@article{8484325482434237909ae2c07b788172,
title = "Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial",
abstract = "Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient{\textquoteright}s leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60–92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.",
author = "Amy Burd and Levine, {Ross L.} and Ruppert, {Amy S.} and Mims, {Alice S.} and Uma Borate and Stein, {Eytan M.} and Prapti Patel and Baer, {Maria R.} and Wendy Stock and Michael Deininger and William Blum and Gary Schiller and Rebecca Olin and Mark Litzow and James Foran and Lin, {Tara L.} and Brian Ball and Michael Boyiadzis and Elie Traer and Olatoyosi Odenike and Martha Arellano and Alison Walker and Duong, {Vu H.} and Tibor Kovacsovics and Robert Collins and Shoben, {Abigail B.} and Heerema, {Nyla A.} and Foster, {Matthew C.} and Vergilio, {Jo Anne} and Tim Brennan and Christine Vietz and Eric Severson and Molly Miller and Leonard Rosenberg and Sonja Marcus and Ashley Yocum and Timothy Chen and Mona Stefanos and Brian Druker and Byrd, {John C.}",
note = "Funding Information: The investigative team thanks the patients and their caregivers who participated in this trial. The study was sponsored by the LLS, which holds the investigational new drug (IND) application for this trial. Funding for the trial was made possible by the Harry T. Mangurian Foundation, many other donors and the sites that enabled resources for rapid turnaround for cytogenetics and other monitoring requirements of patients. The IND and ultimate design and implementation of this trial came forth from integral collaboration of the LLS team and members at the FDA under the leadership of R. Pazdur, D. Przepiorka, A. Deisseroth and A. Farrell, to whom we are greatly indebted. We thank the investigators and coordinators at each of the clinical sites and the patients who participated in this trial and their families who supported them. Sub-studies in this trial were supported by the pharmaceutical sponsor. We thank the pharmaceutical sponsors who paid the cost of performing the specific sub-studies with their investigational drugs. This work was supported by the NCI (grant no. R35 CA198183 to J.C.B.; grant no. R35 CA197594 to R.L.L.) and in part through the NIH/NCI Cancer Center Support grant nos. P30 CA008748, P30CA069533 and P30 CA016058. We acknowledge many references that could not be included based on the limitations of the journal. Funding Information: Trial oversight. The study was sponsored by Beat AML, LLC, a division of the LLS. Clinical sites were selected by the principals (A.B., R.L., J.C.B. and B.D.) after a detailed application process based on patient volume, institutional commitment, ability to use a central institutional review board and location to enable broad enrollment across the USA. A single scientific review board (Ohio State University) was utilized to meet the National Cancer Institute (NCI)-designated Cancer Center requirement for peer review. This required coordination with the NCI leadership (J. Doroshow) to modify clinical trial oversight rules for non-NCI-sponsored studies applicable to NCI-sponsored Beat AML centers. The institutional review board (Western Institutional Review Board) approved the protocol for all sites. The study was conducted according to the principles of the Declaration of Helsinki (version 2013) and the International Conference on Harmonization Guidelines for Good Clinical Practice. Treatment was assigned by a central team (J.C.B., A.S.M., B.D. and M.S.) after receipt and review of all information. Safety calls with sites, the LLS and clinical research organization staff occurred weekly to review the active status of patients enrolled. These calls were essential to enabling rapid adaptation and feedback to sites, if necessary, about local processes and modification of the trial. An independent data and safety monitoring board periodically reviewed all outcome, treatment and toxicity data. Medical monitors from a clinical research organization reviewed selected data centrally and representatives of the sponsor regularly visited the study sites to monitor study compliance. Clinical data were collected using a combination of data management systems. Central review of serious reported events submitted by pharmaceutical sponsors to determine the relevance to the Beat AML trial was implemented, which greatly diminished (approximately 90%) the requirement of individual event review by study investigators. Contracting was done centrally by the LLS on behalf of all clinical sites to shorten individual agreements between the pharmaceutical companies and institutions. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = dec,
doi = "10.1038/s41591-020-1089-8",
language = "English (US)",
volume = "26",
pages = "1852--1858",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "12",
}