RISK-ADAPTED, MRD-DIRECTED THERAPY FOR YOUNG ADULTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA: RESULTS OF THE AML1310 TRIAL OF THE GIMEMA GROUP
(Abstract release date: 05/18/17)
EHA Library. Venditti A. 06/23/17; 181398; S111
Adriano Venditti
Contributions
Contributions
Abstract
Abstract: S111
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Hall C
Background
A comprehensive AML risk assessment, based on the integration of cytogenetic/genetic data and minimal residual disease (MRD) status, can help optimize patients' (pts) therapeutic post-remission allocation.
Aims
To evaluate the feasibility and results of a phase II trial of intensive chemotherapy in which risk-assignment and post-remission therapy of young patients with AML was based on pre-treatment cytogenetic/genetic data and post-consolidation levels of MRD.
Methods
Between January 2012 and May 2015, 515 pts with de novo AML, 18 to 60 years old, seen at 55 GIMEMA institutions were enrolled in the trial. Induction consisted of i.v. daunorubicin 50 mg/m2 daily on days 1,3 and 5; i.v. etoposide 50 mg/m2 daily on days 1 to 5; i.v. cytarabine 100 mg/m2 as a daily continuous infusion, days 1 to 10. All pts in CR/CRi after 1-2 induction cycles, received 1 consolidation course consisting of i.v. daunorubicin 50 mg/m2 daily on days 4,5 and 6 and i.v. cytarabine 500 mg/m2 every 12 hours on days 1 to 6. In pts belonging to ELN low or intermediate-risk category, peripheral blood stem cell collection was attempted by initiating, on day 20 from the start of consolidation therapy, G-CSF until completion of stem cell collection. Post-consolidation therapy was based on risk-allocation. Low-risk pts (NPM1 positive FLT3-ITD negative or CBF positive without c-Kit mutations) were to receive AuSCT; high-risk pts (adverse karyotype or FLT3-ITD positive) were to receive ASCT; intermediate-risk pts (intermediate karyotype or FLT3-TKD positive or c-kit mutated CBF positive) were to receive AuSCT or ASCT depending on the levels of MRD, measured by flow cytometry after consolidation therapy. Allocation to ASCT required the procedure to be performed whatever the source of stem cells (identical sibling, unrelated, cord blood, haploidentical).
Results
500/515 pts started treatment and were available for the analysis. Median age was 49 (18-61) years and 52% were males. Of 429 evaluable pts, ELN cytogenetic distribution was: low-risk 11%, intermediate-risk 73% and poor-risk 16%. RUNX1/RUNX1T1 was detected in 5% of 499 evaluable cases, CBFbeta/MYH11 in 7% of 496, FLT3-ITD in 25% of 497 and NPM1 in 37% of 499. In 494 evaluable pts, complete remission rate (CR) was 73% (361), 18% had refractory AML and 9% died early during induction. Three hundred-41 pts completed the consolidation phase and were risk allocated: 114 (33%) to the low-risk category (=AuSCT), 122 (36%) to the high-risk (=ASCT) and 78 (23%) to the intermediate category (=AuSCT or ASCT). In 27 pts (8%) belonging to the intermediate-risk category, a leukemia associated phenotype was not found and they were to receive AuSCT. Overall, 109 (33%) and 123 (36%) of 341 pts received AuSCT and ASCT, respectively. Median follow-up was 27.9 months. At 24 months, overall (OS) and disease free survival (DFS) of the whole series was 55.9% and 54.9%, respectively; cumulative incidence of relapse was 32.9%. At the same time point of 24 months, OS and DFS in the low-risk category was 74.8% and 63.8%, respectively; in the high-risk category 42.5% and 44.8%, respectively; in the intermediate-risk category MRD negative 78.6% and 61.4%, respectively; in the intermediate-risk category MRD positive 69.8% and 66.6%, respectively (Fig. 1).
Conclusion
A program of risk-adapted, MRD-driven therapy is feasible in a multicenter, cooperative setting. In the intermediate-risk category, ASCT can be avoided if MRD is not detectable; if MRD is positive, ASCT can prolong OS and DFS to equalize those of the low-risk category. ASCT was delivered to 2/3 of pts in the high-risk category, using all the available sources of stem cells.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): MRD, Molecular markers, Cytogenetics, AML
Abstract: S111
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Hall C
Background
A comprehensive AML risk assessment, based on the integration of cytogenetic/genetic data and minimal residual disease (MRD) status, can help optimize patients' (pts) therapeutic post-remission allocation.
Aims
To evaluate the feasibility and results of a phase II trial of intensive chemotherapy in which risk-assignment and post-remission therapy of young patients with AML was based on pre-treatment cytogenetic/genetic data and post-consolidation levels of MRD.
Methods
Between January 2012 and May 2015, 515 pts with de novo AML, 18 to 60 years old, seen at 55 GIMEMA institutions were enrolled in the trial. Induction consisted of i.v. daunorubicin 50 mg/m2 daily on days 1,3 and 5; i.v. etoposide 50 mg/m2 daily on days 1 to 5; i.v. cytarabine 100 mg/m2 as a daily continuous infusion, days 1 to 10. All pts in CR/CRi after 1-2 induction cycles, received 1 consolidation course consisting of i.v. daunorubicin 50 mg/m2 daily on days 4,5 and 6 and i.v. cytarabine 500 mg/m2 every 12 hours on days 1 to 6. In pts belonging to ELN low or intermediate-risk category, peripheral blood stem cell collection was attempted by initiating, on day 20 from the start of consolidation therapy, G-CSF until completion of stem cell collection. Post-consolidation therapy was based on risk-allocation. Low-risk pts (NPM1 positive FLT3-ITD negative or CBF positive without c-Kit mutations) were to receive AuSCT; high-risk pts (adverse karyotype or FLT3-ITD positive) were to receive ASCT; intermediate-risk pts (intermediate karyotype or FLT3-TKD positive or c-kit mutated CBF positive) were to receive AuSCT or ASCT depending on the levels of MRD, measured by flow cytometry after consolidation therapy. Allocation to ASCT required the procedure to be performed whatever the source of stem cells (identical sibling, unrelated, cord blood, haploidentical).
Results
500/515 pts started treatment and were available for the analysis. Median age was 49 (18-61) years and 52% were males. Of 429 evaluable pts, ELN cytogenetic distribution was: low-risk 11%, intermediate-risk 73% and poor-risk 16%. RUNX1/RUNX1T1 was detected in 5% of 499 evaluable cases, CBFbeta/MYH11 in 7% of 496, FLT3-ITD in 25% of 497 and NPM1 in 37% of 499. In 494 evaluable pts, complete remission rate (CR) was 73% (361), 18% had refractory AML and 9% died early during induction. Three hundred-41 pts completed the consolidation phase and were risk allocated: 114 (33%) to the low-risk category (=AuSCT), 122 (36%) to the high-risk (=ASCT) and 78 (23%) to the intermediate category (=AuSCT or ASCT). In 27 pts (8%) belonging to the intermediate-risk category, a leukemia associated phenotype was not found and they were to receive AuSCT. Overall, 109 (33%) and 123 (36%) of 341 pts received AuSCT and ASCT, respectively. Median follow-up was 27.9 months. At 24 months, overall (OS) and disease free survival (DFS) of the whole series was 55.9% and 54.9%, respectively; cumulative incidence of relapse was 32.9%. At the same time point of 24 months, OS and DFS in the low-risk category was 74.8% and 63.8%, respectively; in the high-risk category 42.5% and 44.8%, respectively; in the intermediate-risk category MRD negative 78.6% and 61.4%, respectively; in the intermediate-risk category MRD positive 69.8% and 66.6%, respectively (Fig. 1).
Conclusion
A program of risk-adapted, MRD-driven therapy is feasible in a multicenter, cooperative setting. In the intermediate-risk category, ASCT can be avoided if MRD is not detectable; if MRD is positive, ASCT can prolong OS and DFS to equalize those of the low-risk category. ASCT was delivered to 2/3 of pts in the high-risk category, using all the available sources of stem cells.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): MRD, Molecular markers, Cytogenetics, AML
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