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Impact of Gene Mutations on Survival with Azacitidine or Conventional Care Regimens (CCR) in Older Patients with Acute Myeloid Leukemia
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
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Table: (abstract: 109)
110 IMPACT OF GENE MUTATIONS ON SURVIVAL WITH AZACITIDINE OR CONVENTIONAL CARE REGIMENS (CCR) IN OLDER PATIENTS WITH ACUTE MYELOID LEUKEMIA L. Tang1, A. Dolnik2, K.J. MacBeth3, H. Dombret4, J.F. Seymour5,6, M.D. Minden7, R.M. Stone8, C.L. Beach9, H. Döhner2, L. Bullinger2 1 Computational Bio Informatics and Knowledge Utilization, Celgene Corporation, San Diego, USA; 2Department of Internal Medicine III, Universitätsklinikum Ulm, Ulm, Germany; 3Translational Development, Celgene Corporation, San Francisco, USA; 4Department of Hematology, Hôpital Saint Louis- Institut Universitaire d’Hématologie- University Paris Diderot, Paris, France; 5Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; 6 Department of Haematology, University of Melbourne, Parkville, Australia; 7Department of Medical Biophysics, University of Toronto, Toronto, Canada; 8Department of Medical Oncology, DanaFarber Cancer Institute, Boston, USA; 9Department of Hematology/Oncology, Celgene Corporation, Summit, USA
Figure: (abstract: 109)
Recurrently mutated genes in acute myeloid leukemia (AML) may have value for prognosis and prediction of treatment response. In the phase 3 AZA-AML-001 study, azacitidine prolonged overall survival (OS) vs CCR (10.4 vs 6.5 months; P = 0.101) (Dombret, Blood, 2015). We investigated relationships between gene mutations and OS for AZA-AML-001 patients who consented to participate in exploratory molecular analyses. Patients were aged ≥65 years with newly diagnosed AML (>30% blasts), ECOG PS 0–2, WBC ≤ 15 × 109/L, and NCCN-defined intermediate- or poor-risk cytogenetics. Patients received azacitidine (75 mg/m2/day ×7 days/28-day cycle) or CCR: intensive chemotherapy, low-dose cytarabine, or supportive care only. Targeted sequencing (from all exons to hot-spots) of 39 genes in DNA isolated from bone marrow mononuclear cells was performed. Mutations observed in ≥5 patients were assessed for their relationship to OS vs wild-type (≥5 patients) within treatment arms. Mutation-OS associations were also compared between azacitidine and CCR.
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Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
Table: (abstract: 110)
Molecular analyses included 32% of AZA-AML-001 patients (AZA = 83, CCR = 73). Mutations were observed in 33/39 sequenced genes, most frequently DNMT3A (27%), TET2 (25%), IDH2 (23% [R140 15%, R172 8%]), TP53 (21%), RUNX1 (18%), NPM1 (16%), NRAS (12%), FLT3 (12% [-ITD 10%, -TKD 5%]), ASXL1 (11%), and STAG2 (10%). Compared with wild-type, median OS was significantly reduced for CCRtreated patients with TP53 mut and NRAS mut, and for azacitidinetreated patients with FLT3 mut (Table 1). There was a statistically significant OS difference with azacitidine for TET2 mut vs TET2 wt despite similar median OS (9.6 vs 9.5 months). Median OS with azacitidine was similar for patients with or without mutations in DNA-methylation-associated genes (DNMT3A, IDH1, IDH2, and TET2). Compared with similar CCR patients, azacitidine-treated patients with TP53 mut and/or NRAS mut had nominally better median OS, and those with FLT3 mut had nominally worse OS (Table 2). These exploratory analyses suggest older AML patients with TP53 mut and NRAS mut have a better prognosis with azacitidine than with CCR. Mutations in genes that regulate DNA methylation did not affect median OS with azacitidine, although potential negative effects of TET2 mut and FLT3 mut warrant further evaluation. Larger cohorts are needed to establish the influence of recurring co-mutational patterns in azacitidine-treated patients.
111 AZACITIDINE PROLONGS OVERALL SURVIVAL IN OLDER PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WITH POOR PROGNOSTIC KARYOTYPES H. Döhner1, P. Vyas2, J.F. Seymour3,4, V. Santini5, R.M. Stone6, M.D. Minden7, H.K. Al-Ali8, T. Bernal del Castillo9, J. Morrill10, S. Songer11, J. Weaver10, B.S. Skikne11, C.L. Beach11, H. Dombret12 1 Department of Internal Medicine III, Universitätsklinikum Ulm, Ulm, Germany; 2Department of Haematology, University of Oxford, Oxford, United Kingdom; 3Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; 4Department of Haematology, University of Melbourne, Parkville, Australia; 5Division of Hematology, University of Florence, Florence, Italy; 6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; 7Department of Medical Biophysics, Princess Margaret Cancer Centre, Toronto, Canada; 8Department of Hematology/Oncology, University Hospital of Halle, Halle, Germany; 9Department of Hematology and Hemotherapy, Hospital Central de Asturias, Oviedo, Spain; 10Department of Biostatistics, Celgene Corporation, Summit, USA; 11Department of Hematology/Oncology, Celgene Corporation, Summit, USA; 12 Department of Hematology, Hôpital Saint Louis- Institut Universitaire d’Hématologie- University Paris Diderot, Paris, France Background: Prognosis is dismal for older AML patients with unfavorable karyotypes. In the phase 3 AZA-AML-001 study,
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Table: (abstract: 109)
110 IMPACT OF GENE MUTATIONS ON SURVIVAL WITH AZACITIDINE OR CONVENTIONAL CARE REGIMENS (CCR) IN OLDER PATIENTS WITH ACUTE MYELOID LEUKEMIA L. Tang1, A. Dolnik2, K.J. MacBeth3, H. Dombret4, J.F. Seymour5,6, M.D. Minden7, R.M. Stone8, C.L. Beach9, H. Döhner2, L. Bullinger2 1 Computational Bio Informatics and Knowledge Utilization, Celgene Corporation, San Diego, USA; 2Department of Internal Medicine III, Universitätsklinikum Ulm, Ulm, Germany; 3Translational Development, Celgene Corporation, San Francisco, USA; 4Department of Hematology, Hôpital Saint Louis- Institut Universitaire d’Hématologie- University Paris Diderot, Paris, France; 5Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; 6 Department of Haematology, University of Melbourne, Parkville, Australia; 7Department of Medical Biophysics, University of Toronto, Toronto, Canada; 8Department of Medical Oncology, DanaFarber Cancer Institute, Boston, USA; 9Department of Hematology/Oncology, Celgene Corporation, Summit, USA
Figure: (abstract: 109)
Recurrently mutated genes in acute myeloid leukemia (AML) may have value for prognosis and prediction of treatment response. In the phase 3 AZA-AML-001 study, azacitidine prolonged overall survival (OS) vs CCR (10.4 vs 6.5 months; P = 0.101) (Dombret, Blood, 2015). We investigated relationships between gene mutations and OS for AZA-AML-001 patients who consented to participate in exploratory molecular analyses. Patients were aged ≥65 years with newly diagnosed AML (>30% blasts), ECOG PS 0–2, WBC ≤ 15 × 109/L, and NCCN-defined intermediate- or poor-risk cytogenetics. Patients received azacitidine (75 mg/m2/day ×7 days/28-day cycle) or CCR: intensive chemotherapy, low-dose cytarabine, or supportive care only. Targeted sequencing (from all exons to hot-spots) of 39 genes in DNA isolated from bone marrow mononuclear cells was performed. Mutations observed in ≥5 patients were assessed for their relationship to OS vs wild-type (≥5 patients) within treatment arms. Mutation-OS associations were also compared between azacitidine and CCR.
S70
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
Table: (abstract: 110)
Molecular analyses included 32% of AZA-AML-001 patients (AZA = 83, CCR = 73). Mutations were observed in 33/39 sequenced genes, most frequently DNMT3A (27%), TET2 (25%), IDH2 (23% [R140 15%, R172 8%]), TP53 (21%), RUNX1 (18%), NPM1 (16%), NRAS (12%), FLT3 (12% [-ITD 10%, -TKD 5%]), ASXL1 (11%), and STAG2 (10%). Compared with wild-type, median OS was significantly reduced for CCRtreated patients with TP53 mut and NRAS mut, and for azacitidinetreated patients with FLT3 mut (Table 1). There was a statistically significant OS difference with azacitidine for TET2 mut vs TET2 wt despite similar median OS (9.6 vs 9.5 months). Median OS with azacitidine was similar for patients with or without mutations in DNA-methylation-associated genes (DNMT3A, IDH1, IDH2, and TET2). Compared with similar CCR patients, azacitidine-treated patients with TP53 mut and/or NRAS mut had nominally better median OS, and those with FLT3 mut had nominally worse OS (Table 2). These exploratory analyses suggest older AML patients with TP53 mut and NRAS mut have a better prognosis with azacitidine than with CCR. Mutations in genes that regulate DNA methylation did not affect median OS with azacitidine, although potential negative effects of TET2 mut and FLT3 mut warrant further evaluation. Larger cohorts are needed to establish the influence of recurring co-mutational patterns in azacitidine-treated patients.
111 AZACITIDINE PROLONGS OVERALL SURVIVAL IN OLDER PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WITH POOR PROGNOSTIC KARYOTYPES H. Döhner1, P. Vyas2, J.F. Seymour3,4, V. Santini5, R.M. Stone6, M.D. Minden7, H.K. Al-Ali8, T. Bernal del Castillo9, J. Morrill10, S. Songer11, J. Weaver10, B.S. Skikne11, C.L. Beach11, H. Dombret12 1 Department of Internal Medicine III, Universitätsklinikum Ulm, Ulm, Germany; 2Department of Haematology, University of Oxford, Oxford, United Kingdom; 3Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; 4Department of Haematology, University of Melbourne, Parkville, Australia; 5Division of Hematology, University of Florence, Florence, Italy; 6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; 7Department of Medical Biophysics, Princess Margaret Cancer Centre, Toronto, Canada; 8Department of Hematology/Oncology, University Hospital of Halle, Halle, Germany; 9Department of Hematology and Hemotherapy, Hospital Central de Asturias, Oviedo, Spain; 10Department of Biostatistics, Celgene Corporation, Summit, USA; 11Department of Hematology/Oncology, Celgene Corporation, Summit, USA; 12 Department of Hematology, Hôpital Saint Louis- Institut Universitaire d’Hématologie- University Paris Diderot, Paris, France Background: Prognosis is dismal for older AML patients with unfavorable karyotypes. In the phase 3 AZA-AML-001 study,