CPX-351 TREATMENT OF PREVIOUSLY UNTREATED OLDER AML PATIENTS WITH HIGH RISK AML MARKEDLY INCREASES THE RESPONSE RATE OVER 7+3 IN PATIENTS WITH FLT3 MUTATIONS.
(Abstract release date: 05/19/16)
EHA Library. Lancet J. 06/11/16; 135258; S502
Jeffrey Lancet
Contributions
Contributions
Abstract
Abstract: S502
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A3
Background
CPX-351 is a nano-scale liposomal formulation of 5:1 molar ratio cytarabine and daunorubicin that exhibits marked efficacy improvements among poor risk AML patients. A phase III study of CPX-351 vs. 7+3 treatment in older high-risk (e.g. secondary) AML patients is nearing completion (NCT01696084).
Aims
This report correlates induction response (CR+CRi) with baseline FLT3 ITD/TKD+, NPM1+, and CEBPA+ mutations from the Phase III study.
Methods
Patients 60-75 years of age with t-AML, MDSAML, CMMLAML and de novo AML with MDS cytogenetic abnormalities were eligible for this open label randomized study. 153 patients were randomized to CPX-351 (100 units/m2, days 1, 3, and 5) and 156 patients to 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, and 3) induction. Data for response was reviewed independently and in a blinded manner by the study’s hematopathologist. Patients were assessed at baseline for FLT3, NPM1, and CEBPA mutations.
Results
Mutation status was determined in 278/309 (90%) patients for FLT3 ITD, 275/309 (89%) for FLT3 TKD, 282/309 (91%) for NPM1, and 270/309 (87%) for CEBPA. FLT3 mutations (ITD+ and/or TKD+) were found in 44 (16%) patients. Mutations occurred in 26 pt (9%) for NPM1, and 15 pt (6%) for CEBPA. The complete remission data stratified by FLT3 ITD+, FLT3 TKD+, NPM1+, and CEBPA+ status are presented in the table below.
Compared to control, CPX-351 treatment produced higher response rates among all patients (47.7% vs. 33.3%), all FLT3 mutated patients (68.2% vs. 27.3%, p=0.148), FLT3 ITD+ patients (12/19 (63.2%) vs. 3/14 (21.4%)), FLT3 TKD+ patients (5/6 (83.3%) vs. 4/11 (36.4%)), and NPM1+ patients (92.3% vs. 53.9%). Most FLT3 ITD+ patients were NPM1- (26/33, 78.8%) with responses in 8/15 (53.3%) CPX-351 vs. 2/11 (18.2%) in 7+3 patients.
Conclusion
Treatment with CPX-351 appears to be associated with improved response rates in patients with common AML mutations, including those associated with poor outcomes, such as FLT3 ITD mutations. Preliminary findings from cytotoxicity assays using fresh AML patient blasts suggest that AML blasts exhibiting FLT3 ITD mutations were more sensitive to CPX-351 than FLT3 WT blasts. Moreover, increased cytotoxicity was associated with increased uptake of CPX-351 liposomes by AML blasts. While the clinical findings are based on small patient numbers, the remission data presented here, combined with the early preclinical data provide a provocative hypothesis for how CPX-351 might be advantageous for specific types of AML mutations and provide a rationale for expanded trials of CPX-351, particularly in the FLT3 ITD mutated population, which is expected to respond poorly to conventional treatment regimens.
Session topic: New Compounds in AML Treatment
Keyword(s): FLT3, Phase III, Randomized
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A3
Background
CPX-351 is a nano-scale liposomal formulation of 5:1 molar ratio cytarabine and daunorubicin that exhibits marked efficacy improvements among poor risk AML patients. A phase III study of CPX-351 vs. 7+3 treatment in older high-risk (e.g. secondary) AML patients is nearing completion (NCT01696084).
Aims
This report correlates induction response (CR+CRi) with baseline FLT3 ITD/TKD+, NPM1+, and CEBPA+ mutations from the Phase III study.
Methods
Patients 60-75 years of age with t-AML, MDSAML, CMMLAML and de novo AML with MDS cytogenetic abnormalities were eligible for this open label randomized study. 153 patients were randomized to CPX-351 (100 units/m2, days 1, 3, and 5) and 156 patients to 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, and 3) induction. Data for response was reviewed independently and in a blinded manner by the study’s hematopathologist. Patients were assessed at baseline for FLT3, NPM1, and CEBPA mutations.
Results
Mutation status was determined in 278/309 (90%) patients for FLT3 ITD, 275/309 (89%) for FLT3 TKD, 282/309 (91%) for NPM1, and 270/309 (87%) for CEBPA. FLT3 mutations (ITD+ and/or TKD+) were found in 44 (16%) patients. Mutations occurred in 26 pt (9%) for NPM1, and 15 pt (6%) for CEBPA. The complete remission data stratified by FLT3 ITD+, FLT3 TKD+, NPM1+, and CEBPA+ status are presented in the table below.
| CR+CRi Rate n(%) | |||
| Group: | CPX-351 Arm | 7+3 Arm | p-value |
| All patients | 73/153 (47.7) | 52/156 (33.3) | |
| FLT3 mutated (all) | 15/22 (68.2) | 6/22 (27.3) | 0.0148 |
| FLT3 ITD+/TKD- | 10/16 (62.5) | 2/11 (18.2) | |
| FLT3 ITD+/TKD+ | 2/3 (66.7) | 1/3 (33.3) | |
| FLT3 ITD-/TKD+ | 3/3 (100) | 3/8 (37.5) | |
| FLT3 ITD+/NPM1- | 8/15 (53.3) | 2/11 (18.2) | |
| NPM-1mutated (all) | 12/13 (92.3) | 7/13 (53.9) | |
| NPM1+/FLT3 wt | 5/6 (83.3) | 6/7 (85.7) | |
| NPM1+/FLT3 mutated | 6/6 (100) | 1/5 (20.0) | |
| NPM1+/FLT3 unknown | 1/1 (100) | 0/1 (0.0) | |
| CEBPA mutated (all) | 3/11 (27.3) | 1/4 (25.0) | |
Conclusion
Treatment with CPX-351 appears to be associated with improved response rates in patients with common AML mutations, including those associated with poor outcomes, such as FLT3 ITD mutations. Preliminary findings from cytotoxicity assays using fresh AML patient blasts suggest that AML blasts exhibiting FLT3 ITD mutations were more sensitive to CPX-351 than FLT3 WT blasts. Moreover, increased cytotoxicity was associated with increased uptake of CPX-351 liposomes by AML blasts. While the clinical findings are based on small patient numbers, the remission data presented here, combined with the early preclinical data provide a provocative hypothesis for how CPX-351 might be advantageous for specific types of AML mutations and provide a rationale for expanded trials of CPX-351, particularly in the FLT3 ITD mutated population, which is expected to respond poorly to conventional treatment regimens.
Session topic: New Compounds in AML Treatment
Keyword(s): FLT3, Phase III, Randomized
Abstract: S502
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A3
Background
CPX-351 is a nano-scale liposomal formulation of 5:1 molar ratio cytarabine and daunorubicin that exhibits marked efficacy improvements among poor risk AML patients. A phase III study of CPX-351 vs. 7+3 treatment in older high-risk (e.g. secondary) AML patients is nearing completion (NCT01696084).
Aims
This report correlates induction response (CR+CRi) with baseline FLT3 ITD/TKD+, NPM1+, and CEBPA+ mutations from the Phase III study.
Methods
Patients 60-75 years of age with t-AML, MDSAML, CMMLAML and de novo AML with MDS cytogenetic abnormalities were eligible for this open label randomized study. 153 patients were randomized to CPX-351 (100 units/m2, days 1, 3, and 5) and 156 patients to 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, and 3) induction. Data for response was reviewed independently and in a blinded manner by the study’s hematopathologist. Patients were assessed at baseline for FLT3, NPM1, and CEBPA mutations.
Results
Mutation status was determined in 278/309 (90%) patients for FLT3 ITD, 275/309 (89%) for FLT3 TKD, 282/309 (91%) for NPM1, and 270/309 (87%) for CEBPA. FLT3 mutations (ITD+ and/or TKD+) were found in 44 (16%) patients. Mutations occurred in 26 pt (9%) for NPM1, and 15 pt (6%) for CEBPA. The complete remission data stratified by FLT3 ITD+, FLT3 TKD+, NPM1+, and CEBPA+ status are presented in the table below.
Compared to control, CPX-351 treatment produced higher response rates among all patients (47.7% vs. 33.3%), all FLT3 mutated patients (68.2% vs. 27.3%, p=0.148), FLT3 ITD+ patients (12/19 (63.2%) vs. 3/14 (21.4%)), FLT3 TKD+ patients (5/6 (83.3%) vs. 4/11 (36.4%)), and NPM1+ patients (92.3% vs. 53.9%). Most FLT3 ITD+ patients were NPM1- (26/33, 78.8%) with responses in 8/15 (53.3%) CPX-351 vs. 2/11 (18.2%) in 7+3 patients.
Conclusion
Treatment with CPX-351 appears to be associated with improved response rates in patients with common AML mutations, including those associated with poor outcomes, such as FLT3 ITD mutations. Preliminary findings from cytotoxicity assays using fresh AML patient blasts suggest that AML blasts exhibiting FLT3 ITD mutations were more sensitive to CPX-351 than FLT3 WT blasts. Moreover, increased cytotoxicity was associated with increased uptake of CPX-351 liposomes by AML blasts. While the clinical findings are based on small patient numbers, the remission data presented here, combined with the early preclinical data provide a provocative hypothesis for how CPX-351 might be advantageous for specific types of AML mutations and provide a rationale for expanded trials of CPX-351, particularly in the FLT3 ITD mutated population, which is expected to respond poorly to conventional treatment regimens.
Session topic: New Compounds in AML Treatment
Keyword(s): FLT3, Phase III, Randomized
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A3
Background
CPX-351 is a nano-scale liposomal formulation of 5:1 molar ratio cytarabine and daunorubicin that exhibits marked efficacy improvements among poor risk AML patients. A phase III study of CPX-351 vs. 7+3 treatment in older high-risk (e.g. secondary) AML patients is nearing completion (NCT01696084).
Aims
This report correlates induction response (CR+CRi) with baseline FLT3 ITD/TKD+, NPM1+, and CEBPA+ mutations from the Phase III study.
Methods
Patients 60-75 years of age with t-AML, MDSAML, CMMLAML and de novo AML with MDS cytogenetic abnormalities were eligible for this open label randomized study. 153 patients were randomized to CPX-351 (100 units/m2, days 1, 3, and 5) and 156 patients to 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, and 3) induction. Data for response was reviewed independently and in a blinded manner by the study’s hematopathologist. Patients were assessed at baseline for FLT3, NPM1, and CEBPA mutations.
Results
Mutation status was determined in 278/309 (90%) patients for FLT3 ITD, 275/309 (89%) for FLT3 TKD, 282/309 (91%) for NPM1, and 270/309 (87%) for CEBPA. FLT3 mutations (ITD+ and/or TKD+) were found in 44 (16%) patients. Mutations occurred in 26 pt (9%) for NPM1, and 15 pt (6%) for CEBPA. The complete remission data stratified by FLT3 ITD+, FLT3 TKD+, NPM1+, and CEBPA+ status are presented in the table below.
| CR+CRi Rate n(%) | |||
| Group: | CPX-351 Arm | 7+3 Arm | p-value |
| All patients | 73/153 (47.7) | 52/156 (33.3) | |
| FLT3 mutated (all) | 15/22 (68.2) | 6/22 (27.3) | 0.0148 |
| FLT3 ITD+/TKD- | 10/16 (62.5) | 2/11 (18.2) | |
| FLT3 ITD+/TKD+ | 2/3 (66.7) | 1/3 (33.3) | |
| FLT3 ITD-/TKD+ | 3/3 (100) | 3/8 (37.5) | |
| FLT3 ITD+/NPM1- | 8/15 (53.3) | 2/11 (18.2) | |
| NPM-1mutated (all) | 12/13 (92.3) | 7/13 (53.9) | |
| NPM1+/FLT3 wt | 5/6 (83.3) | 6/7 (85.7) | |
| NPM1+/FLT3 mutated | 6/6 (100) | 1/5 (20.0) | |
| NPM1+/FLT3 unknown | 1/1 (100) | 0/1 (0.0) | |
| CEBPA mutated (all) | 3/11 (27.3) | 1/4 (25.0) | |
Conclusion
Treatment with CPX-351 appears to be associated with improved response rates in patients with common AML mutations, including those associated with poor outcomes, such as FLT3 ITD mutations. Preliminary findings from cytotoxicity assays using fresh AML patient blasts suggest that AML blasts exhibiting FLT3 ITD mutations were more sensitive to CPX-351 than FLT3 WT blasts. Moreover, increased cytotoxicity was associated with increased uptake of CPX-351 liposomes by AML blasts. While the clinical findings are based on small patient numbers, the remission data presented here, combined with the early preclinical data provide a provocative hypothesis for how CPX-351 might be advantageous for specific types of AML mutations and provide a rationale for expanded trials of CPX-351, particularly in the FLT3 ITD mutated population, which is expected to respond poorly to conventional treatment regimens.
Session topic: New Compounds in AML Treatment
Keyword(s): FLT3, Phase III, Randomized
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