User login
Care coordination, equity can eliminate disparities for nonwhite patients with DLBCL
ORLANDO – Patients with diffuse large B-cell lymphoma (DLBCL) who are members of an ethnic or racial minority do not have worse outcomes than whites when they receive appropriate treatment and institutional support, a study on disparities in cancer care shows.
Although previous studies have shown that minorities with DLBCL have worse outcomes than do whites, results of a study comparing outcomes from 155 patients of white heritage with those of 41 patients from black, Hispanic, or other minority backgrounds found no significant differences in either progression-free survival (PFS) or overall survival in 2 years over follow-up, reported Nilanjan Ghosh, MD, PhD, from the Levine Cancer Institute, Atrium Health, in Charlotte, N.C.
He attributes the results to his center’s robust nurse navigation program, equal access among all patients – regardless of ability to pay – to standard treatments, and to the availability of clinical trial participation and stem cell transplantation.
“I think a key message is that if you are able to offer the same treatment and clinical trials to people irrespective of their race or socioeconomic status and can provide support, you can get equal outcomes as long as the biology is the same in both groups,” he said at a briefing prior to presentation of data in an oral abstract session at the annual meeting of the American Society of Hematology.
Dr. Ghosh pointed to four separate studies that showed that minority populations with DLBCL have worse outcomes than did whites, and noted that both uninsured and Medicaid-insured patients have also been shown to have poorer results, suggesting a role of socioeconomic factors in determining who gets optimum care and who does not.
The investigators compared PFS and OS among white and nonwhite patients with DLBCL treated in their institution, which has a safety-net cancer center. They also looked at the frequencies of clinical trial participation and stem cell transplantation between the groups.
The study included all patients with de novo DLBCL who presented to their center during January 2016–January 2019. They used patient-reported descriptors of race/ethnicity to create one of two cohorts: either self-identified whites (155 patients) or nonwhites (41), a group that included black patients, Hispanic patients, Asian Americans, and Native Americans.
The authors collected data on demographics, disease characteristics (including revised International Prognostic Index and double-hit status), insurance data, treatment, trial enrollment, progression, and death.
They found that nonwhites were significantly younger at diagnosis (median 56 vs. 64 years; P = .007), with an even distribution between the sexes in each group.
Two-thirds of both white and nonwhite patients had government insurance (Medicare or Medicaid). Of the remaining patients, 33% of white had private insurance, compared with 27% of nonwhites. No whites were uninsured, but 3 of the 41 nonwhites (7%) had no insurance.
Of the 155 white patients, 121 (86%) received nurse navigation services, as did 33 of 41 (81%) of nonwhites. The services include lodging assistance for homeless patients, transportation services for patients without cars, and care coordination among primary care physicians, oncologists, and other specialists. The services are part of the center’s standard practice, with excess costs, if any, folded into the budget, Dr. Ghosh said.
Looking at disease characteristics and treatment, the investigators found that risk profiles were similar between the groups. A higher percentage of whites had double-hit lymphoma (11% vs. 7%), but this difference was not statistically significant.
The investigators also found that in their program race was not a barrier to optimum therapy, with 96% of whites and 98% of nonwhites receiving frontline therapy with an anthracycline and rituximab-based regimen, and 4% and 2%, respectively received a non–anthracycline based regimen.
In each group, 39% of patients had disease that either relapsed or was refractory to frontline therapy.
In all, 11% of whites and 12% of nonwhites enrolled in clinical trials, 11% and 19%, respectively, underwent stem cell transplantation.
For patients with relapsed/refractory disease, the 2-year PFS rates were 60% for whites, and 63% for nonwhites, and the 2-year OS rates were 74% and 81%, respectively.
Dr. Ghosh and colleagues concluded that “our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants, and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported.”
The study was internally funded. Dr. Ghosh reported consulting fees, research funding, speakers bureau activity, and/or honoraria from multiple companies.
SOURCE: Hu B et al. ASH 2019. Abstract 425.
ORLANDO – Patients with diffuse large B-cell lymphoma (DLBCL) who are members of an ethnic or racial minority do not have worse outcomes than whites when they receive appropriate treatment and institutional support, a study on disparities in cancer care shows.
Although previous studies have shown that minorities with DLBCL have worse outcomes than do whites, results of a study comparing outcomes from 155 patients of white heritage with those of 41 patients from black, Hispanic, or other minority backgrounds found no significant differences in either progression-free survival (PFS) or overall survival in 2 years over follow-up, reported Nilanjan Ghosh, MD, PhD, from the Levine Cancer Institute, Atrium Health, in Charlotte, N.C.
He attributes the results to his center’s robust nurse navigation program, equal access among all patients – regardless of ability to pay – to standard treatments, and to the availability of clinical trial participation and stem cell transplantation.
“I think a key message is that if you are able to offer the same treatment and clinical trials to people irrespective of their race or socioeconomic status and can provide support, you can get equal outcomes as long as the biology is the same in both groups,” he said at a briefing prior to presentation of data in an oral abstract session at the annual meeting of the American Society of Hematology.
Dr. Ghosh pointed to four separate studies that showed that minority populations with DLBCL have worse outcomes than did whites, and noted that both uninsured and Medicaid-insured patients have also been shown to have poorer results, suggesting a role of socioeconomic factors in determining who gets optimum care and who does not.
The investigators compared PFS and OS among white and nonwhite patients with DLBCL treated in their institution, which has a safety-net cancer center. They also looked at the frequencies of clinical trial participation and stem cell transplantation between the groups.
The study included all patients with de novo DLBCL who presented to their center during January 2016–January 2019. They used patient-reported descriptors of race/ethnicity to create one of two cohorts: either self-identified whites (155 patients) or nonwhites (41), a group that included black patients, Hispanic patients, Asian Americans, and Native Americans.
The authors collected data on demographics, disease characteristics (including revised International Prognostic Index and double-hit status), insurance data, treatment, trial enrollment, progression, and death.
They found that nonwhites were significantly younger at diagnosis (median 56 vs. 64 years; P = .007), with an even distribution between the sexes in each group.
Two-thirds of both white and nonwhite patients had government insurance (Medicare or Medicaid). Of the remaining patients, 33% of white had private insurance, compared with 27% of nonwhites. No whites were uninsured, but 3 of the 41 nonwhites (7%) had no insurance.
Of the 155 white patients, 121 (86%) received nurse navigation services, as did 33 of 41 (81%) of nonwhites. The services include lodging assistance for homeless patients, transportation services for patients without cars, and care coordination among primary care physicians, oncologists, and other specialists. The services are part of the center’s standard practice, with excess costs, if any, folded into the budget, Dr. Ghosh said.
Looking at disease characteristics and treatment, the investigators found that risk profiles were similar between the groups. A higher percentage of whites had double-hit lymphoma (11% vs. 7%), but this difference was not statistically significant.
The investigators also found that in their program race was not a barrier to optimum therapy, with 96% of whites and 98% of nonwhites receiving frontline therapy with an anthracycline and rituximab-based regimen, and 4% and 2%, respectively received a non–anthracycline based regimen.
In each group, 39% of patients had disease that either relapsed or was refractory to frontline therapy.
In all, 11% of whites and 12% of nonwhites enrolled in clinical trials, 11% and 19%, respectively, underwent stem cell transplantation.
For patients with relapsed/refractory disease, the 2-year PFS rates were 60% for whites, and 63% for nonwhites, and the 2-year OS rates were 74% and 81%, respectively.
Dr. Ghosh and colleagues concluded that “our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants, and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported.”
The study was internally funded. Dr. Ghosh reported consulting fees, research funding, speakers bureau activity, and/or honoraria from multiple companies.
SOURCE: Hu B et al. ASH 2019. Abstract 425.
ORLANDO – Patients with diffuse large B-cell lymphoma (DLBCL) who are members of an ethnic or racial minority do not have worse outcomes than whites when they receive appropriate treatment and institutional support, a study on disparities in cancer care shows.
Although previous studies have shown that minorities with DLBCL have worse outcomes than do whites, results of a study comparing outcomes from 155 patients of white heritage with those of 41 patients from black, Hispanic, or other minority backgrounds found no significant differences in either progression-free survival (PFS) or overall survival in 2 years over follow-up, reported Nilanjan Ghosh, MD, PhD, from the Levine Cancer Institute, Atrium Health, in Charlotte, N.C.
He attributes the results to his center’s robust nurse navigation program, equal access among all patients – regardless of ability to pay – to standard treatments, and to the availability of clinical trial participation and stem cell transplantation.
“I think a key message is that if you are able to offer the same treatment and clinical trials to people irrespective of their race or socioeconomic status and can provide support, you can get equal outcomes as long as the biology is the same in both groups,” he said at a briefing prior to presentation of data in an oral abstract session at the annual meeting of the American Society of Hematology.
Dr. Ghosh pointed to four separate studies that showed that minority populations with DLBCL have worse outcomes than did whites, and noted that both uninsured and Medicaid-insured patients have also been shown to have poorer results, suggesting a role of socioeconomic factors in determining who gets optimum care and who does not.
The investigators compared PFS and OS among white and nonwhite patients with DLBCL treated in their institution, which has a safety-net cancer center. They also looked at the frequencies of clinical trial participation and stem cell transplantation between the groups.
The study included all patients with de novo DLBCL who presented to their center during January 2016–January 2019. They used patient-reported descriptors of race/ethnicity to create one of two cohorts: either self-identified whites (155 patients) or nonwhites (41), a group that included black patients, Hispanic patients, Asian Americans, and Native Americans.
The authors collected data on demographics, disease characteristics (including revised International Prognostic Index and double-hit status), insurance data, treatment, trial enrollment, progression, and death.
They found that nonwhites were significantly younger at diagnosis (median 56 vs. 64 years; P = .007), with an even distribution between the sexes in each group.
Two-thirds of both white and nonwhite patients had government insurance (Medicare or Medicaid). Of the remaining patients, 33% of white had private insurance, compared with 27% of nonwhites. No whites were uninsured, but 3 of the 41 nonwhites (7%) had no insurance.
Of the 155 white patients, 121 (86%) received nurse navigation services, as did 33 of 41 (81%) of nonwhites. The services include lodging assistance for homeless patients, transportation services for patients without cars, and care coordination among primary care physicians, oncologists, and other specialists. The services are part of the center’s standard practice, with excess costs, if any, folded into the budget, Dr. Ghosh said.
Looking at disease characteristics and treatment, the investigators found that risk profiles were similar between the groups. A higher percentage of whites had double-hit lymphoma (11% vs. 7%), but this difference was not statistically significant.
The investigators also found that in their program race was not a barrier to optimum therapy, with 96% of whites and 98% of nonwhites receiving frontline therapy with an anthracycline and rituximab-based regimen, and 4% and 2%, respectively received a non–anthracycline based regimen.
In each group, 39% of patients had disease that either relapsed or was refractory to frontline therapy.
In all, 11% of whites and 12% of nonwhites enrolled in clinical trials, 11% and 19%, respectively, underwent stem cell transplantation.
For patients with relapsed/refractory disease, the 2-year PFS rates were 60% for whites, and 63% for nonwhites, and the 2-year OS rates were 74% and 81%, respectively.
Dr. Ghosh and colleagues concluded that “our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants, and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported.”
The study was internally funded. Dr. Ghosh reported consulting fees, research funding, speakers bureau activity, and/or honoraria from multiple companies.
SOURCE: Hu B et al. ASH 2019. Abstract 425.
REPORTING FROM ASH 2019
Aspirin plus a DOAC may do more harm than good in some
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
REPORTING FROM ASH 2019
Off-the-shelf cellular therapy shows promise in the lab
ORLANDO – A cellular therapy called FT596 is active against B-cell malignancies and, when combined with rituximab, can be more effective than traditional chimeric antigen receptor (CAR) T cells, preclinical research findings suggest.
FT596 is a universal, anti-CD19 CAR natural killer (NK) cell therapy derived from a master induced pluripotent stem cell (iPSC) line.
FT596 reduced tumor growth in mouse models of leukemia and lymphoma. When combined with rituximab, FT596 was able to overcome CD19 antigen escape.
Jode P. Goodridge, PhD, of Fate Therapeutics in San Diego, presented these results at the annual meeting of the American Society of Hematology.
Dr. Goodridge explained that FT596 begins with a source material, such as a fibroblast, that is reprogrammed into an iPSC progenitor cell. That cell is sorted and expanded into a renewable, homogeneous, pluripotent master iPSC line. The iPSCs are differentiated into CD34 cells, which are differentiated into NK cells. The iPSC-derived NK cells are then modified with the following:
- An anti-CD19 CAR that is optimized for NK-cell biology and contains an NKG2D transmembrane domain, a 2B4 costimulatory domain, and a CD3-zeta signaling domain.
- An interleukin-15 receptor fusion that promotes cell survival and reduces the need for cytokine support.
- A high-affinity 158V, noncleavable CD16 Fc receptor that enhances antibody-dependent cellular cytotoxicity when FT596 is combined with a monoclonal antibody such as rituximab.
Dr. Goodridge presented results with FT596, both alone and in combination with rituximab, in vitro and in vivo.
When compared with no treatment, three doses of FT596 monotherapy reduced tumor growth in a mouse model of leukemia (Nalm6). FT596 plus rituximab reduced tumor growth in a mouse model of lymphoma (Raji), when compared with no treatment or rituximab alone.
Three doses of FT596 proved more effective than a single dose of CD19 CAR T-cell therapy in a mouse model of lymphoma (Raji). FT596 both reduced tumor growth and prolonged survival in the mice.
Lastly, in vitro experiments in Raji cells showed that FT596 plus rituximab can produce deeper responses than primary CAR-T cells, and the combination can prevent antigen escape.
Dr. Goodridge said these results support the phase 1 study of FT596, given as monotherapy or in combination with rituximab or obinutuzumab, in patients with relapsed/refractory B-cell lymphomas or chronic lymphocytic leukemia.
Dr. Goodridge is employed by Fate Therapeutics, the company developing FT596.
SOURCE: Goodridge JP et al. ASH 2019. Abstract 301.
ORLANDO – A cellular therapy called FT596 is active against B-cell malignancies and, when combined with rituximab, can be more effective than traditional chimeric antigen receptor (CAR) T cells, preclinical research findings suggest.
FT596 is a universal, anti-CD19 CAR natural killer (NK) cell therapy derived from a master induced pluripotent stem cell (iPSC) line.
FT596 reduced tumor growth in mouse models of leukemia and lymphoma. When combined with rituximab, FT596 was able to overcome CD19 antigen escape.
Jode P. Goodridge, PhD, of Fate Therapeutics in San Diego, presented these results at the annual meeting of the American Society of Hematology.
Dr. Goodridge explained that FT596 begins with a source material, such as a fibroblast, that is reprogrammed into an iPSC progenitor cell. That cell is sorted and expanded into a renewable, homogeneous, pluripotent master iPSC line. The iPSCs are differentiated into CD34 cells, which are differentiated into NK cells. The iPSC-derived NK cells are then modified with the following:
- An anti-CD19 CAR that is optimized for NK-cell biology and contains an NKG2D transmembrane domain, a 2B4 costimulatory domain, and a CD3-zeta signaling domain.
- An interleukin-15 receptor fusion that promotes cell survival and reduces the need for cytokine support.
- A high-affinity 158V, noncleavable CD16 Fc receptor that enhances antibody-dependent cellular cytotoxicity when FT596 is combined with a monoclonal antibody such as rituximab.
Dr. Goodridge presented results with FT596, both alone and in combination with rituximab, in vitro and in vivo.
When compared with no treatment, three doses of FT596 monotherapy reduced tumor growth in a mouse model of leukemia (Nalm6). FT596 plus rituximab reduced tumor growth in a mouse model of lymphoma (Raji), when compared with no treatment or rituximab alone.
Three doses of FT596 proved more effective than a single dose of CD19 CAR T-cell therapy in a mouse model of lymphoma (Raji). FT596 both reduced tumor growth and prolonged survival in the mice.
Lastly, in vitro experiments in Raji cells showed that FT596 plus rituximab can produce deeper responses than primary CAR-T cells, and the combination can prevent antigen escape.
Dr. Goodridge said these results support the phase 1 study of FT596, given as monotherapy or in combination with rituximab or obinutuzumab, in patients with relapsed/refractory B-cell lymphomas or chronic lymphocytic leukemia.
Dr. Goodridge is employed by Fate Therapeutics, the company developing FT596.
SOURCE: Goodridge JP et al. ASH 2019. Abstract 301.
ORLANDO – A cellular therapy called FT596 is active against B-cell malignancies and, when combined with rituximab, can be more effective than traditional chimeric antigen receptor (CAR) T cells, preclinical research findings suggest.
FT596 is a universal, anti-CD19 CAR natural killer (NK) cell therapy derived from a master induced pluripotent stem cell (iPSC) line.
FT596 reduced tumor growth in mouse models of leukemia and lymphoma. When combined with rituximab, FT596 was able to overcome CD19 antigen escape.
Jode P. Goodridge, PhD, of Fate Therapeutics in San Diego, presented these results at the annual meeting of the American Society of Hematology.
Dr. Goodridge explained that FT596 begins with a source material, such as a fibroblast, that is reprogrammed into an iPSC progenitor cell. That cell is sorted and expanded into a renewable, homogeneous, pluripotent master iPSC line. The iPSCs are differentiated into CD34 cells, which are differentiated into NK cells. The iPSC-derived NK cells are then modified with the following:
- An anti-CD19 CAR that is optimized for NK-cell biology and contains an NKG2D transmembrane domain, a 2B4 costimulatory domain, and a CD3-zeta signaling domain.
- An interleukin-15 receptor fusion that promotes cell survival and reduces the need for cytokine support.
- A high-affinity 158V, noncleavable CD16 Fc receptor that enhances antibody-dependent cellular cytotoxicity when FT596 is combined with a monoclonal antibody such as rituximab.
Dr. Goodridge presented results with FT596, both alone and in combination with rituximab, in vitro and in vivo.
When compared with no treatment, three doses of FT596 monotherapy reduced tumor growth in a mouse model of leukemia (Nalm6). FT596 plus rituximab reduced tumor growth in a mouse model of lymphoma (Raji), when compared with no treatment or rituximab alone.
Three doses of FT596 proved more effective than a single dose of CD19 CAR T-cell therapy in a mouse model of lymphoma (Raji). FT596 both reduced tumor growth and prolonged survival in the mice.
Lastly, in vitro experiments in Raji cells showed that FT596 plus rituximab can produce deeper responses than primary CAR-T cells, and the combination can prevent antigen escape.
Dr. Goodridge said these results support the phase 1 study of FT596, given as monotherapy or in combination with rituximab or obinutuzumab, in patients with relapsed/refractory B-cell lymphomas or chronic lymphocytic leukemia.
Dr. Goodridge is employed by Fate Therapeutics, the company developing FT596.
SOURCE: Goodridge JP et al. ASH 2019. Abstract 301.
REPORTING FROM ASH 2019
Kidney function in African American AML patients not linked to reduced survival compared with whites
ORLANDO – While African Americans with acute myeloid leukemia were more likely to have evidence of abnormal kidney function, the excess of this comorbidity didn’t affect overall survival, compared with whites, according to a study of more than 1,000 patients.
A total of 63% of African Americans with acute myeloid leukemia (AML) presented with a renal function abnormality that could have excluded them from a clinical trial, compared with 56% in the overall cohort; however, analysis of outcomes data suggested that renal function abnormalities were not associated with decreased survival in African Americans versus whites, said Abby Statler, PhD, MPH, of the Cleveland Clinic.
The findings may have implications for the design of clinical trials that might exclude patients on the basis of comorbidities that don’t actually affect survival, according to Dr. Statler.
“If we’re able to liberalize renal function eligibility criteria ... this may reduce racial disparities in clinical trial enrollment, which might be a major step in improving the diversity of cancer patient populations,” Dr. Statler said in a press conference at the annual meeting of the American Society of Hematology.
Overly restrictive criteria could be a significant barrier to clinical trial enrollment among minority patient populations, according to Dr. Statler.
Eligibility criteria are generally biased toward “fit” patient populations, which means they may discriminate against less-fit groups, such as African Americans who, compared with whites, have higher rates of comorbidities and report poorer overall health, according to Dr. Statler.
Laura Michaelis, MD, who chaired the press conference, said these findings suggest current clinical trial designs may be “too restrictive.”
“Once it’s published and validated, [these] data should definitely make us think twice about when you limit a patient’s enrollment in a trial,” Dr. Michaelis said in an interview.
Restrictive eligibility criteria may not only limit access to minority populations, but also may slow clinical trial accrual and completion, and make it harder to generalize clinical trial findings to the overall population, said Dr. Michaelis, associate professor of medicine in the division of hematology and oncology, Medical College of Wisconsin, Milwaukee.
The study by Dr. Statler and colleagues included 1,040 AML patients who received chemotherapy at Cleveland Clinic between 2003 and 2019. About 10% of the patients in the analysis were African American and 90% were white.
Median overall survival was not significantly different by race, at 13.7 months for African Americans and 14.9 months for whites (P = 0.89), according to results published in the study abstract.
Mild creatinine elevation did not appear to affect survival in this study, according to the investigator. Survival was not significantly different between patients with normal creatinine and those with creatinine up to 1.5 times the upper limit of normal. However, higher levels of creatinine were significantly associated with worse survival, Dr. Statler said.
Further analyses showed that these survival findings by creatinine level held up specifically in the African American subgroup as well, Dr. Statler said in the press conference.
Dr. Statler provided no disclosures related to the presentation. Study coauthors described disclosures related to Amgen, SimulStat, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Celgene Corporation, Abbvie, and Incyte, among others.
SOURCE: Statler A et al. ASH 2019, Abstract 381.
ORLANDO – While African Americans with acute myeloid leukemia were more likely to have evidence of abnormal kidney function, the excess of this comorbidity didn’t affect overall survival, compared with whites, according to a study of more than 1,000 patients.
A total of 63% of African Americans with acute myeloid leukemia (AML) presented with a renal function abnormality that could have excluded them from a clinical trial, compared with 56% in the overall cohort; however, analysis of outcomes data suggested that renal function abnormalities were not associated with decreased survival in African Americans versus whites, said Abby Statler, PhD, MPH, of the Cleveland Clinic.
The findings may have implications for the design of clinical trials that might exclude patients on the basis of comorbidities that don’t actually affect survival, according to Dr. Statler.
“If we’re able to liberalize renal function eligibility criteria ... this may reduce racial disparities in clinical trial enrollment, which might be a major step in improving the diversity of cancer patient populations,” Dr. Statler said in a press conference at the annual meeting of the American Society of Hematology.
Overly restrictive criteria could be a significant barrier to clinical trial enrollment among minority patient populations, according to Dr. Statler.
Eligibility criteria are generally biased toward “fit” patient populations, which means they may discriminate against less-fit groups, such as African Americans who, compared with whites, have higher rates of comorbidities and report poorer overall health, according to Dr. Statler.
Laura Michaelis, MD, who chaired the press conference, said these findings suggest current clinical trial designs may be “too restrictive.”
“Once it’s published and validated, [these] data should definitely make us think twice about when you limit a patient’s enrollment in a trial,” Dr. Michaelis said in an interview.
Restrictive eligibility criteria may not only limit access to minority populations, but also may slow clinical trial accrual and completion, and make it harder to generalize clinical trial findings to the overall population, said Dr. Michaelis, associate professor of medicine in the division of hematology and oncology, Medical College of Wisconsin, Milwaukee.
The study by Dr. Statler and colleagues included 1,040 AML patients who received chemotherapy at Cleveland Clinic between 2003 and 2019. About 10% of the patients in the analysis were African American and 90% were white.
Median overall survival was not significantly different by race, at 13.7 months for African Americans and 14.9 months for whites (P = 0.89), according to results published in the study abstract.
Mild creatinine elevation did not appear to affect survival in this study, according to the investigator. Survival was not significantly different between patients with normal creatinine and those with creatinine up to 1.5 times the upper limit of normal. However, higher levels of creatinine were significantly associated with worse survival, Dr. Statler said.
Further analyses showed that these survival findings by creatinine level held up specifically in the African American subgroup as well, Dr. Statler said in the press conference.
Dr. Statler provided no disclosures related to the presentation. Study coauthors described disclosures related to Amgen, SimulStat, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Celgene Corporation, Abbvie, and Incyte, among others.
SOURCE: Statler A et al. ASH 2019, Abstract 381.
ORLANDO – While African Americans with acute myeloid leukemia were more likely to have evidence of abnormal kidney function, the excess of this comorbidity didn’t affect overall survival, compared with whites, according to a study of more than 1,000 patients.
A total of 63% of African Americans with acute myeloid leukemia (AML) presented with a renal function abnormality that could have excluded them from a clinical trial, compared with 56% in the overall cohort; however, analysis of outcomes data suggested that renal function abnormalities were not associated with decreased survival in African Americans versus whites, said Abby Statler, PhD, MPH, of the Cleveland Clinic.
The findings may have implications for the design of clinical trials that might exclude patients on the basis of comorbidities that don’t actually affect survival, according to Dr. Statler.
“If we’re able to liberalize renal function eligibility criteria ... this may reduce racial disparities in clinical trial enrollment, which might be a major step in improving the diversity of cancer patient populations,” Dr. Statler said in a press conference at the annual meeting of the American Society of Hematology.
Overly restrictive criteria could be a significant barrier to clinical trial enrollment among minority patient populations, according to Dr. Statler.
Eligibility criteria are generally biased toward “fit” patient populations, which means they may discriminate against less-fit groups, such as African Americans who, compared with whites, have higher rates of comorbidities and report poorer overall health, according to Dr. Statler.
Laura Michaelis, MD, who chaired the press conference, said these findings suggest current clinical trial designs may be “too restrictive.”
“Once it’s published and validated, [these] data should definitely make us think twice about when you limit a patient’s enrollment in a trial,” Dr. Michaelis said in an interview.
Restrictive eligibility criteria may not only limit access to minority populations, but also may slow clinical trial accrual and completion, and make it harder to generalize clinical trial findings to the overall population, said Dr. Michaelis, associate professor of medicine in the division of hematology and oncology, Medical College of Wisconsin, Milwaukee.
The study by Dr. Statler and colleagues included 1,040 AML patients who received chemotherapy at Cleveland Clinic between 2003 and 2019. About 10% of the patients in the analysis were African American and 90% were white.
Median overall survival was not significantly different by race, at 13.7 months for African Americans and 14.9 months for whites (P = 0.89), according to results published in the study abstract.
Mild creatinine elevation did not appear to affect survival in this study, according to the investigator. Survival was not significantly different between patients with normal creatinine and those with creatinine up to 1.5 times the upper limit of normal. However, higher levels of creatinine were significantly associated with worse survival, Dr. Statler said.
Further analyses showed that these survival findings by creatinine level held up specifically in the African American subgroup as well, Dr. Statler said in the press conference.
Dr. Statler provided no disclosures related to the presentation. Study coauthors described disclosures related to Amgen, SimulStat, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Celgene Corporation, Abbvie, and Incyte, among others.
SOURCE: Statler A et al. ASH 2019, Abstract 381.
REPORTING FROM ASH 2019
More states pushing plans to pay for telehealth care
More states are enacting laws that require private plans to cover telehealth services, but fair payment remains a challenge for providers, a new analysis finds.
In 2019, 42 states and the District of Columbia had commercial payer telehealth laws, according to a December report by Foley & Lardner LLP, an international law firm. In contrast, about 30 states had such laws in 2015, according to a 2015 report by the National Conference of State Legislatures. Telehealth coverage laws generally require private plans to cover services provided via telehealth to the extent they cover in-person services of the same nature. The measures also frequently protect patients from cost-shifting, in which an insurer imposes higher deductibles or copays for telehealth services.
Private coverage for asynchronous telehealth and remote patient monitoring (RPM) is also growing. Twenty-four states mandate coverage for store and forward asynchronous telehealth, while 13 states require commercial health plans to cover RPM services, the analysis found. In addition, most telehealth coverage laws do not limit where a patient can receive telehealth services. However, some states, such as Arizona, Tennessee, and Washington, still require that patients be located in a particular clinical setting at the time of the telehealth consultation.
Overall, the landscape for reimbursement of telehealth services by commercial payers has improved, said Jacqueline Acosta, a health care attorney with Foley & Lardner and a coauthor of the report.
“[Foley& Lardner’s] 2017 report really noted that implementation [of telehealth] had really picked up both from providers and patients asking for telemedicine, but reimbursement still lagged behind,” Ms. Acosta said in an interview. “This one shows real progress on that front.”
However, the survey notes that payment parity for telehealth services remains lacking. Payment parity refers to insurers paying for telehealth services at the same or an equivalent rate as those delivered in-person. In 2019, 16 states had laws that specifically addressed reimbursement of telehealth services, but only 10 offer true payment parity, according to the Foley analysis. The 10 states with payment parity laws are Arkansas, Delaware, Georgia, Hawaii, Kentucky, Minnesota, Missouri, New Mexico, Utah, and Virginia. Other telehealth reimbursement measures often include ambiguity or allow room for payment negotiation, Ms. Acosta said.
She predicts that more payment parity laws and improved telehealth coverage laws are on the horizon for 2020 and beyond. California, for example, recently revised its telehealth law to require both coverage and payment parity for telehealth services. Mississippi meanwhile, recently expanded its law to include RPM coverage.
That states are revising existing laws and expanding their statutes shows an optimistic trend toward telehealth acceptance and coverage growth, Ms. Acosta said.
More states are enacting laws that require private plans to cover telehealth services, but fair payment remains a challenge for providers, a new analysis finds.
In 2019, 42 states and the District of Columbia had commercial payer telehealth laws, according to a December report by Foley & Lardner LLP, an international law firm. In contrast, about 30 states had such laws in 2015, according to a 2015 report by the National Conference of State Legislatures. Telehealth coverage laws generally require private plans to cover services provided via telehealth to the extent they cover in-person services of the same nature. The measures also frequently protect patients from cost-shifting, in which an insurer imposes higher deductibles or copays for telehealth services.
Private coverage for asynchronous telehealth and remote patient monitoring (RPM) is also growing. Twenty-four states mandate coverage for store and forward asynchronous telehealth, while 13 states require commercial health plans to cover RPM services, the analysis found. In addition, most telehealth coverage laws do not limit where a patient can receive telehealth services. However, some states, such as Arizona, Tennessee, and Washington, still require that patients be located in a particular clinical setting at the time of the telehealth consultation.
Overall, the landscape for reimbursement of telehealth services by commercial payers has improved, said Jacqueline Acosta, a health care attorney with Foley & Lardner and a coauthor of the report.
“[Foley& Lardner’s] 2017 report really noted that implementation [of telehealth] had really picked up both from providers and patients asking for telemedicine, but reimbursement still lagged behind,” Ms. Acosta said in an interview. “This one shows real progress on that front.”
However, the survey notes that payment parity for telehealth services remains lacking. Payment parity refers to insurers paying for telehealth services at the same or an equivalent rate as those delivered in-person. In 2019, 16 states had laws that specifically addressed reimbursement of telehealth services, but only 10 offer true payment parity, according to the Foley analysis. The 10 states with payment parity laws are Arkansas, Delaware, Georgia, Hawaii, Kentucky, Minnesota, Missouri, New Mexico, Utah, and Virginia. Other telehealth reimbursement measures often include ambiguity or allow room for payment negotiation, Ms. Acosta said.
She predicts that more payment parity laws and improved telehealth coverage laws are on the horizon for 2020 and beyond. California, for example, recently revised its telehealth law to require both coverage and payment parity for telehealth services. Mississippi meanwhile, recently expanded its law to include RPM coverage.
That states are revising existing laws and expanding their statutes shows an optimistic trend toward telehealth acceptance and coverage growth, Ms. Acosta said.
More states are enacting laws that require private plans to cover telehealth services, but fair payment remains a challenge for providers, a new analysis finds.
In 2019, 42 states and the District of Columbia had commercial payer telehealth laws, according to a December report by Foley & Lardner LLP, an international law firm. In contrast, about 30 states had such laws in 2015, according to a 2015 report by the National Conference of State Legislatures. Telehealth coverage laws generally require private plans to cover services provided via telehealth to the extent they cover in-person services of the same nature. The measures also frequently protect patients from cost-shifting, in which an insurer imposes higher deductibles or copays for telehealth services.
Private coverage for asynchronous telehealth and remote patient monitoring (RPM) is also growing. Twenty-four states mandate coverage for store and forward asynchronous telehealth, while 13 states require commercial health plans to cover RPM services, the analysis found. In addition, most telehealth coverage laws do not limit where a patient can receive telehealth services. However, some states, such as Arizona, Tennessee, and Washington, still require that patients be located in a particular clinical setting at the time of the telehealth consultation.
Overall, the landscape for reimbursement of telehealth services by commercial payers has improved, said Jacqueline Acosta, a health care attorney with Foley & Lardner and a coauthor of the report.
“[Foley& Lardner’s] 2017 report really noted that implementation [of telehealth] had really picked up both from providers and patients asking for telemedicine, but reimbursement still lagged behind,” Ms. Acosta said in an interview. “This one shows real progress on that front.”
However, the survey notes that payment parity for telehealth services remains lacking. Payment parity refers to insurers paying for telehealth services at the same or an equivalent rate as those delivered in-person. In 2019, 16 states had laws that specifically addressed reimbursement of telehealth services, but only 10 offer true payment parity, according to the Foley analysis. The 10 states with payment parity laws are Arkansas, Delaware, Georgia, Hawaii, Kentucky, Minnesota, Missouri, New Mexico, Utah, and Virginia. Other telehealth reimbursement measures often include ambiguity or allow room for payment negotiation, Ms. Acosta said.
She predicts that more payment parity laws and improved telehealth coverage laws are on the horizon for 2020 and beyond. California, for example, recently revised its telehealth law to require both coverage and payment parity for telehealth services. Mississippi meanwhile, recently expanded its law to include RPM coverage.
That states are revising existing laws and expanding their statutes shows an optimistic trend toward telehealth acceptance and coverage growth, Ms. Acosta said.
Newly identified genetic changes contribute to transformation of follicular lymphoma
A molecular analysis of a patient with follicular lymphoma (FL) that became B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) uncovered genetic changes that may improve understanding of this transformation.
“The study provides new insights into the pathogenesis of FL-B-ALL/LBL transformation and suggests novel, disease biology–based therapeutic approaches to this aggressive and currently incurable disease,” wrote Jonathan Belman, MD, PhD, of the Hospital of the University of Pennsylvania, Philadelphia, and coauthors. Their findings were published in Cold Spring Harbor Molecular Case Studies.
To further understand the rare occasions when FL transforms into a more aggressive form of lymphoma, the researchers investigated a 36-year-old man with low-grade FL that became B-ALL/LBL roughly 1 year after diagnosis. Their analysis included immunoglobulin (Ig) gene rearrangement studies, cytogenetic analysis, and whole exome sequencing of the patient’s FL, B-ALL/LBL, and normal cells.
Next generation sequencing of Ig rearrangements from normal, FL, and B-ALL/LBL specimens revealed considerable somatic hypermutation (SHM) in a single neoplastic clone – IgHV4-34_JH6 – in the FL cells. By comparison, though no dominant clone was found in the B-ALL/LBL specimen, there was even more extensive SHM, along with clones that could be traced to the FL lineage.
In addition, fluorescence in situ hybridization (FISH) studies on the FL specimen were positive for rearrangements of BCL2 and BCL6 genes; a rearrangement of BCL6 is associated with clinical aggressiveness. Those same two rearrangements were found in the B-ALL/LBL specimen, along with a MYC gene rearrangement unseen in the FL.
“MYC translocations are well known to contribute to high aggressiveness of lymphomas, and are hallmark of FL-B-ALL/LBL transformation,” the researchers wrote.
Finally, comparative whole exome sequencing of normal tissue plus the cancerous specimens identified 751 single nucleotide variants. The normal tissue contained 111 of those mutations, while the FL specimens contained 116 mutations – 11 of which were shared solely with B-ALL/LBL – and the B-ALL/LBL specimens contained a striking 575 unique mutations. Notably, a nonsense mutation in the KMT2D gene that was shared by FL and B-ALL/LBL may have contributed to lymphomagenesis.
The study was funded by a grant from the National Institutes of Health, the Abramson Cancer Center Translational Center in Lymphoma, the Daniel B. Allanoff Foundation, and a Hematopathology Divisional Training grant.
SOURCE: Belman JP et al. Cold Spring Harb Mol Case Stud. 2019 Nov 27. doi: 10.1101/mcs.a004614.
A molecular analysis of a patient with follicular lymphoma (FL) that became B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) uncovered genetic changes that may improve understanding of this transformation.
“The study provides new insights into the pathogenesis of FL-B-ALL/LBL transformation and suggests novel, disease biology–based therapeutic approaches to this aggressive and currently incurable disease,” wrote Jonathan Belman, MD, PhD, of the Hospital of the University of Pennsylvania, Philadelphia, and coauthors. Their findings were published in Cold Spring Harbor Molecular Case Studies.
To further understand the rare occasions when FL transforms into a more aggressive form of lymphoma, the researchers investigated a 36-year-old man with low-grade FL that became B-ALL/LBL roughly 1 year after diagnosis. Their analysis included immunoglobulin (Ig) gene rearrangement studies, cytogenetic analysis, and whole exome sequencing of the patient’s FL, B-ALL/LBL, and normal cells.
Next generation sequencing of Ig rearrangements from normal, FL, and B-ALL/LBL specimens revealed considerable somatic hypermutation (SHM) in a single neoplastic clone – IgHV4-34_JH6 – in the FL cells. By comparison, though no dominant clone was found in the B-ALL/LBL specimen, there was even more extensive SHM, along with clones that could be traced to the FL lineage.
In addition, fluorescence in situ hybridization (FISH) studies on the FL specimen were positive for rearrangements of BCL2 and BCL6 genes; a rearrangement of BCL6 is associated with clinical aggressiveness. Those same two rearrangements were found in the B-ALL/LBL specimen, along with a MYC gene rearrangement unseen in the FL.
“MYC translocations are well known to contribute to high aggressiveness of lymphomas, and are hallmark of FL-B-ALL/LBL transformation,” the researchers wrote.
Finally, comparative whole exome sequencing of normal tissue plus the cancerous specimens identified 751 single nucleotide variants. The normal tissue contained 111 of those mutations, while the FL specimens contained 116 mutations – 11 of which were shared solely with B-ALL/LBL – and the B-ALL/LBL specimens contained a striking 575 unique mutations. Notably, a nonsense mutation in the KMT2D gene that was shared by FL and B-ALL/LBL may have contributed to lymphomagenesis.
The study was funded by a grant from the National Institutes of Health, the Abramson Cancer Center Translational Center in Lymphoma, the Daniel B. Allanoff Foundation, and a Hematopathology Divisional Training grant.
SOURCE: Belman JP et al. Cold Spring Harb Mol Case Stud. 2019 Nov 27. doi: 10.1101/mcs.a004614.
A molecular analysis of a patient with follicular lymphoma (FL) that became B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) uncovered genetic changes that may improve understanding of this transformation.
“The study provides new insights into the pathogenesis of FL-B-ALL/LBL transformation and suggests novel, disease biology–based therapeutic approaches to this aggressive and currently incurable disease,” wrote Jonathan Belman, MD, PhD, of the Hospital of the University of Pennsylvania, Philadelphia, and coauthors. Their findings were published in Cold Spring Harbor Molecular Case Studies.
To further understand the rare occasions when FL transforms into a more aggressive form of lymphoma, the researchers investigated a 36-year-old man with low-grade FL that became B-ALL/LBL roughly 1 year after diagnosis. Their analysis included immunoglobulin (Ig) gene rearrangement studies, cytogenetic analysis, and whole exome sequencing of the patient’s FL, B-ALL/LBL, and normal cells.
Next generation sequencing of Ig rearrangements from normal, FL, and B-ALL/LBL specimens revealed considerable somatic hypermutation (SHM) in a single neoplastic clone – IgHV4-34_JH6 – in the FL cells. By comparison, though no dominant clone was found in the B-ALL/LBL specimen, there was even more extensive SHM, along with clones that could be traced to the FL lineage.
In addition, fluorescence in situ hybridization (FISH) studies on the FL specimen were positive for rearrangements of BCL2 and BCL6 genes; a rearrangement of BCL6 is associated with clinical aggressiveness. Those same two rearrangements were found in the B-ALL/LBL specimen, along with a MYC gene rearrangement unseen in the FL.
“MYC translocations are well known to contribute to high aggressiveness of lymphomas, and are hallmark of FL-B-ALL/LBL transformation,” the researchers wrote.
Finally, comparative whole exome sequencing of normal tissue plus the cancerous specimens identified 751 single nucleotide variants. The normal tissue contained 111 of those mutations, while the FL specimens contained 116 mutations – 11 of which were shared solely with B-ALL/LBL – and the B-ALL/LBL specimens contained a striking 575 unique mutations. Notably, a nonsense mutation in the KMT2D gene that was shared by FL and B-ALL/LBL may have contributed to lymphomagenesis.
The study was funded by a grant from the National Institutes of Health, the Abramson Cancer Center Translational Center in Lymphoma, the Daniel B. Allanoff Foundation, and a Hematopathology Divisional Training grant.
SOURCE: Belman JP et al. Cold Spring Harb Mol Case Stud. 2019 Nov 27. doi: 10.1101/mcs.a004614.
FROM COLD SPRING HARBOR MOLECULAR CASE STUDIES
Myeloma patients over age 70 can benefit from auto-HC transplant
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
REPORTING FROM ASH 2019
Bispecific CAR T-cells yield high response rate in relapsed/refractory myeloma
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
REPORTING FROM ASH 2019
High complete response rate seen with novel CAR-T for myeloma
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
REPORTING FROM ASH 2019
Women with epilepsy less likely than controls to breastfeed
BALTIMORE – , according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.
“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
A retrospective study of women who underwent pregnancy
Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.
The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
Education and support were correlated with breastfeeding
Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.
The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.
“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”
The study did not have external funding, and the investigators reported no disclosures.
SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.
BALTIMORE – , according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.
“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
A retrospective study of women who underwent pregnancy
Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.
The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
Education and support were correlated with breastfeeding
Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.
The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.
“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”
The study did not have external funding, and the investigators reported no disclosures.
SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.
BALTIMORE – , according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.
“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
A retrospective study of women who underwent pregnancy
Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.
The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
Education and support were correlated with breastfeeding
Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.
The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.
“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”
The study did not have external funding, and the investigators reported no disclosures.
SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.
REPORTING FROM AES 2019