EFFICACY OF FRONT-LINE TREATMENT COMBINATIONS WITH PONATINIB VERSUS 1ST- AND 2ND-GENERATION TYROSINE KINASE INHIBITORS FOR PH+ ACUTE LYMPHOBLASTIC LEUKEMIA: A META-ANALYSIS AND META-REGRESSION
(Abstract release date: 05/19/16)
EHA Library. Jabbour E. 06/10/16; 133157; P169
Dr. Elias Jabbour
Contributions
Contributions
Abstract
Abstract: P169
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The combination of a tyrosine kinase inhibitor (TKI) and either chemotherapy or corticosteroids is effective induction therapy in de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a multi-targeted TKI that is a more potent BCR-ABL1 inhibitor than previous generations of TKIs and selectively suppresses T315I resistance. However, evidence on the comparative effectiveness of ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established.
Aims
This study aims to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2-year overall survival (OS), of front-line treatment combinations with ponatinib versus first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib) in Ph+ ALL.
Methods
Nineteen Phase 2 through 4 trials and one retrospective analysis of front-line Ph+ ALL treatments were identified from a 2015 targeted literature review published by the American Society of Hematology. One study used ponatinib with chemotherapy and nineteen studies used a combination of first- or second-generation TKIs with either chemotherapy or corticosteroids. The proportions of patients achieving CMR and 2-year OS were extracted from all study arms and summarized by TKI group (ponatinib vs. all other TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between TKI groups and CMR rates as well as between TKI groups and 2-year OS, adjusting for age, gender, and in the OS model only, the proportion of patients receiving subsequent hematopoietic stem cell transplantation (SCT). P-values were calculated using non-parametric bootstrapping with 20,000 permutations.
Results
Across the 30 TKI-treatment arms from the 20 included studies, the median (range) age was 46 years (38-69 years), percent of male patients was 53% (40-67%), and percent of patients receiving subsequent SCT was 63% (0-100%). The pooled proportion of patients achieving CMR with ponatinib was 78% (95% CI: 62-90%) vs. 30% (95% CI: 22-38%) with other TKIs. The pooled 2-year OS with ponatinib was 80% (95% CI: 65-92%) compared to 58% (95% CI: 53-63%) with other TKIs. The odds ratio (OR) for ponatinib vs. other TKIs from the adjusted meta-regression for CMR (N=18) was 9.12 (95% CI: 1.59-52.21, p=0.025), and was 3.00 (95% CI: 0.63-14.43, p=0.136) for 2-year OS (N=19).
Conclusion
Our results support the hypothesis that ponatinib in combination with chemotherapy is associated with better clinical efficacy in newly diagnosed Ph+ ALL than combination therapy with older TKIs. In particular, compared to first- and second-generation TKIs, ponatinib was associated with a statistically significant 9-fold increase in the odds of CMR and a higher, though non-statistically significant, odds of 2-year OS. A limitation of our analysis is its reliance on study-level data from a small number of studies with heterogeneous therapy combinations; adjustment for heterogeneity across studies was limited to available covariates only. Nevertheless, our results suggest that ponatinib in combination with chemotherapy may represent a highly effective front-line treatment option for patients newly diagnosed with Ph+ ALL. Further prospective head-to-head clinical trials to confirm these results are warranted.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): Molecular response, Ph+ ALL, Survival, Tyrosine kinase inhibitor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The combination of a tyrosine kinase inhibitor (TKI) and either chemotherapy or corticosteroids is effective induction therapy in de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a multi-targeted TKI that is a more potent BCR-ABL1 inhibitor than previous generations of TKIs and selectively suppresses T315I resistance. However, evidence on the comparative effectiveness of ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established.
Aims
This study aims to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2-year overall survival (OS), of front-line treatment combinations with ponatinib versus first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib) in Ph+ ALL.
Methods
Nineteen Phase 2 through 4 trials and one retrospective analysis of front-line Ph+ ALL treatments were identified from a 2015 targeted literature review published by the American Society of Hematology. One study used ponatinib with chemotherapy and nineteen studies used a combination of first- or second-generation TKIs with either chemotherapy or corticosteroids. The proportions of patients achieving CMR and 2-year OS were extracted from all study arms and summarized by TKI group (ponatinib vs. all other TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between TKI groups and CMR rates as well as between TKI groups and 2-year OS, adjusting for age, gender, and in the OS model only, the proportion of patients receiving subsequent hematopoietic stem cell transplantation (SCT). P-values were calculated using non-parametric bootstrapping with 20,000 permutations.
Results
Across the 30 TKI-treatment arms from the 20 included studies, the median (range) age was 46 years (38-69 years), percent of male patients was 53% (40-67%), and percent of patients receiving subsequent SCT was 63% (0-100%). The pooled proportion of patients achieving CMR with ponatinib was 78% (95% CI: 62-90%) vs. 30% (95% CI: 22-38%) with other TKIs. The pooled 2-year OS with ponatinib was 80% (95% CI: 65-92%) compared to 58% (95% CI: 53-63%) with other TKIs. The odds ratio (OR) for ponatinib vs. other TKIs from the adjusted meta-regression for CMR (N=18) was 9.12 (95% CI: 1.59-52.21, p=0.025), and was 3.00 (95% CI: 0.63-14.43, p=0.136) for 2-year OS (N=19).
Conclusion
Our results support the hypothesis that ponatinib in combination with chemotherapy is associated with better clinical efficacy in newly diagnosed Ph+ ALL than combination therapy with older TKIs. In particular, compared to first- and second-generation TKIs, ponatinib was associated with a statistically significant 9-fold increase in the odds of CMR and a higher, though non-statistically significant, odds of 2-year OS. A limitation of our analysis is its reliance on study-level data from a small number of studies with heterogeneous therapy combinations; adjustment for heterogeneity across studies was limited to available covariates only. Nevertheless, our results suggest that ponatinib in combination with chemotherapy may represent a highly effective front-line treatment option for patients newly diagnosed with Ph+ ALL. Further prospective head-to-head clinical trials to confirm these results are warranted.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): Molecular response, Ph+ ALL, Survival, Tyrosine kinase inhibitor
Abstract: P169
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The combination of a tyrosine kinase inhibitor (TKI) and either chemotherapy or corticosteroids is effective induction therapy in de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a multi-targeted TKI that is a more potent BCR-ABL1 inhibitor than previous generations of TKIs and selectively suppresses T315I resistance. However, evidence on the comparative effectiveness of ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established.
Aims
This study aims to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2-year overall survival (OS), of front-line treatment combinations with ponatinib versus first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib) in Ph+ ALL.
Methods
Nineteen Phase 2 through 4 trials and one retrospective analysis of front-line Ph+ ALL treatments were identified from a 2015 targeted literature review published by the American Society of Hematology. One study used ponatinib with chemotherapy and nineteen studies used a combination of first- or second-generation TKIs with either chemotherapy or corticosteroids. The proportions of patients achieving CMR and 2-year OS were extracted from all study arms and summarized by TKI group (ponatinib vs. all other TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between TKI groups and CMR rates as well as between TKI groups and 2-year OS, adjusting for age, gender, and in the OS model only, the proportion of patients receiving subsequent hematopoietic stem cell transplantation (SCT). P-values were calculated using non-parametric bootstrapping with 20,000 permutations.
Results
Across the 30 TKI-treatment arms from the 20 included studies, the median (range) age was 46 years (38-69 years), percent of male patients was 53% (40-67%), and percent of patients receiving subsequent SCT was 63% (0-100%). The pooled proportion of patients achieving CMR with ponatinib was 78% (95% CI: 62-90%) vs. 30% (95% CI: 22-38%) with other TKIs. The pooled 2-year OS with ponatinib was 80% (95% CI: 65-92%) compared to 58% (95% CI: 53-63%) with other TKIs. The odds ratio (OR) for ponatinib vs. other TKIs from the adjusted meta-regression for CMR (N=18) was 9.12 (95% CI: 1.59-52.21, p=0.025), and was 3.00 (95% CI: 0.63-14.43, p=0.136) for 2-year OS (N=19).
Conclusion
Our results support the hypothesis that ponatinib in combination with chemotherapy is associated with better clinical efficacy in newly diagnosed Ph+ ALL than combination therapy with older TKIs. In particular, compared to first- and second-generation TKIs, ponatinib was associated with a statistically significant 9-fold increase in the odds of CMR and a higher, though non-statistically significant, odds of 2-year OS. A limitation of our analysis is its reliance on study-level data from a small number of studies with heterogeneous therapy combinations; adjustment for heterogeneity across studies was limited to available covariates only. Nevertheless, our results suggest that ponatinib in combination with chemotherapy may represent a highly effective front-line treatment option for patients newly diagnosed with Ph+ ALL. Further prospective head-to-head clinical trials to confirm these results are warranted.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): Molecular response, Ph+ ALL, Survival, Tyrosine kinase inhibitor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The combination of a tyrosine kinase inhibitor (TKI) and either chemotherapy or corticosteroids is effective induction therapy in de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a multi-targeted TKI that is a more potent BCR-ABL1 inhibitor than previous generations of TKIs and selectively suppresses T315I resistance. However, evidence on the comparative effectiveness of ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established.
Aims
This study aims to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2-year overall survival (OS), of front-line treatment combinations with ponatinib versus first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib) in Ph+ ALL.
Methods
Nineteen Phase 2 through 4 trials and one retrospective analysis of front-line Ph+ ALL treatments were identified from a 2015 targeted literature review published by the American Society of Hematology. One study used ponatinib with chemotherapy and nineteen studies used a combination of first- or second-generation TKIs with either chemotherapy or corticosteroids. The proportions of patients achieving CMR and 2-year OS were extracted from all study arms and summarized by TKI group (ponatinib vs. all other TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between TKI groups and CMR rates as well as between TKI groups and 2-year OS, adjusting for age, gender, and in the OS model only, the proportion of patients receiving subsequent hematopoietic stem cell transplantation (SCT). P-values were calculated using non-parametric bootstrapping with 20,000 permutations.
Results
Across the 30 TKI-treatment arms from the 20 included studies, the median (range) age was 46 years (38-69 years), percent of male patients was 53% (40-67%), and percent of patients receiving subsequent SCT was 63% (0-100%). The pooled proportion of patients achieving CMR with ponatinib was 78% (95% CI: 62-90%) vs. 30% (95% CI: 22-38%) with other TKIs. The pooled 2-year OS with ponatinib was 80% (95% CI: 65-92%) compared to 58% (95% CI: 53-63%) with other TKIs. The odds ratio (OR) for ponatinib vs. other TKIs from the adjusted meta-regression for CMR (N=18) was 9.12 (95% CI: 1.59-52.21, p=0.025), and was 3.00 (95% CI: 0.63-14.43, p=0.136) for 2-year OS (N=19).
Conclusion
Our results support the hypothesis that ponatinib in combination with chemotherapy is associated with better clinical efficacy in newly diagnosed Ph+ ALL than combination therapy with older TKIs. In particular, compared to first- and second-generation TKIs, ponatinib was associated with a statistically significant 9-fold increase in the odds of CMR and a higher, though non-statistically significant, odds of 2-year OS. A limitation of our analysis is its reliance on study-level data from a small number of studies with heterogeneous therapy combinations; adjustment for heterogeneity across studies was limited to available covariates only. Nevertheless, our results suggest that ponatinib in combination with chemotherapy may represent a highly effective front-line treatment option for patients newly diagnosed with Ph+ ALL. Further prospective head-to-head clinical trials to confirm these results are warranted.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): Molecular response, Ph+ ALL, Survival, Tyrosine kinase inhibitor
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