RESPONSE-ADAPTED SEQUENTIAL AZACITIDINE AND INDUCTION CHEMOTHERAPY IN PATIENTS > 60 YEARS OLD WITH NEWLY DIAGNOSED AML ELIGIBLE FOR CHEMOTHERAPY (RAS-AZIC): INTERIM ANALYSIS OF THE DRKS00004519 STUDY
(Abstract release date: 05/19/16)
EHA Library. Jaekel N. 06/12/16; 135305; S811
Prof. Nadja Jaekel
Contributions
Contributions
Abstract
Abstract: S811
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C13
Background
Treatment options for AML in patients (pts) >60 years (y) include intensive chemotherapy (IC) and/or azacitidine (AZA). Yet, AZA and IC need not automatically be mutually exclusive.
Aims
In the multicenter DRKS00004519 (RAS-AZIC) study of the East German Study Group (OSHO), first-line treatment with AZA followed by AZA or IC in pts >60 y with AML was evaluated. Data of a planned interim analysis per protocol of the first 40 consecutive pts are presented.
Methods
Patients >60 y with newly diagnosed AML and eligible for IC were included irrespective of white blood count (WBC). In the phase I part of the trial, safety of upfront AZA (75 mg/m2/day s.c.) for 7 days followed by IC (mitoxantrone 10 mg/ m²/day on day (d) 1-3 and cytarabine 1g/ m²/BID on d 1, 3, 5, 7) on d 17 was established through a 3+3 design. In the multicenter phase II part (figure), upfront AZA was sequentially followed by AZA or IC based on d 15 bone marrow (BM) blast count (<45 versus >45%) and CR, CRi on d 56 previously identified as early predictors for long-term response to AZA in AML (Al-Ali et al., Leuk Lymph 2012). The primary endpoint was response (OR) [CR, CRi, and PR] at d 90 according to the International Working Group criteria. Safety, OS, and TRM were main secondary end points. On the basis of an optimal two-stage design (Simon, Control Clin Trials 1989), an expected OR of 61% at the end of the trial was estimated. Thus, in an intention-to-treat analysis, if <19 of the first 40 pts did not achieve the primary endpoint, protocol treatment would be considered inferior to standard IC. The trial is supervised by an independent Data Monitoring Committee. Adverse events (AEs) are reported according to the NCI CTCAE 4.03. All pts gave written informed consent.
Results
The median age of the 40 pts was 70y (55% males). de novo AML was present in 63% of pts. Median BM blasts and WBC were 39% and 6.7x109/L respectively. Cytogenetics was high- in 29% and intermediate-risk in 71% (normal cytogenetics 50%) of 38 pts. FLT3 and NPM1 were mutated in 11% and 17% of 36 pts respectively. All pts received the upfront AZA. 37 (92.5%) pts received protocol assigned treatment based on BM blasts on d 15 (54% continued with AZA; 46% received IC). Overall, in the 33 (82.5%) pts who continued therapy per protocol until d90, an OR was achieved in 27 (82%) pts [CR/CRi (n=17/7); PR (n=3)]. In the intention-to-treat cohort (n=40), this represents an OR of 67.5% [CR/CRi (60%); PR (7.5%)] with AZA + one IC cycle (n=28) or two IC cycles (n=3). TRM on d 30 and d 90 was 0% and 5% respectively. After a median follow-up of 202 days, OS for the entire cohort was 84.5%. OS for responding pts was 95.5%.Except for one patient, upfront AZA was not complicated by leukocytosis even in pts with WBC >15x109/L and was generally well tolerated. Constipation grade 1+2 was the most frequently reported AE under AZA (45%). Overall, the most frequent grade 3+4 non-hematologic AE was infection [11 times in 31 IC-cycles (35%); 7 times in 60 AZA-cycles (12%)].
Conclusion
These data imply that sequential epigenetic therapy and intensive chemotherapy in elderly pts with AML in an individualized response-based approach is feasible with a very low treatment-related mortality and yields responses that are at least comparable to those achieved after repeated cycles of standard chemotherapy. The final results of this trial will substantiate these data and scrutinize the impact of this approach on long-term survival
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Chemotherapy, Epigenetic
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C13
Background
Treatment options for AML in patients (pts) >60 years (y) include intensive chemotherapy (IC) and/or azacitidine (AZA). Yet, AZA and IC need not automatically be mutually exclusive.
Aims
In the multicenter DRKS00004519 (RAS-AZIC) study of the East German Study Group (OSHO), first-line treatment with AZA followed by AZA or IC in pts >60 y with AML was evaluated. Data of a planned interim analysis per protocol of the first 40 consecutive pts are presented.
Methods
Patients >60 y with newly diagnosed AML and eligible for IC were included irrespective of white blood count (WBC). In the phase I part of the trial, safety of upfront AZA (75 mg/m2/day s.c.) for 7 days followed by IC (mitoxantrone 10 mg/ m²/day on day (d) 1-3 and cytarabine 1g/ m²/BID on d 1, 3, 5, 7) on d 17 was established through a 3+3 design. In the multicenter phase II part (figure), upfront AZA was sequentially followed by AZA or IC based on d 15 bone marrow (BM) blast count (<45 versus >45%) and CR, CRi on d 56 previously identified as early predictors for long-term response to AZA in AML (Al-Ali et al., Leuk Lymph 2012). The primary endpoint was response (OR) [CR, CRi, and PR] at d 90 according to the International Working Group criteria. Safety, OS, and TRM were main secondary end points. On the basis of an optimal two-stage design (Simon, Control Clin Trials 1989), an expected OR of 61% at the end of the trial was estimated. Thus, in an intention-to-treat analysis, if <19 of the first 40 pts did not achieve the primary endpoint, protocol treatment would be considered inferior to standard IC. The trial is supervised by an independent Data Monitoring Committee. Adverse events (AEs) are reported according to the NCI CTCAE 4.03. All pts gave written informed consent.
Results
The median age of the 40 pts was 70y (55% males). de novo AML was present in 63% of pts. Median BM blasts and WBC were 39% and 6.7x109/L respectively. Cytogenetics was high- in 29% and intermediate-risk in 71% (normal cytogenetics 50%) of 38 pts. FLT3 and NPM1 were mutated in 11% and 17% of 36 pts respectively. All pts received the upfront AZA. 37 (92.5%) pts received protocol assigned treatment based on BM blasts on d 15 (54% continued with AZA; 46% received IC). Overall, in the 33 (82.5%) pts who continued therapy per protocol until d90, an OR was achieved in 27 (82%) pts [CR/CRi (n=17/7); PR (n=3)]. In the intention-to-treat cohort (n=40), this represents an OR of 67.5% [CR/CRi (60%); PR (7.5%)] with AZA + one IC cycle (n=28) or two IC cycles (n=3). TRM on d 30 and d 90 was 0% and 5% respectively. After a median follow-up of 202 days, OS for the entire cohort was 84.5%. OS for responding pts was 95.5%.Except for one patient, upfront AZA was not complicated by leukocytosis even in pts with WBC >15x109/L and was generally well tolerated. Constipation grade 1+2 was the most frequently reported AE under AZA (45%). Overall, the most frequent grade 3+4 non-hematologic AE was infection [11 times in 31 IC-cycles (35%); 7 times in 60 AZA-cycles (12%)].
Conclusion
These data imply that sequential epigenetic therapy and intensive chemotherapy in elderly pts with AML in an individualized response-based approach is feasible with a very low treatment-related mortality and yields responses that are at least comparable to those achieved after repeated cycles of standard chemotherapy. The final results of this trial will substantiate these data and scrutinize the impact of this approach on long-term survival
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Chemotherapy, Epigenetic
Abstract: S811
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C13
Background
Treatment options for AML in patients (pts) >60 years (y) include intensive chemotherapy (IC) and/or azacitidine (AZA). Yet, AZA and IC need not automatically be mutually exclusive.
Aims
In the multicenter DRKS00004519 (RAS-AZIC) study of the East German Study Group (OSHO), first-line treatment with AZA followed by AZA or IC in pts >60 y with AML was evaluated. Data of a planned interim analysis per protocol of the first 40 consecutive pts are presented.
Methods
Patients >60 y with newly diagnosed AML and eligible for IC were included irrespective of white blood count (WBC). In the phase I part of the trial, safety of upfront AZA (75 mg/m2/day s.c.) for 7 days followed by IC (mitoxantrone 10 mg/ m²/day on day (d) 1-3 and cytarabine 1g/ m²/BID on d 1, 3, 5, 7) on d 17 was established through a 3+3 design. In the multicenter phase II part (figure), upfront AZA was sequentially followed by AZA or IC based on d 15 bone marrow (BM) blast count (<45 versus >45%) and CR, CRi on d 56 previously identified as early predictors for long-term response to AZA in AML (Al-Ali et al., Leuk Lymph 2012). The primary endpoint was response (OR) [CR, CRi, and PR] at d 90 according to the International Working Group criteria. Safety, OS, and TRM were main secondary end points. On the basis of an optimal two-stage design (Simon, Control Clin Trials 1989), an expected OR of 61% at the end of the trial was estimated. Thus, in an intention-to-treat analysis, if <19 of the first 40 pts did not achieve the primary endpoint, protocol treatment would be considered inferior to standard IC. The trial is supervised by an independent Data Monitoring Committee. Adverse events (AEs) are reported according to the NCI CTCAE 4.03. All pts gave written informed consent.
Results
The median age of the 40 pts was 70y (55% males). de novo AML was present in 63% of pts. Median BM blasts and WBC were 39% and 6.7x109/L respectively. Cytogenetics was high- in 29% and intermediate-risk in 71% (normal cytogenetics 50%) of 38 pts. FLT3 and NPM1 were mutated in 11% and 17% of 36 pts respectively. All pts received the upfront AZA. 37 (92.5%) pts received protocol assigned treatment based on BM blasts on d 15 (54% continued with AZA; 46% received IC). Overall, in the 33 (82.5%) pts who continued therapy per protocol until d90, an OR was achieved in 27 (82%) pts [CR/CRi (n=17/7); PR (n=3)]. In the intention-to-treat cohort (n=40), this represents an OR of 67.5% [CR/CRi (60%); PR (7.5%)] with AZA + one IC cycle (n=28) or two IC cycles (n=3). TRM on d 30 and d 90 was 0% and 5% respectively. After a median follow-up of 202 days, OS for the entire cohort was 84.5%. OS for responding pts was 95.5%.Except for one patient, upfront AZA was not complicated by leukocytosis even in pts with WBC >15x109/L and was generally well tolerated. Constipation grade 1+2 was the most frequently reported AE under AZA (45%). Overall, the most frequent grade 3+4 non-hematologic AE was infection [11 times in 31 IC-cycles (35%); 7 times in 60 AZA-cycles (12%)].
Conclusion
These data imply that sequential epigenetic therapy and intensive chemotherapy in elderly pts with AML in an individualized response-based approach is feasible with a very low treatment-related mortality and yields responses that are at least comparable to those achieved after repeated cycles of standard chemotherapy. The final results of this trial will substantiate these data and scrutinize the impact of this approach on long-term survival
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Chemotherapy, Epigenetic
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:45 - 09:00
Location: Hall C13
Background
Treatment options for AML in patients (pts) >60 years (y) include intensive chemotherapy (IC) and/or azacitidine (AZA). Yet, AZA and IC need not automatically be mutually exclusive.
Aims
In the multicenter DRKS00004519 (RAS-AZIC) study of the East German Study Group (OSHO), first-line treatment with AZA followed by AZA or IC in pts >60 y with AML was evaluated. Data of a planned interim analysis per protocol of the first 40 consecutive pts are presented.
Methods
Patients >60 y with newly diagnosed AML and eligible for IC were included irrespective of white blood count (WBC). In the phase I part of the trial, safety of upfront AZA (75 mg/m2/day s.c.) for 7 days followed by IC (mitoxantrone 10 mg/ m²/day on day (d) 1-3 and cytarabine 1g/ m²/BID on d 1, 3, 5, 7) on d 17 was established through a 3+3 design. In the multicenter phase II part (figure), upfront AZA was sequentially followed by AZA or IC based on d 15 bone marrow (BM) blast count (<45 versus >45%) and CR, CRi on d 56 previously identified as early predictors for long-term response to AZA in AML (Al-Ali et al., Leuk Lymph 2012). The primary endpoint was response (OR) [CR, CRi, and PR] at d 90 according to the International Working Group criteria. Safety, OS, and TRM were main secondary end points. On the basis of an optimal two-stage design (Simon, Control Clin Trials 1989), an expected OR of 61% at the end of the trial was estimated. Thus, in an intention-to-treat analysis, if <19 of the first 40 pts did not achieve the primary endpoint, protocol treatment would be considered inferior to standard IC. The trial is supervised by an independent Data Monitoring Committee. Adverse events (AEs) are reported according to the NCI CTCAE 4.03. All pts gave written informed consent.
Results
The median age of the 40 pts was 70y (55% males). de novo AML was present in 63% of pts. Median BM blasts and WBC were 39% and 6.7x109/L respectively. Cytogenetics was high- in 29% and intermediate-risk in 71% (normal cytogenetics 50%) of 38 pts. FLT3 and NPM1 were mutated in 11% and 17% of 36 pts respectively. All pts received the upfront AZA. 37 (92.5%) pts received protocol assigned treatment based on BM blasts on d 15 (54% continued with AZA; 46% received IC). Overall, in the 33 (82.5%) pts who continued therapy per protocol until d90, an OR was achieved in 27 (82%) pts [CR/CRi (n=17/7); PR (n=3)]. In the intention-to-treat cohort (n=40), this represents an OR of 67.5% [CR/CRi (60%); PR (7.5%)] with AZA + one IC cycle (n=28) or two IC cycles (n=3). TRM on d 30 and d 90 was 0% and 5% respectively. After a median follow-up of 202 days, OS for the entire cohort was 84.5%. OS for responding pts was 95.5%.Except for one patient, upfront AZA was not complicated by leukocytosis even in pts with WBC >15x109/L and was generally well tolerated. Constipation grade 1+2 was the most frequently reported AE under AZA (45%). Overall, the most frequent grade 3+4 non-hematologic AE was infection [11 times in 31 IC-cycles (35%); 7 times in 60 AZA-cycles (12%)].
Conclusion
These data imply that sequential epigenetic therapy and intensive chemotherapy in elderly pts with AML in an individualized response-based approach is feasible with a very low treatment-related mortality and yields responses that are at least comparable to those achieved after repeated cycles of standard chemotherapy. The final results of this trial will substantiate these data and scrutinize the impact of this approach on long-term survival
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Chemotherapy, Epigenetic
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