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2705 Evaluation of the Impact of Minimal Residual Disease, FLT3 Allelic Ratio, and FLT3 Mutation Status on Overall Survival in FLT3 Mutation-Positive Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) in the Chrysalis Phase 1/2 Study

Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis
Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II
Sunday, December 10, 2017, 6:00 PM-8:00 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Mark J. Levis, MD, PhD1, Alexander E. Perl, MD2, Jessica K. Altman, MD3, Jorge E. Cortes, MD4, Catherine C. Smith, MD5, Maria R. Baer, MD6, David F. Claxton7, Joseph G. Jurcic, MD8, Ellen K Ritchie, MD9, Stephen A Strickland10, Raoul Tibes11,12*, Jason Hill13*, Shufang Liu13* and Erkut Bahceci, MD13

1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
2Division of Hematology/Oncology, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA
3Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
4Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
5University of California (San Francisco), San Francisco, CA
6University of Maryland Greenebaum Cancer Center, Baltimore, MD
7Penn State Milton S. Hershey Medical Center, Hershey, PA
8Department of Medicine, Columbia University Medical Center, New York, NY
9Weill Cornell Medical College, New York, NY
10Vanderbilt-Ingram Cancer Center, Nashville, TN
11Julius-Maximilians University, Würzburg, Germany
12Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ
13Astellas Pharma Global Development, Northbrook, IL

Background: Gilteritinib (formerly ASP2215), a highly selective fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor, demonstrated strong antileukemic activity at doses ≥80 mg/day in a FLT3 mutation-positive (FLT3mut+) R/R AML patient population enrolled in the CHRYSALIS Phase 1/2 study (NCT02014558). In this exploratory analysis, we analyzed the impact of minimal residual disease (MRD), FLT3 allelic ratio, and FLT3 mutation status on overall survival (OS) in FLT3mut+R/R AML patients from the CHRYSALIS study.

Methods: Minimal residual disease was assessed by next-generation sequencing (NGS) using an Illumina® sequencing platform that quantified FLT3-ITD and total FLT3 alleles in a subgroup of FLT3mut+ patients with internal tandem duplication (ITD) mutations (central laboratory-derived) who were enrolled in the 120 mg/day or 200 mg/day gilteritinib dose cohorts and had bone marrow samples available at baseline and ≥1 post-baseline time point. The ITD signal ratio was the FLT3-ITD to total FLT3 ratio. An ITD signal ratio of ≤10−4 defined MRD-negative status. For analyses of FLT3 allelic ratio and mutation status, a capture-based NGS assay that included all exons of FLT3 was used. Sample DNA was used to generate whole genome libraries which were hybridized with a custom probe to capture target fragments that were then sequenced on an Illumina® MiSeq platform. FLT3 mutation status was assessed at baseline and at relapse (investigator-assessed or central laboratory-derived relapse).

Results: Eighty FLT3-ITDmut+ patients enrolled in the 120 mg/day or 200 mg/day gilteritinib dose cohorts were analyzed for MRD. Thirteen of the 80 patients achieved MRD-negative status at any post-baseline time point. Patients who were MRD-negative (n=13; 6 achieved complete remission [CR] and 5 achieved CR with incomplete hematologic recovery) had longer median OS (417 days) than those who were MRD-positive (213 days; P=.002). There were several long-term survivors among patients who received ≥80 mg/day dose of gilteritinib (Figure 1). Of the 9 patients still remaining in the study, 5 who were included in the MRD analysis subgroup were all MRD-negative. Six of the 9 patients, including 2 of the 5 MRD-negative patients, underwent on-study transplantation. FLT3 allelic ratio was available at baseline from 6 of the 9 patients remaining on study. The median baseline allelic ratio was 61.5% in these 6 patients, which was similar to that for all 157 FLT3-ITDmut+ patients with available variant allele frequencies (50.4%).

Analysis of FLT3 mutation status in 241 patients showed that of the 35 patients with ≥1 FLT3 mutation detected at baseline and who had a relapse sample available for analysis, 27 had a relapse sample with ≥1 FLT3 mutation detected at relapse. Of these 35 patients, 15 received a starting dose of ≥200 mg/day gilteritinib and 20 received a starting dose of <200 mg/day. We detected the gatekeeper F691L mutation in relapse samples, but not in baseline samples, from 4 patients who had received <200 mg/day starting doses. In 2 of these 4 patients, 2 different DNA mutations were detected that both led to a F691L mutation, possibly suggesting the presence of multiple resistant clones at relapse. Although none of the patients who received ≥200 mg/day starting doses acquired F691L mutations, patients who received 120 mg/day doses had the longest OS of all dose groups (Figure 2). In one patient who did not undergo on-study transplantation and had re-enrolled in the CHRYSALIS study at a higher starting dose of gilteritinib (40 mg/day) and had samples available at both initial enrollment and re-enrollment, a F691L mutation that had not been detected at initial enrollment, was detected at the time of re-enrollment. One of the 4 patients with F691L mutations detected at relapse had achieved MRD negativity prior to relapse. Additional known FLT3 mutations, related to resistance, were not detected in relapse samples.

Conclusions: As a single agent, gilteritinib induced deep molecular responses, including MRD negativity, in heavily pre-treated FLT3-ITDmut+ patients with R/R AML. Our data suggest a potential association between MRD-negative status and longer survival duration in patients with FLT3-ITDmut+ R/R AML. Median FLT3 allelic ratio at baseline in patients remaining in the study was similar to that for all enrolled patients. Only F691L was detected as a known acquired resistance mutation in patients who had relapsed.

Disclosures: Levis: FujiFilm: Research Funding; Astellas Pharma Us: Consultancy, Research Funding; Daiichi Sankyo, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Perl: Actinium Pharmaceuticals: Other: Scientific Advisory Board; Astellas: Consultancy; Arog Pharmaceuticals: Consultancy; Pfizer: Other: Advisory Board; Daiichi Sankyo: Consultancy; Asana Biosciences: Other: Scientific advisory board; Novartis: Other: Advisory Board; Seattle Genetics: Other: Advisory board. Altman: Janssen Pharmaceuticals: Consultancy; Ceplene: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Syros: Consultancy; BMS: Consultancy; Novartis: Consultancy; Hemedicus: Other: Advisor to CME Company; NCCN: Other: Educational speaker; ASH: Other: Educational speaker. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding. Smith: Astellas Pharma: Research Funding; Plexxikon Inc.: Research Funding. Jurcic: Astellas Pharma, Inc: Research Funding; Incyte: Consultancy; Genentech: Research Funding; Celgene: Research Funding; Daiichi-Sankyo: Research Funding; Syros Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy. Ritchie: Astellas Pharma: Other: Research funding to my institution; Celgene: Consultancy, Other: Travel, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau; NS Pharma: Other: Research funding to my institution. Strickland: Daiichi Sankyo: Consultancy; Sunesis Pharamaceuticals: Consultancy, Research Funding; Tolero Pharmaceuticals: Consultancy; CTI BioPharma: Consultancy; Alexion Pharmaceuticals: Consultancy; Boehringer Ingelheim: Consultancy; Astellas Pharma: Honoraria; Baxalta: Consultancy. Hill: Ligacept, LLC: Equity Ownership; Astellas Global Pharma Development: Employment; Patent: Patents & Royalties: US7862995B2 - Issued; Patent: Patents & Royalties: WO2013163419A1 - pending. Liu: Abbvie: Equity Ownership; Astellas Pharma Global Development: Employment. Bahceci: Astellas Pharma Global Development: Employment.

*signifies non-member of ASH