The implementation of targeted therapies for acute myeloid leukemia has been challenged by complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here, we report initial findings from the Beat AML program on a cohort of 672 tumor specimens collected from 562 patients. We assessed these specimens using whole exome sequencing, RNA-sequencing, and ex vivo drug sensitivity analyses. Our data reveal Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. This portion of the NCCN Guidelines for AML focuses on management and provides recommendations on the workup, diagnostic evaluation, and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients. Please NoteThe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.

SUMMARY Background Hypomethylating agents azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia (AML), but responses are limited and of short duration, possibly due to short half-lives and suboptimal bone marrow exposure. Guadecitabine (SGI-110), a dinucleotide of decitabine and deoxyguanosine, is resistant to degradation by cytidine deaminase thus achieving longer half-life and exposure of its active metabolite, decitabine. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in treatment-naïve older patients with AML who were not candidates for intensive chemotherapy. Methods In this multicentre, open-label, phase 2 study, treatment-naïve older patients from 14 North American medical centres with AML who were not candidates for intensive chemotherapy were randomly assigned (1:1, using a computer algorithm) to subcutaneous guadecitabine at 60 or 90 mg/m2 on days 1–5 (5-day schedule) of a 28-day treatment cycle. Subsequently, patients were assigned sequentially to subcutaneous guadecitabine at 60 mg/m2 in a 10-day schedule (at least 2 cycles administered on days 1–5 and 8–12, with subsequent cycles given on a 5-day schedule). The objective was to evaluate and compare the activity and safety of two doses and schedules of guadecitabine, with a primary endpoint of composite complete response (including complete response [CR], CR with incomplete platelet recovery [CRp], and CR with incomplete neutrophil recovery regardless of platelets [CRi]). Response was evaluated in all patients (as-treated) as long as a patient received at least one guadecitabine treatment. Secondary endpoints included safety, survival, and pharmacodynamics. We present the final trial analyses, although at time of database lock, 15 patients were still being monitored for survival including six continuing treatment. This study is registered with ClinicalTrials.gov, number NCT01261312 Findings Between Aug 24, 2012, and Sep 15, 2014, 103 patients received treatment: 51 on a 5-day schedule of guadecitabine (24 received 60 mg/m2, 27 received 90 mg/m2) and 52 on the 10-day schedule. Median age was 77 years. Poor prognostic features included ECOG status ≥2 (39 [38%]), poor-risk cytogenetics (43 [42%]), and secondary AML (37 [36%]). Characteristics were generally balanced across doses and schedules. CRc rates were 54% (13 patients), 59% (16 patients), and 50% (26 patients) for the 5-day 60, 5-day 90, and 10-day 60 mg/m2 regimens, respectively. The most common grade 3 or higher adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, included febrile neutropenia (31 [61%] and 36 [69%]), thrombocytopenia (25 [49%] and 22 [42%]), neutropenia (20 [39%] and 18 [35%]), pneumonia (15 [29%] and 19 [37%]), anaemia (15 [29%] and 12 [23%]), and sepsis (8 [16%] and 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, were febrile neutropenia (2...