Samples from patients with AML show high concordance in detection of mutations by NGS at local institutions vs central laboratories.

Next-generation sequencing (NGS) to identify pathogenic mutations is an integral part of acute myeloid leukemia (AML) therapeutic decision-making. The concordance in identifying pathogenic mutations among different NGS platforms at different diagnostic laboratories has been studied in solid tumors but not in myeloid malignancies to date. To determine this interlaboratory concordance, we collected a total of 194 AML bone marrow or peripheral blood samples from newly diagnosed patients with AML enrolled in the Beat AML Master Trial (BAMT) at 2 academic institutions. We analyzed the diagnostic samples from patients with AML for the detection of pathogenic myeloid mutations in 8 genes (DNMT3A, FLT3, IDH1, IDH2, NPM1, TET2, TP53, and WT1) locally using the Hematologic Neoplasm Mutation Panel (50-gene myeloid indication filter) (site 1) or the GeneTrails Comprehensive Heme Panel (site 2) at the 2 institutions and compared them with the central results from the diagnostic laboratory for the BAMT, Foundation Medicine, Inc. The overall percent agreement was over 95% each in all 8 genes, with almost perfect agreement (κ > 0.906) in all but WT1, which had substantial agreement (κ = 0.848) when controlling for site. The minimal discrepancies were due to reporting variants of unknown significance (VUS) for the WT1 and TP53 genes. These results indicate that the various NGS methods used to analyze samples from patients with AML enrolled in the BAMT show high concordance, a reassuring finding given the wide use of NGS for therapeutic decision-making in AML.

Representation of therapy-related myelodysplastic syndrome in clinical trials over the past 20 years.

Therapy-related myelodysplastic syndrome (t-MDS), defined as MDS occurring after previous exposure to chemotherapy or radiotherapy, constitutes 10% to 20% of all MDS diagnoses. t-MDS patients tend to have higher-risk disease and worse outcomes than de novo MDS patients and are often excluded from therapeutic clinical trials. To explore this further, we extracted clinical trials across all status types registered on ClinicalTrials.gov from 1999 to 2018 studying untreated MDS patients. Using these specific search criteria, we analyzed 317 therapeutic MDS trials based on study status, therapeutic indication, eligibility criteria, and sponsor type to examine if these factors influenced t-MDS patient inclusion. Only 18 studies (5.7%) accrued 231 t-MDS patients in total, representing 3.2% of the total accrued MDS trial patient population. Fewer t-MDS patients were accrued in therapeutic trials sponsored by pharmaceutical sponsors vs nonpharmaceutical sponsors (2.8% vs 4.0%; P = .0073). This pattern of exclusion continues in actively enrolling trials; only 5 (10%) of 49 studies specifically mention the inclusion of t-MDS patients in their eligibility criteria. Our results indicate that therapeutic MDS trials seem to exclude t-MDS patients, rendering study results less applicable to this subset of MDS patients, who often have poor outcomes. Our study emphasizes the importance of the recent focus by National Cancer Institute cooperative groups and societies to broaden eligibility criteria for all patients.