase in death among allogeneic HSCT recipients who develop COVID-19 within 12 months of transplant, they explained.
However, the findings are limited by a substantial amount of missing data, short follow-up, and the possibility of selection bias, they noted.
“Further large and well-designed studies with longer follow-up are needed to confirm and refine the results,” the editorialists wrote.
“[A] better understanding of the distinctive features of COVID-19 infection in HSCT recipients will be a necessary and essential step toward improvement of the remarkably poor prognosis observed in this setting,” they added.
The study was funded by the American Society of Hematology; the Leukemia and Lymphoma Society; the National Cancer Institute; the National Heart, Lung and Blood Institute; the National Institute of Allergy and Infectious Diseases; the National Institutes of Health; the Health Resources and Services Administration; and the Office of Naval Research. Dr. Sharma receives support for the conduct of industry-sponsored trials from Vertex Pharmaceuticals, CRISPR Therapeutics, and Novartis and consulting fees from Spotlight Therapeutics. Dr. Leclerc and Dr. Maury disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among individuals who have received a hematopoietic stem cell transplant (HSCT), often used in the treatment of blood cancers, rates of survival are poor for those who develop COVID-19.
The probability of survival 30 days after being diagnosed with COVID-19 is only 68% for persons who have received an allogeneic HSCT and 67% for autologous HSCT recipients, according to new data from the Center for International Blood and Marrow Transplant Research.
These findings underscore the need for “stringent surveillance and aggressive treatment measures” in this population, Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital, Memphis, and colleagues wrote.
The findings were published online March 1, 2021, in The Lancet Haematology.
The study is “of importance for physicians caring for HSCT recipients worldwide,” Mathieu Leclerc, MD, and Sébastien Maury, MD, Hôpital Henri Mondor, Créteil, France, commented in an accompanying editorial.
Study details
For their study, Dr. Sharma and colleagues analyzed outcomes for all HSCT recipients who developed COVID-19 and whose cases were reported to the CIBMTR. Of 318 such patients, 184 had undergone allogeneic HSCT, and 134 had undergone autologous HSCT.
Overall, about half of these patients (49%) had mild COVID-19.
Severe COVID-19 that required mechanical ventilation developed in 15% and 13% of the allogeneic and autologous HSCT recipients, respectively.
About one-fifth of patients died: 22% and 19% of allogeneic and autologous HSCT recipients, respectively.
Factors associated with greater mortality risk included age of 50 years or older (hazard ratio, 2.53), male sex (HR, 3.53), and development of COVID-19 within 12 months of undergoing HSCT (HR, 2.67).
Among autologous HSCT recipients, lymphoma was associated with higher mortality risk in comparison with a plasma cell disorder or myeloma (HR, 2.41), the authors noted.
“Two important messages can be drawn from the results reported by Sharma and colleagues,” Dr. Leclerc and Dr. Maury wrote in their editorial. “The first is the confirmation that the prognosis of COVID-19 is particularly poor in HSCT recipients, and that its prevention, in the absence of any specific curative treatment with sufficient efficacy, should be at the forefront of concerns.”
The second relates to the risk factors for death among HSCT recipients who develop COVID-19. In addition to previously known risk factors, such as age and gender, the investigators identified transplant-specific factors potentially associated with prognosis – namely, the nearly threefold increase in death among allogeneic HSCT recipients who develop COVID-19 within 12 months of transplant, they explained.
However, the findings are limited by a substantial amount of missing data, short follow-up, and the possibility of selection bias, they noted.
“Further large and well-designed studies with longer follow-up are needed to confirm and refine the results,” the editorialists wrote.
“[A] better understanding of the distinctive features of COVID-19 infection in HSCT recipients will be a necessary and essential step toward improvement of the remarkably poor prognosis observed in this setting,” they added.
The study was funded by the American Society of Hematology; the Leukemia and Lymphoma Society; the National Cancer Institute; the National Heart, Lung and Blood Institute; the National Institute of Allergy and Infectious Diseases; the National Institutes of Health; the Health Resources and Services Administration; and the Office of Naval Research. Dr. Sharma receives support for the conduct of industry-sponsored trials from Vertex Pharmaceuticals, CRISPR Therapeutics, and Novartis and consulting fees from Spotlight Therapeutics. Dr. Leclerc and Dr. Maury disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Don’t delay: Cancer patients need both doses of COVID vaccine
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Novel ddPCR assay precisely measures CAR T-cells after infusion
A novel quantitative assay used with flow cytometry helps to precisely measure chimeric antigen receptor (CAR) T-cell engraftment and in vivo expansion to predict patient outcomes after CAR T-cell infusion, according to researchers at the Fondazione IRCCS Istituto Nazionale Tumorion in Milan.
Higher frequencies of CAR-positive T cells at day 9 after infusion, as measured using the polymerase chain reaction (PCR)-based assay, accurately distinguished responders from nonresponders, Paolo Corradini, MD, said at the 3rd European CAR T-cell Meeting.
The findings, first presented in December at the American Society of Hematology annual conference, suggest the assay could improve treatment decision-making, Dr. Corradini of the University of Milan said at the meeting, which is jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association
He and his colleagues prospectively collected samples from 16 patients with diffuse large B-cell lymphoma, 5 with transformed follicular lymphoma, and 7 with primary mediastinal B-cell lymphoma who were treated with either axicabtagene ciloleucel (axi-cel; Yescarta) or tisagenlecleucel (tisa-cal; Kymriah) between November 2019 and July 2020. CAR T cells were monitored using flow cytometry.
Pivotal trial data and subsequent findings with respect to tisa-cel and axi-cel have demonstrated that CAR T-cell engraftment and in vivo expansion have a crucial impact on disease response and toxicity: a cut-off value of CAR+ cells at day 9 greater than 24.5/microliters distinguished responders from nonresponders with a sensitivity of 87.5% and specificity of 81%, Dr. Corradini noted.
“But we have also devised a methodology by digital droplet PCR (ddPCR) recently that correlates perfectly with the flow cytometry data,” he said, adding that the assay is “easy and allowed precise enumeration of the CAR T cells in the blood of the patient.”
The R square (coefficient of determination) for ddPCR and flow cytometry was 0.9995 and 0.9997 for tisa-cel and axi-cel, respectively (P < .0001 for each). This is particularly useful for assessing whether low CAR T-cell levels on flow cytometry are background signals resulting from nonspecific binding of the antibodies or true low levels, and the findings therefore have implications for improving clinical decision-making and outcomes in CAR T-cell therapy recipients, he said.
A novel quantitative assay used with flow cytometry helps to precisely measure chimeric antigen receptor (CAR) T-cell engraftment and in vivo expansion to predict patient outcomes after CAR T-cell infusion, according to researchers at the Fondazione IRCCS Istituto Nazionale Tumorion in Milan.
Higher frequencies of CAR-positive T cells at day 9 after infusion, as measured using the polymerase chain reaction (PCR)-based assay, accurately distinguished responders from nonresponders, Paolo Corradini, MD, said at the 3rd European CAR T-cell Meeting.
The findings, first presented in December at the American Society of Hematology annual conference, suggest the assay could improve treatment decision-making, Dr. Corradini of the University of Milan said at the meeting, which is jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association
He and his colleagues prospectively collected samples from 16 patients with diffuse large B-cell lymphoma, 5 with transformed follicular lymphoma, and 7 with primary mediastinal B-cell lymphoma who were treated with either axicabtagene ciloleucel (axi-cel; Yescarta) or tisagenlecleucel (tisa-cal; Kymriah) between November 2019 and July 2020. CAR T cells were monitored using flow cytometry.
Pivotal trial data and subsequent findings with respect to tisa-cel and axi-cel have demonstrated that CAR T-cell engraftment and in vivo expansion have a crucial impact on disease response and toxicity: a cut-off value of CAR+ cells at day 9 greater than 24.5/microliters distinguished responders from nonresponders with a sensitivity of 87.5% and specificity of 81%, Dr. Corradini noted.
“But we have also devised a methodology by digital droplet PCR (ddPCR) recently that correlates perfectly with the flow cytometry data,” he said, adding that the assay is “easy and allowed precise enumeration of the CAR T cells in the blood of the patient.”
The R square (coefficient of determination) for ddPCR and flow cytometry was 0.9995 and 0.9997 for tisa-cel and axi-cel, respectively (P < .0001 for each). This is particularly useful for assessing whether low CAR T-cell levels on flow cytometry are background signals resulting from nonspecific binding of the antibodies or true low levels, and the findings therefore have implications for improving clinical decision-making and outcomes in CAR T-cell therapy recipients, he said.
A novel quantitative assay used with flow cytometry helps to precisely measure chimeric antigen receptor (CAR) T-cell engraftment and in vivo expansion to predict patient outcomes after CAR T-cell infusion, according to researchers at the Fondazione IRCCS Istituto Nazionale Tumorion in Milan.
Higher frequencies of CAR-positive T cells at day 9 after infusion, as measured using the polymerase chain reaction (PCR)-based assay, accurately distinguished responders from nonresponders, Paolo Corradini, MD, said at the 3rd European CAR T-cell Meeting.
The findings, first presented in December at the American Society of Hematology annual conference, suggest the assay could improve treatment decision-making, Dr. Corradini of the University of Milan said at the meeting, which is jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association
He and his colleagues prospectively collected samples from 16 patients with diffuse large B-cell lymphoma, 5 with transformed follicular lymphoma, and 7 with primary mediastinal B-cell lymphoma who were treated with either axicabtagene ciloleucel (axi-cel; Yescarta) or tisagenlecleucel (tisa-cal; Kymriah) between November 2019 and July 2020. CAR T cells were monitored using flow cytometry.
Pivotal trial data and subsequent findings with respect to tisa-cel and axi-cel have demonstrated that CAR T-cell engraftment and in vivo expansion have a crucial impact on disease response and toxicity: a cut-off value of CAR+ cells at day 9 greater than 24.5/microliters distinguished responders from nonresponders with a sensitivity of 87.5% and specificity of 81%, Dr. Corradini noted.
“But we have also devised a methodology by digital droplet PCR (ddPCR) recently that correlates perfectly with the flow cytometry data,” he said, adding that the assay is “easy and allowed precise enumeration of the CAR T cells in the blood of the patient.”
The R square (coefficient of determination) for ddPCR and flow cytometry was 0.9995 and 0.9997 for tisa-cel and axi-cel, respectively (P < .0001 for each). This is particularly useful for assessing whether low CAR T-cell levels on flow cytometry are background signals resulting from nonspecific binding of the antibodies or true low levels, and the findings therefore have implications for improving clinical decision-making and outcomes in CAR T-cell therapy recipients, he said.
REPORTING FROM CART21
Steroid complications in GVHD common, boost costs of care
Steroids are usually the first choice of therapy for the treatment of patients with graft-vs.-host disease (GVHD), but complications from steroid use may carry a high financial cost, investigators caution.
Among 689 patients with a diagnosis of GVHD following a hematopoietic stem cell transplant (HSCT) who received steroids, 685 (97%) had at least one steroid-related complication, resulting in nearly $165,000 in mean health-care costs over 24 months, said Elizabeth J. Bell, PhD, MPH, an epidemiologist at Optum Inc.
“For both acute and chronic GVHD, the standard of care for first-line treatment is systemic steroids. The complications associated with steroid treatment are well known. However, the health-care resources utilized and the costs incurred by these patients are not well-quantified,” she said at the Transplantation & Cellular Therapies Meetings (Abstract 12).
Dr. Bell reported the results of a retrospective database analysis on costs associated with steroid complications in HSCT recipients at the meeting, which was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
She and colleagues from Optum, Incyte, and the University of Minnesota in Minneapolis looked at data on 689 patients with a diagnosis of GVHD after HSCT who received systemic steroids from July 1, 2010, through Aug. 31, 2019. The data were extracted from the Optum Research database, and included U.S. commercial and Medicare Advantage patients.
They looked at total complications and steroid-associated complications in each of four categories: infections; metabolic or endocrine complications (for example, diabetes, dyslipidemia); gastrointestinal (GI) complications (e.g., peptic ulcer disease); and bone or muscle complications (myopathy, etc).
They estimated costs based on International Classification of Diseases (ICD) codes for any steroid complications during the 24 months after steroid initiation, including those complications that may have been present at the time of GVHD diagnosis.
The median patient age was 55 years, and 60% of the sample were male. The mean Charlson Comorbidity Index score at baseline was 3.
Overall, 22% of patients had only acute GVHD, 21% had only chronic GVHD, and 39% had both acute and chronic disease. The GVHD type was unspecified in the remaining 18%.
The median time from GVHD diagnosis to initiating steroids was 30 days for patients with both acute and chronic disease, as well as those with both presentations. The median time to initiation was 36 days for patients with unspecified GVHD type.
The median cumulative duration of steroid use over 24 months was 62 days for patients with acute GVHD, 208 days for those with chronic GVHD, 166 days for those with both, and 74 days for patients with unspecified GVHD type.
As noted before, complications occurred in 97% of patients, with infections being the most common complications, occurring in 80% of patients, followed by metabolic/endocrine complications in 32%, gastrointestinal in 29%, and bone/muscle complications in 20%.
For the 665 patients who had any steroid-related complication, the mean costs of steroid-associated care in the 24 months after they were started on steroids was $164,787, and the median cost was $50,834.
Health care costs were highest among patients with infections, at a mean of $167,473, and a median of $57,680, followed by bone/muscle conditions ($75,289 and $2,057, respectively), GI conditions ($67,861 and $3,360), and metabolic or endocrine conditions ($47, 101 and $1,164).
In all categories, hospitalizations accounted for the large majority of costs.
Two-thirds (66%) of patients who experienced any steroid-related complication required hospitalization, primarily for infections.
Among all patients with complications, the median cumulative hospital stay over 24 months was 20 days, with bone/muscle complications and infections associated with a median of 19 and 18 days of hospitalization, respectively.
Dr. Bell acknowledged that the study was limited by use of ICD coding to identify steroid complication-related health-care utilization and costs, which can be imprecise, and by the fact that the analysis included only complications resulting in health care use as documented in medical claims. In addition, the investigators noted that they could not control for the possibility that steroids exacerbated conditions that existed at baseline.
“These findings emphasize the need to cautiously evaluate the treatment options for patients with GVHD. Future study with medical records is needed to provide insights on the clinical aspects of the complications (e.g., severity and suspected causality),” Dr. Bell and colleagues concluded in the study’s abstract.
Definitions questioned
An HSCT specialist approached for comment said that the findings of the study made sense, but she had questions regarding the study methodology.
“I would intuitively think that steroid-associated complications are a major cause of health care use in GVHD patients and it’s interesting to see that there is emerging data to support this hypothesis,” HSCT specialist Hélène Schoemans, MD of the University of Leuven, Belgium, said in an interview.
She noted, however, that “it is surprising that the period of steroid initiation was the same for acute and chronic GVHD,” and questioned whether that anomalous finding could be due to the study’s definition of acute and chronic GVHD or to how the period from baseline to steroid initiation was defined.
The questions about the definitions and timing of therapy make it uncertain as to whether the complications reported were caused by steroids or by some other factor, she suggested.
The study was supported by Optum Inc. Dr. Bell is an employee of the company, and a paid consultant of Incyte. Dr. Schoemans has received travel expenses from Celgene, Abbvie, and Incyte; is part of the advisory boards for Incyte; and has received speakers fees from Novartis, Incyte, Jazz Pharmaceuticals, and Takeda.
Steroids are usually the first choice of therapy for the treatment of patients with graft-vs.-host disease (GVHD), but complications from steroid use may carry a high financial cost, investigators caution.
Among 689 patients with a diagnosis of GVHD following a hematopoietic stem cell transplant (HSCT) who received steroids, 685 (97%) had at least one steroid-related complication, resulting in nearly $165,000 in mean health-care costs over 24 months, said Elizabeth J. Bell, PhD, MPH, an epidemiologist at Optum Inc.
“For both acute and chronic GVHD, the standard of care for first-line treatment is systemic steroids. The complications associated with steroid treatment are well known. However, the health-care resources utilized and the costs incurred by these patients are not well-quantified,” she said at the Transplantation & Cellular Therapies Meetings (Abstract 12).
Dr. Bell reported the results of a retrospective database analysis on costs associated with steroid complications in HSCT recipients at the meeting, which was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
She and colleagues from Optum, Incyte, and the University of Minnesota in Minneapolis looked at data on 689 patients with a diagnosis of GVHD after HSCT who received systemic steroids from July 1, 2010, through Aug. 31, 2019. The data were extracted from the Optum Research database, and included U.S. commercial and Medicare Advantage patients.
They looked at total complications and steroid-associated complications in each of four categories: infections; metabolic or endocrine complications (for example, diabetes, dyslipidemia); gastrointestinal (GI) complications (e.g., peptic ulcer disease); and bone or muscle complications (myopathy, etc).
They estimated costs based on International Classification of Diseases (ICD) codes for any steroid complications during the 24 months after steroid initiation, including those complications that may have been present at the time of GVHD diagnosis.
The median patient age was 55 years, and 60% of the sample were male. The mean Charlson Comorbidity Index score at baseline was 3.
Overall, 22% of patients had only acute GVHD, 21% had only chronic GVHD, and 39% had both acute and chronic disease. The GVHD type was unspecified in the remaining 18%.
The median time from GVHD diagnosis to initiating steroids was 30 days for patients with both acute and chronic disease, as well as those with both presentations. The median time to initiation was 36 days for patients with unspecified GVHD type.
The median cumulative duration of steroid use over 24 months was 62 days for patients with acute GVHD, 208 days for those with chronic GVHD, 166 days for those with both, and 74 days for patients with unspecified GVHD type.
As noted before, complications occurred in 97% of patients, with infections being the most common complications, occurring in 80% of patients, followed by metabolic/endocrine complications in 32%, gastrointestinal in 29%, and bone/muscle complications in 20%.
For the 665 patients who had any steroid-related complication, the mean costs of steroid-associated care in the 24 months after they were started on steroids was $164,787, and the median cost was $50,834.
Health care costs were highest among patients with infections, at a mean of $167,473, and a median of $57,680, followed by bone/muscle conditions ($75,289 and $2,057, respectively), GI conditions ($67,861 and $3,360), and metabolic or endocrine conditions ($47, 101 and $1,164).
In all categories, hospitalizations accounted for the large majority of costs.
Two-thirds (66%) of patients who experienced any steroid-related complication required hospitalization, primarily for infections.
Among all patients with complications, the median cumulative hospital stay over 24 months was 20 days, with bone/muscle complications and infections associated with a median of 19 and 18 days of hospitalization, respectively.
Dr. Bell acknowledged that the study was limited by use of ICD coding to identify steroid complication-related health-care utilization and costs, which can be imprecise, and by the fact that the analysis included only complications resulting in health care use as documented in medical claims. In addition, the investigators noted that they could not control for the possibility that steroids exacerbated conditions that existed at baseline.
“These findings emphasize the need to cautiously evaluate the treatment options for patients with GVHD. Future study with medical records is needed to provide insights on the clinical aspects of the complications (e.g., severity and suspected causality),” Dr. Bell and colleagues concluded in the study’s abstract.
Definitions questioned
An HSCT specialist approached for comment said that the findings of the study made sense, but she had questions regarding the study methodology.
“I would intuitively think that steroid-associated complications are a major cause of health care use in GVHD patients and it’s interesting to see that there is emerging data to support this hypothesis,” HSCT specialist Hélène Schoemans, MD of the University of Leuven, Belgium, said in an interview.
She noted, however, that “it is surprising that the period of steroid initiation was the same for acute and chronic GVHD,” and questioned whether that anomalous finding could be due to the study’s definition of acute and chronic GVHD or to how the period from baseline to steroid initiation was defined.
The questions about the definitions and timing of therapy make it uncertain as to whether the complications reported were caused by steroids or by some other factor, she suggested.
The study was supported by Optum Inc. Dr. Bell is an employee of the company, and a paid consultant of Incyte. Dr. Schoemans has received travel expenses from Celgene, Abbvie, and Incyte; is part of the advisory boards for Incyte; and has received speakers fees from Novartis, Incyte, Jazz Pharmaceuticals, and Takeda.
Steroids are usually the first choice of therapy for the treatment of patients with graft-vs.-host disease (GVHD), but complications from steroid use may carry a high financial cost, investigators caution.
Among 689 patients with a diagnosis of GVHD following a hematopoietic stem cell transplant (HSCT) who received steroids, 685 (97%) had at least one steroid-related complication, resulting in nearly $165,000 in mean health-care costs over 24 months, said Elizabeth J. Bell, PhD, MPH, an epidemiologist at Optum Inc.
“For both acute and chronic GVHD, the standard of care for first-line treatment is systemic steroids. The complications associated with steroid treatment are well known. However, the health-care resources utilized and the costs incurred by these patients are not well-quantified,” she said at the Transplantation & Cellular Therapies Meetings (Abstract 12).
Dr. Bell reported the results of a retrospective database analysis on costs associated with steroid complications in HSCT recipients at the meeting, which was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
She and colleagues from Optum, Incyte, and the University of Minnesota in Minneapolis looked at data on 689 patients with a diagnosis of GVHD after HSCT who received systemic steroids from July 1, 2010, through Aug. 31, 2019. The data were extracted from the Optum Research database, and included U.S. commercial and Medicare Advantage patients.
They looked at total complications and steroid-associated complications in each of four categories: infections; metabolic or endocrine complications (for example, diabetes, dyslipidemia); gastrointestinal (GI) complications (e.g., peptic ulcer disease); and bone or muscle complications (myopathy, etc).
They estimated costs based on International Classification of Diseases (ICD) codes for any steroid complications during the 24 months after steroid initiation, including those complications that may have been present at the time of GVHD diagnosis.
The median patient age was 55 years, and 60% of the sample were male. The mean Charlson Comorbidity Index score at baseline was 3.
Overall, 22% of patients had only acute GVHD, 21% had only chronic GVHD, and 39% had both acute and chronic disease. The GVHD type was unspecified in the remaining 18%.
The median time from GVHD diagnosis to initiating steroids was 30 days for patients with both acute and chronic disease, as well as those with both presentations. The median time to initiation was 36 days for patients with unspecified GVHD type.
The median cumulative duration of steroid use over 24 months was 62 days for patients with acute GVHD, 208 days for those with chronic GVHD, 166 days for those with both, and 74 days for patients with unspecified GVHD type.
As noted before, complications occurred in 97% of patients, with infections being the most common complications, occurring in 80% of patients, followed by metabolic/endocrine complications in 32%, gastrointestinal in 29%, and bone/muscle complications in 20%.
For the 665 patients who had any steroid-related complication, the mean costs of steroid-associated care in the 24 months after they were started on steroids was $164,787, and the median cost was $50,834.
Health care costs were highest among patients with infections, at a mean of $167,473, and a median of $57,680, followed by bone/muscle conditions ($75,289 and $2,057, respectively), GI conditions ($67,861 and $3,360), and metabolic or endocrine conditions ($47, 101 and $1,164).
In all categories, hospitalizations accounted for the large majority of costs.
Two-thirds (66%) of patients who experienced any steroid-related complication required hospitalization, primarily for infections.
Among all patients with complications, the median cumulative hospital stay over 24 months was 20 days, with bone/muscle complications and infections associated with a median of 19 and 18 days of hospitalization, respectively.
Dr. Bell acknowledged that the study was limited by use of ICD coding to identify steroid complication-related health-care utilization and costs, which can be imprecise, and by the fact that the analysis included only complications resulting in health care use as documented in medical claims. In addition, the investigators noted that they could not control for the possibility that steroids exacerbated conditions that existed at baseline.
“These findings emphasize the need to cautiously evaluate the treatment options for patients with GVHD. Future study with medical records is needed to provide insights on the clinical aspects of the complications (e.g., severity and suspected causality),” Dr. Bell and colleagues concluded in the study’s abstract.
Definitions questioned
An HSCT specialist approached for comment said that the findings of the study made sense, but she had questions regarding the study methodology.
“I would intuitively think that steroid-associated complications are a major cause of health care use in GVHD patients and it’s interesting to see that there is emerging data to support this hypothesis,” HSCT specialist Hélène Schoemans, MD of the University of Leuven, Belgium, said in an interview.
She noted, however, that “it is surprising that the period of steroid initiation was the same for acute and chronic GVHD,” and questioned whether that anomalous finding could be due to the study’s definition of acute and chronic GVHD or to how the period from baseline to steroid initiation was defined.
The questions about the definitions and timing of therapy make it uncertain as to whether the complications reported were caused by steroids or by some other factor, she suggested.
The study was supported by Optum Inc. Dr. Bell is an employee of the company, and a paid consultant of Incyte. Dr. Schoemans has received travel expenses from Celgene, Abbvie, and Incyte; is part of the advisory boards for Incyte; and has received speakers fees from Novartis, Incyte, Jazz Pharmaceuticals, and Takeda.
FROM TCT 2021
CAR T-cell products shine in real-world setting, reveal new insights
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
FROM CART21
Chronic GVHD therapies offer hope for treating refractory disease
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.
“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.
Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.
Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.
Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).
There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
Treatment goals
Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:
- Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
- Preventing further tissue and organ damage
- Minimizing toxicity
- Maintaining graft-versus-tumor effect
- Achieving graft tolerance and stopping immunosuppression
- Decreasing nonrelapse mortality and improving survival
Active trials
Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.
Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.
“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
BTK inhibitors
The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.
The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.
Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
JAK1/2 inhibition
The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.
The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
Selective T-cell expansion
Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.
Monocyte/macrophage depletion
Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.
It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
Hedgehog pathway inhibition
There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.
This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.
The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
ROCK2 inhibition
Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.
This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.
At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
Hard-to-manage patients
“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.
“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
‘Exciting time’
“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.
“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.
She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.
“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.
Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.
FROM TCT 2021
Prognostic gene signature identifies high- vs. low-risk DLBCL patients
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
according to the results of a database analysis.
A total of 33 genes formed the signature that could be transformed into a risk score, according to a study by Santosh Khanal, a senior bioinformatics scientist at Children’s Mercy Kansas City (Mo.), and colleagues published in Cancer Genetics.
Their study used gene expression and clinical parameters from the Lymphoma/Leukemia Molecular Profiling Project from 233 patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy to identify genes whose expression was associated with overall survival (OS). They refined the information to develop prognostic gene signature that could be used to calculate risk scores for each individual and predict OS.
Significant separation
The researchers initially found 61 genes individually associated with OS that had a nonadjusted P ≤ .001 using the univariate Cox regression model. The 61 genes were then assessed using multivariate Cox analysis to identify a minimal set of genes that could predict OS, resulting in a minimal set of 33 genes that were used to develop a survival risk score for each individual.
The OS of the high-risk group was significantly reduced, compared with the low-risk group (hazard ratio, 0.046; P < .0001). Upon stratification of individuals by risk score into quartiles, patients in the lowest quartile risk score had a 100% probability of survival, while individuals in the highest quartile had a 9.2% OS by year 5.
In order to validate their results, the researchers calculated risk scores using their prognostic gene set in three additional published DLBCL studies. For all three studies, individuals with low risk score had significantly better OS, “indicating the robustness of the gene signature for multiple external datasets,” according to the researchers.
The top biological pathways and processes that were significantly overrepresented in the 33-gene set were the thioester biosynthetic process (P = .00005), cellular response to hormone stimulus (P = .002), G protein–coupled receptor ligand binding (P = .003), and myeloid cell activation involved in immune responses (P = 0.006).
“As new therapies for lymphoma become available, including new immunotherapies and personalized medicine approaches such as [chimeric antigen receptor] T cells, it will be important to identify candidate individuals that are at high risk and may benefit from experimental therapeutic approaches compared with individuals who will have lower risk of death with current therapies,” the researchers concluded.
The authors reported that they had no competing interests.
FROM CANCER GENETICS
Synthetic lethality: Triple combination is a viable strategy for B-cell malignancies
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.
FROM ASH 2020
Bispecific antibody odronextamab demonstrates durable complete responses in refractory NHL
The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.
Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.
Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.
For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.
Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.
This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.
“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
Durability with further follow-up
Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.
In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.
In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.
In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.
In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.
Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.
Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).
No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.
No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
More research needed
Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.
“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.
A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.
The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
SOURCE: Bannerji R et al. ASH 2020, Abstract 400.
The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.
Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.
Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.
For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.
Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.
This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.
“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
Durability with further follow-up
Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.
In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.
In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.
In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.
In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.
Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.
Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).
No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.
No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
More research needed
Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.
“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.
A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.
The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
SOURCE: Bannerji R et al. ASH 2020, Abstract 400.
The novel bispecific antibody odronextamab (REGN1979) is demonstrating encouraging activity, durable responses, and acceptable safety in a phase 1 study of patients with highly refractory B-cell non-Hodgkin lymphoma, according to an investigator.
Durable complete responses (CRs) to odronextamab are being observed in more than 80% of heavily pretreated patients with follicular lymphoma (FL) in the ongoing study, said Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey, New Brunswick.
Likewise, durable CRs were seen in greater than 80% of patients diffuse large B-cell lymphoma (DLBCL) not previously exposed to chimeric antigen receptor (CAR) T-cell therapy, and also in about 20% of patients who were treated with CAR T cells, Dr. Bannerji reported at the annual meeting of the American Society of Hematology, held virtually this year.
For these patients with FL or DLBCL in the phase 1 study, cytokine release syndrome (CRS) and neurotoxicity events did not exceed grade 3 in severity, and no cases of tumor lysis syndrome (TLS) were observed, Dr. Bannerji added in his presentation.
Those findings suggest odronextamab, which binds to CD3 on T cells and CD20 on malignant B cells, may offer an “off-the-shelf, primarily outpatient treatment option” for patients with relapsed or refractory B-cell NHL, he said in concluding remarks on the study.
This first-in-human study took a conservative approach, according to Dr. Bannerji, by mandating hospital admission during an initial step-up dosing schedule used along with dexamethasone to mitigate risk of CRS.
“With our step-up dosing and steroid premedication, we really have not seen too many cytokine release issues, and I do think that in the future it would be safe even to do step-up in the majority of patients as an outpatient,” he said in a discussion following his presentation.
Durability with further follow-up
Phase 1 data for odronextamab reported by Dr. Bannerji at the 2019 ASH meeting showed encouraging safety, tolerability, and preliminary efficacy in patients with relapsed or refractory B-cell NHL at doses up to 320 mg weekly.
In the presentation at this year’s ASH meeting, Dr. Bannerji provided updated safety and efficacy results, including longer follow-up for duration of response.
In patients with relapsed/refractory FL, the overall response rate (ORR) was 90% (27 of 30 patients), including a CR rate of 70% (21 of 30 patients), it was reported at ASH 2020. The median duration of complete response (DoCR) was not reached, with 81% of CRs durable and ongoing for up to 41 months, according to Dr. Bannerji.
In patients with relapsed/refractory DLBCL who had not received prior CAR T-cell therapy, the ORR was 55% (6 of 11 patients), all of which were complete responses, data show. The median DoCR was again not reached, with 83% of CRs durable and ongoing for up to 21 months as of this report.
In a larger group of patients with relapsed/refractory DLBCL who had received CAR T-cell therapy, the ORR was 33% (8 of 24 patients) including a 21% CR rate (5 of 24 patients). Median DoCR was not reached, the study data show, with 100% of these CRs ongoing for up to 20 months.
Odronextamab was given up to 320 mg weekly with no dose-limiting toxicities and the maximum tolerated dose not reached, according to Dr. Bannerji, who noted that no patients had discontinued treatment because of CRS or neurotoxicity.
Cytokine release syndrome was seen in about 35% of patients with DLBCL, FL, or other B-cell NHLs (48 of 136 patients), and most cases were grade 1 or 2 in severity. No FL or DLBCL patients experienced CRS higher than grade 3, according to the investigator, who reported one case of grade 3 CRS occurring out of 38 FL patients (about 3%) and four cases of grade 3 CRS out of 78 total DLBCL patients (about 5%).
No patients with FL experienced immune effector cell-associated neurotoxicity syndrome (ICANS)-like events of grade 3 or greater, the investigator said. Three cases of grade 3 ICANS-like events were reported among DLBCL patients: two cases that occurred during the step-up dosing phase and one that occurred at full dose.
No TLS events of grade 3 or greater were observed in any FL or DLBCL patients, he added.
More research needed
Although efficacy and safety results from this phase 1 study of odronextamab are encouraging, the durability, combinability, and potential for sequencing of bispecific antibodies deserves further investigation, said Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center in New York.
“Bispecifics in lymphoma as a class are extremely promising,” Dr. Diefenbach said in an interview. “They’re highly active and they activate an immune response against the tumor without inducing, for the most part, the same degree of neurotoxicity and CRS most CAR T cells do.
“I think the challenge is going to be to figure out how to give them in combination with other therapies to maximize durability, and how to sequence bispecifics and CAR T cells,” she added.
A global phase 2 trial of odronextamab in patients with relapsed or refractory B-cell NHL is currently recruiting. According to Dr. Bannerji, further studies are planned to evaluate odronextamab with chemotherapy and in chemotherapy-free combinations in earlier lines of treatment.
The study is sponsored by Regeneron Pharmaceuticals. Dr. Bannerji reported research funding from Regeneron, AbbVie, F. Hoffmann La Roche Ltd/Genentech Inc., and Pharmacyclics LLC, an AbbVie company. Dr. Bannerji’s spouse is an employee of Sanofi Pasteur.
SOURCE: Bannerji R et al. ASH 2020, Abstract 400.
FROM ASH 2020