-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1458 Impact of Minimal Residual Disease and Achievement of Complete Remission/Complete Remission with Partial Hematologic Recovery (CR/CRh) on Overall Survival Following Treatment with Gilteritinib in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) with FLT3 MutationsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Adult, AML, Diseases, Non-Biological, Therapies, Study Population, Clinically relevant, Myeloid Malignancies, pharmacology
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Mark J. Levis, MD1, Alexander E. Perl, MD2, Jessica K. Altman, MD3, Jorge E. Cortes, MD4, Catherine C. Smith, MD5, Maria R. Baer, MD6, David F. Claxton, MD7, Joseph G. Jurcic, MD8, Ellen K. Ritchie, MD9, Stephen A. Strickland, MD10, Raoul Tibes, MD, PhD11*, Jason E. Hill12*, Matt Rosales12* and Erkut Bahceci, MD12

1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
4Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5University of California, San Francisco, San Francisco, CA
6University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
7Penn State Milton S. Hershey Medical Center, Hershey, PA
8Columbia University Medical Center, New York, NY
9Weill Cornell Medical College, New York, NY
10Vanderbilt-Ingram Cancer Center, Nashville, TN
11Laura & Isaac Perlmutter Cancer Center, NYU Langone Health and NYU School of Medicine, New York, NY
12Astellas Pharma Global Development, Northbrook, IL

Background: Gilteritinib, a highly selective fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor, demonstrated strong antileukemic activity at doses ≥80 mg/day in patients with R/R AML with FLT3 mutations (FLT3mut+) enrolled in the CHRYSALIS phase 1/2 study (NCT02014558). We analyzed the impact of minimal residual disease (MRD) and achievement of complete remission/complete remission with partial hematologic recovery (CR/CRh) on overall survival (OS) in patients with FLT3mut+ R/R AML 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 across all gilteritinib doses who had bone marrow samples available at baseline and at ≥1 post-baseline time point. The ITD variant allele frequency (VAF) was the FLT3-ITD to total FLT3 ratio. An ITD VAF ≤10−4 defined MRD-negative status. For FLT3 VAF, 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 sequenced on an Illumina® MiSeq platform. Treatment response was evaluated according to the CR/CRh rate. Complete remission was assessed according to the 2003 modified International Working Group criteria and CRh was defined as absolute neutrophil count >0.5 × 109/L and platelet count >50 × 109/L. The rate of CR/CRh has been used as an approval endpoint for R/R AML.

Results: The demographic and baseline characteristics of patients who were assessed for MRD and CR/CRh were representative of the entire CHRYSALIS R/R AML population. A total of 108 FLT3-ITDmut+ patients were analyzed for MRD; 95 of these patients had received ≥80 mg/day gilteritinib, which was shown to induce maximum FLT3 inhibition and antileukemic response. Eighty-two of the 95 patients were MRD-positive and 13 achieved MRD-negative status at any post-baseline time point. Of these 95 patients, 49 had a best overall response of composite complete remission (CRc; ie, CR plus CR with incomplete hematologic plus CR with incomplete platelet recovery) and 11 were MRD-negative. None of the patients who received <80 mg/day gilteritinib achieved MRD-negative status. Of the 46 patients who did not achieve CRc, two were MRD-negative. As seen in Figure 1, patients who had achieved CRc and were MRD-negative (n=11) had longer median OS (168.7 weeks; 95% CI: 41.7, not reached) than those who had achieved CRc and were MRD-positive (n=38; 36.1 weeks; 95% CI: 27.1, 51.7; P=.004). Excluding patients with an OS duration less than the median time to reach MRD-negative status, MRD-negative patients (n=12) had a median OS of 131.4 weeks (95% CI: 35.1, not reached) compared with MRD-positive patients (n=38) who had a median OS of 47.3 weeks (95% CI: 42.7, 61.1). Of the 95 patients who received ≥80 mg/day gilteritinib in the MRD analysis, 24 had a best overall response of CR/CRh. Of the 24 patients with CR/CRh, 10 (41.67%) were MRD-negative. Of the 71 patients without CR/CRh, three (4.2%) were MRD-negative.

Patients who received 120 mg/day gilteritinib were previously shown to have longer survival than patients in other dose cohorts. Of the 56 patients who received 120 mg/day gilteritinib, 13 achieved a best overall response of CR/CRh. As shown in Figure 2, patients who achieved CR/CRh had a median OS of 70.6 weeks (95% CI: 27.1, not reached) and a 52-week survival probability of 66.7% (95% CI: 33.7, 86.0) compared with patients who did not achieve CR/CRh who had a median OS of 32.4 weeks (95% CI: 16.0, 40.9) and a 52-week survival probability of 20.2% (95% CI: 9.5, 33.6).

Conclusions: Single-agent therapy with gilteritinib induced deep molecular responses, including MRD negativity, in heavily pretreated patients with FLT3-ITDmut+ R/R AML. Our results suggest a potential association between MRD-negative status and longer survival in patients with FLT3-ITDmut+ R/R AML. Additionally, patients who achieved CR/CRh appear to have both a higher rate of MRD negativity and longer OS than patients who did not achieve CR/CRh.

Disclosures: Levis: Astellas: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Consultancy; FujiFilm: Research Funding. Perl: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Astellas: Consultancy; NewLink Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Takeda Oncology: Honoraria; Asana Biosciences: Honoraria; Seattle Genetics: Honoraria. Altman: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Other; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Pfizer: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Epizyme: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Celator: Other: payment to the institution to conduct clinical trial work. Cortes: Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Smith: Astellas Pharma: Research Funding. Jurcic: Daiichi-Sankyo: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Forma Therapeutics: Research Funding; Astellas: Research Funding; Genetech: Research Funding; Incyte: Consultancy; Syros Pharmaceuticals: Research Funding; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Kura Oncology: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Ritchie: Incyte: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Research Funding; NS Pharma: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Strickland: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharma: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding. Hill: Ligacept, LLC: Other: Shareholder. Rosales: Astellas Pharma: Employment. Bahceci: Astellas Pharma: Employment.

<< Previous Abstract | Next Abstract
*signifies non-member of ASH