Determinants of Outcomes of FLT3mut Acute Myeloid Leukemia with First Salvage Therapy
Authors: Maiti Abhishek , Kantarjian Hagop M. , Garcia-Manero Guillermo , Konopleva Marina Y , Verstovsek Srdan , Andreeff Michael , Borthakur Gautam M. , Kadia Tapan M. , Daver Naval G. , Pemmaraju Naveen , DiNardo Courtney D. , Pierce Sherry A. , Xiao Lian-Chun , Huang Xuelin , Wierda William G. , Kornblau Steven M. , Ravandi Farhad , Cortes Jorge E. 
Published: November 2019

Background: Patients (pt) with relapsed or refractory acute myeloid leukemia (R/R AML) with FLT3mut have poor prognosis. FLT3 inhibitors (FLT3i) as single agent, and in combination improve outcomes in FLT3mut AML. However, recent clinical trials of FLT3i have had different inclusion criteria, and determinants of outcomes with FLT3i are not well known.
Methods: We conducted a retrospective study to determine factors affecting outcomes in FLT3mut R/R AML with first salvage therapy. We reviewed medical records of R/R FLT3mut AML pts for data regarding prior therapy, salvage regimen and outcomes. Univariate analysis and multivariate Cox analysis were performed to evaluate the association of baseline covariates and outcomes. Evaluated baseline factors included ECOG PS, ELN cytogenetic risk group, FLT-ITD ratio, FLT3-D835 mutation, frontline therapy factors including intensive chemotherapy (IC), hypomethylating agent (HMA), or non-intensive chemotherapy (NIC)-based regimen, anthracycline use, FLT3i use, stem-cell transplantation (SCT), response to frontline therapy, salvage regimen related factors including IC vs. HMA vs NIC-based regimen, FLT3i use, SCT, AML mutations, etc. Efficacy endpoints of interest included CR/CRi per modified IWG criteria for AML, overall survival (OS) and duration of response (DOR).
Results: Between June 2002 and July 2019 we identified 202 pts with R/R FLT3mut AML who received first salvage therapy at our institution with or without an FDA-approved or investigational FLT3i. The baseline characteristics are shown in Table 1 and treatment characteristics and outcomes are shown in Table 2. The median follow-up duration was 54 months (mo, 95% CI 46-89) and median OS 7.9 mo (95% CI 6.2-9.8). 53 out of 105 responding pts relapsed and median DOR was 3.6 mo (95% CI 2.7-5.8). Multivariate logistic regression analysis showed higher odds of achieving CR/CRi with salvage IC (OR 2.9), and IC+FLT3i (OR 8.1) compared to HMA, and RUNX1mut was associated with lower odds of achieving CR/CRi compared to RUNX1-WT (OR 0.06, Table 3). Single agent FLT3i as salvage therapy did not have significant association with CR/CRi or OS, as compared to HMA. Similarly, multivariate Cox model for analysis of factors associated with OS showed higher risk of death in pts who had received FLT3i in frontline setting (HR = 2.9) and pts with TET2mut (HR = 2.2, Table 4). Different salvage regimens of IC, NIC, HMA with or without FLT3i, and single agent FLT3i did not show survival benefit compared to HMA alone. Pairwise comparison between salvage regimens for OS censored at SCT (Fig. 1a-f) showed HMA improved OS compared to IC (median OS 10.2 vs 6.4 HR 0.64, 95% CI 0.36-0.99, p=0.046). Addition of FLT3i to HMA or IC did not yield significantly different OS compared to single agent FLT3i (Fig. 1 a-d). On univariate analysis, there was no significant difference in DOR between salvage HMA vs other salvage therapies including IC, NIC, single agent FLT3i, and IC with FLT3i. Covariates not associated with CR/CRi or OS on univariate analysis included ECOG PS, ELN cytogenetic risk group, frontline HMA or IC, prior anthracycline, prior SCT, response to prior regimen, FLT3-ITD ratio, FLT3-D835, and other recurrent AML mutations. Hence, these factors were not included in the multivariate models. Limitations of this study included retrospective nature and small sample sizes in subgroups.
Conclusions: This multivariate analysis of a large cohort of R/R FLT3mut AML undergoing first salvage therapy showed association of RUNX1mut with lower odds of achieving CR/CRi, and frontline FLT3i use and TET2mut with worse OS. Both IC, and IC with FLT3i were associated with higher odds of achieving CR/CRi compared to HMAs. However, pairwise comparison of salvage regimens suggested improved OS with HMA compared to IC.

Disclosures
Maiti: Celgene: Other: research funding. Kantarjian:Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Ariad: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding. Garcia-Manero:Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; AbbVie: Research Funding. Konopleva:Ablynx: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Amgen: Consultancy, Honoraria; Astra Zeneca: Research Funding; Agios: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Genentech: Honoraria, Research Funding. Verstovsek:Pharma Essentia: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding. Andreeff:AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Aptose: Equity Ownership; Breast Cancer Research Foundation: Research Funding; NIH/NCI: Research Funding; CPRIT: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Borthakur:Strategia Therapeutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cyclacel: Research Funding; Agensys: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; GSK: Research Funding; Eisai: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; AstraZeneca: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Polaris: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding. Daver:Abbvie: Consultancy, Research Funding; Agios: Consultancy; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; Servier: Research Funding; Servier: Research Funding; Karyopharm: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Agios: Consultancy; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding. DiNardo:medimmune: Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Wierda:Miragen: Research Funding; Cyclcel: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Loxo Oncology Inc.: Research Funding; Oncternal Therapeutics Inc.: Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding. Cortes:Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding.