In:
Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 175-175
Abstract:
*equal contribution of AB, RLL, BD and JCB Background: Acute myeloid leukemia (AML) is common with increasing age, and older adults with AML rarely achieve long-term remission with chemotherapy. Gene discovery studies in older adults with AML have shown that this malignancy is characterized by a multitude of somatic genomic alterations beginning with initiating somatic events followed by acquisition of collaborative transforming mutations. Despite these important biologic insights, current therapeutic approaches to AML remain limited, particularly in adults ≥ 60 years of age. The Beat AML trial was designed to assess the feasibility of using genetic profiling to assign patients (pts) to molecularly defined, subtype-specific therapies within 7 days of the initial diagnosis in a multi-center clinical trial setting, and to delineate the role of molecularly informed first-line treatment of AML with mechanism based novel therapies. Methods: Treatment-naïve patients with AML were enrolled in this prospective trial which offered accelerated cytogenetic and comprehensive mutational testing within 7 days followed by treatment assignment using these molecular data. Pt eligibility included age ≥ 60 years with non-APML AML, no known CNS leukemia, no prior hypomethylating agent (HMA) therapy and no clinical need for emergent therapy. Eligible pts were profiled by local cytogenetics analysis and using a central next generation sequencing (NGS) assay (Foundation Medicine, Inc.) with all molecular data required for treatment assignment (TA) obtained & lt; 7 days. TA was made centrally using a pre-determined algorithm considering somatic cytogenetic and molecular alterations in the dominant clone, available targeted therapeutics for specific AML subsets, and the likelihood of cure with intensive chemotherapy. Results: From November 2016 to January 2019, 487 pts with a suspected diagnosis of AML had enrolled at 14 clinical sites; 395 were eligible for the study (77% of the patients not eligible for the study had an alternative diagnosis). The median age of eligible patients was 72 years (range: 60 to 92) with 38% being≥ 75 years and 16% with treatment-related AML. From the 395 eligible patients, 374 (94.7%) were centrally assigned to the different cytogenetic/genomic groups within 7 days. The most common groups were TP53 mutated (19%) and marker negative (18%) molecular groups. The Beat AML trial is dynamic by design, thereby allowing different arms to open over time; all trial arms are designed to evaluate for substantial clinical efficacy in small, molecularly defined patient subsets. As shown in Figure 1, 224 patients (57%) had a TA and consented to a BEAT AML sub-study. Of the remaining 171 patients, 103 received standard therapy defined as induction therapy (7+3) or hypomethylation agent (25 before TA and 78 after TA), 28 received an alternative investigational agent (5 before TA and 23 after TA), 38 received palliative care, and 2 had an unknown treatment status and are grouped with the palliative care patients in subsequent analyses; 9 patients died before TA (2 who received standard therapy and 7 in the palliative care group). Demographic, clinical, performance and molecular characteristics were not largely different between pts who elected targeted therapy as part of the BEAT AML trial versus those who elected standard therapy. As shown in Figure 2, the overall survival was significantly longer for patients enrolled in a targeted therapy arm as part of the BEAT AML trial compared to those who elected standard therapy. (p & lt;0.0001). The 30-day estimated death rate was 3.7% (95% CI: 1.9-7.2) for patients electing treatment on a BEAT AML sub-study, 20.4% (95% CI: 13.0-31.2) for those receiving standard therapy, 0% for those receiving an investigational therapy, and 72.6% (95% CI: 57.8-85.7) for the palliative care group. Conclusion: Our data support the feasibility of a rapid precision medicine approach in older patients with previously untreated AML. Patients with AML who elected treatment assigned based upon cytogenetic and molecular alterations in the dominant clone using a novel precision medicine approach had significantly improved overall survival versus those who elected standard of care treatment. Disclosures Levine: Gilead: Consultancy; Prelude Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Lilly: Honoraria. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Takeda: Research Funding; Incyte: Research Funding; Kite: Research Funding; Forma: Research Funding; AI Therapeutics: Research Funding; Abbvie: Research Funding; Astellas: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Deininger:Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Sangamo: Consultancy; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Blum:Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Astellas,: Research Funding; Xencor: Research Funding; Forma: Research Funding; AmerisourceBergen: Consultancy. Schiller:Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J & J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Bristol Myer Squibb: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding. Olin:Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Revolution Medicine: Consultancy; AstraZeneca: Research Funding; Clovis: Research Funding; Ignyta: Research Funding; MedImmune: Research Funding; Mirati Therapeutics: Research Funding; Novartis: Research Funding; Spectrum: Research Funding. Foran:Agios: Honoraria, Research Funding. Lin:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria. Traer:AbbVie: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Notable Labs: Equity Ownership. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Astex Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; Oncotherapy: Research Funding; Agios: Research Funding; CTI/Baxalta: Research Funding. Arellano:Gilead: Consultancy. Vergilio:Roche Holding AG: Equity Ownership; Foundation Medicine: Employment. Brennan:Foundation Medicine: Employment. Vietz:Foundation Medicine: Employment. Druker:ALLCRON: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Honoraria; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; CureOne: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding. Byrd:Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2019-130201
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2019
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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