Abstract 2721: Prospective whole exome and whole transcriptome sequencing of hematologic cancers for biomarker-driven treatment : Preliminary results of a randomized pragmatic clinical trial
Authors: Kim Sanga , Kim Ryul , Koh Youngil , Sun Choong Hyun , Im Hogune , Yun Hong Seok , Shin Dong-Yeop , Kim Inho , Yoon Sung-soo 
Published: July 2017

Abstract
Introduction: Biomarker-driven early clinical trials of molecularly targeted agents have reported improvement of the response rate in various malignancies. In this pragmatic clinical trial, we aimed to assess whether biomarker-driven treatment strategy could improve outcomes of incurable hematologic cancer patients.
Methods: This is an open-label, randomized, pragmatic trial in adult patients with hematologic cancer. Patients with any kind of hematologic cancer refractory to standard-of-care are eligible. We randomly assigned these patients to receive a matched molecularly targeted agent (experimental group) or treatment at physician’s choice (control group). Randomizations are determined by central block randomization in 2:1 ratio. Clinicians and patients are not masked to allocation. Whole exome and whole transcriptome sequencing (WES/WTS) are applied for detecting all classes of genomic alterations: single nucleotide variation (SNV), insertions and deletions (INDEL), copy number alterations, Fms-Related Tyrosine Kinase 3 (FLT3) internal tandem duplication (ITD), Mixed-lineage leukemia partial tandem duplication and gene rearrangements. The primary endpoint is response rate in the intention-to-treat population.
Results: Twenty-three patients with median age of 53 years and male to female ratio of 11:12 were enrolled between December 2015 and October 2016; 15 patients in experimental group, 8 patients in control group. Actionable mutations were identified in four patients in experimental arm. A 78-year-old female with acute myelogenous leukemia (AML) had FLT3 ITD at exon 14, which was identified as a long insertion mutation in SNV/INDEL calling. She received ASP2215 (FLT3 inhibitor), and showed a dramatic reduction in blast counts of peripheral blood. A 75-year-old female with myelodysplastic syndrome had TSC1P39A mutation. Because mTOR exists in downstream signaling pathway of TSC1, everolimus was administered and regression of disease activity, reflected by reduction of C-reactive protein level, was observed. NOTCH2 c.17′ and KITD815V mutation were identified in two patient; 69-year-old female with multiple myeloma and 42-year-old male with AML, respectively. Among 8 patients in control arm, seven patients received cytotoxic chemotherapy. One undergone another comprehensive genomic profiling called FoundationOne Heme, however no actionable mutations was identified.
Conclusions: Among patients with incurable hematologic malignancy, actionable mutations could be identified in one fourth of patients for whom WES/WTS were performed. They showed favorable initial response to molecularly targeted agents. This randomized pragmatic clinical trial is currently ongoing(NCT02758080).
Citation Format: Sanga Kim, Ryul Kim, Youngil Koh, Choong Hyun Sun, Hogune Im, Hong Seok Yun, Dong-Yeop Shin, Inho Kim, Sung-soo Yoon. Prospective whole exome and whole transcriptome sequencing of hematologic cancers for biomarker-driven treatment : Preliminary results of a randomized pragmatic clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2721. doi:10.1158/1538-7445.AM2017-2721