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“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”
The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.
Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.
In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”
Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.
Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.
After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10-7) after treatment with axi-cel, compared with those who did not have the signature.
The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”
Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10-13) and progression-free survival (HR, 7.58; P = 2.70 x 10-14).
The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.
“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.
Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.
Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.
Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”
“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.
A key caveat is that the results need more validation before they true gain clinical value, he noted.
“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”
Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.
“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.”
Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.
“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.
“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”
Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.
“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”
The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.
Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.
In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”
Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.
Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.
After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10-7) after treatment with axi-cel, compared with those who did not have the signature.
The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”
Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10-13) and progression-free survival (HR, 7.58; P = 2.70 x 10-14).
The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.
“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.
Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.
Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.
Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”
“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.
A key caveat is that the results need more validation before they true gain clinical value, he noted.
“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”
Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.
“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.”
Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.
“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.
“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”
Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.
“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”
The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.
Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.
In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”
Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.
Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.
After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10-7) after treatment with axi-cel, compared with those who did not have the signature.
The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”
Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10-13) and progression-free survival (HR, 7.58; P = 2.70 x 10-14).
The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.
“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.
Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.
Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.
Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”
“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.
A key caveat is that the results need more validation before they true gain clinical value, he noted.
“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”
Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.
“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.”
Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.
“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.
“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”
Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.
FROM AACR 2024