Concurrent FLT3 Inhibitor and IDH Inhibitor Therapy in Patients with Acute Myeloid Leukemia (AML)
Authors: Fathi Amir T. , Perl Alexander E. , Levis Mark , Smith Catherine C. , Brunner Andrew M. , Takahashi Koichi , Amrein Philip C. , Hock Hanno R. , Hobbs Gabriela S. , Narayan Rupa , Moran Jenna A. , Bergeron Meghan , Foster Julia E. , Daver Naval , DiNardo Courtney D. 
Published: November 2020

Characterization of pathogenic alterations in acute myeloid leukemia (AML) has led to development of promising targeted therapies, including FLT3 (FLT3i) and IDH1/2 inhibitors (IDHi), with several approved for use; midostaurin (MIDO), gilteritinib, enasidenib (ENA), and ivosidenib (IVO). A proportion of patients (pts) have concurrentFLT3andIDHmutations at diagnosis or develop a second mutation during therapy.FLT3mutations, in particular, are associated with poor response rates to IDHi therapy, and treatment-emergentFLT3mutations also appear to confer therapeutic resistance to these agents. There is therefore growing interest to study combined therapies that target multiple pathways, but the clinical experience with combined IDHi and FLT3i therapy has not yet been reported.
We performed a retrospective data collection and analysis at 5 institutions (Massachusetts General Hospital, University of Pennsylvania, Johns Hopkins University, University of California San Francisco, and MD Anderson). Using de-identified information from institutional databases, pts treated with concurrent IDHi and FLT3i were identified. Collected data included demographic data, date of initial diagnosis, number of prior therapies, prior hematopoietic cell transplant (HCT), prior targeted therapy, type ofIDHandFLT3mutation, concurrent mutations and cytogenetics, duration of concurrent therapy, therapy-related toxicity, best response, toxicities, and vital status.
We identified 12 pts who received concurrent IDHi and FLT3i therapy, 11 of which had relapsed/refractory (R/R) AML. Median age was 57 (range 31-84) and 9 (75%) were male. 7 (58%) were Caucasian, 3 (25%) African American, and 2 (17%) Asian. All pts had intermediate-risk cytogenetics.IDH1R132 mutations were detected in 3 (25%), andIDH2R140 mutations in 9 (75%) pts. OneIDH2mutation arose at relapse. All pts hadFLT3-ITDmutations, and for 3 (38%), this mutation was known to have emerged at relapse. Common concurrent mutations includedDNMT3A(75%) andNPM1(58%). Median number of prior lines of therapy was 2 (range 0-6), and 4 pts (33%) had underwent prior HCT. Six pts (50%) had received FLT3i monotherapy in a prior line of treatment; 4 sorafenib, 1 gilteritinib, 1 MIDO, and 1 with FF-10101 (one pt had 2 prior lines of FLT3i). Six pts were initiated on concurrent therapy in simultaneous fashion, and the remainder were sequential; 2 pts (17%) were on IDHi therapy to which the FLT3i was added, and 4 (33%) had been on FLT3i with subsequent IDHi addition. Four pts (33%) received concurrent gilteritinib and ENA, 3 (25%) received gilteritinib and IVO, 3 (25%) received sorafenib and ENA, and 2 (17%) MIDO and ENA. Three pts received hypomethylating therapy concurrent with combined FLT3i/IDHi therapy; 2 received azacitidine (AZA) with ENA/MIDO, and 1 received AZA with ENA/gilteritinib. Pts were on concurrent therapy for a median of 75 days (range 9-343). Two pts had rash attributable to sorafenib, leading to temporary treatment pause in one and discontinuation in the other. No other toxicities were thought to be related to concurrent treatment. Four pts (33%) achieved CR or CRi (2 CR, 2 CRi), all with persistence of molecular residual disease (MRD). The median duration of remission for these pts was 310 days (range 85-326), and 3 have since relapsed. One pt experienced MLFS, 1 had peripheral blast reduction and 1 had improvement in platelets. An additional pt had MRD(+) CR (byNPM1PCR) on gilteritinib prior to addition of ENA, and then achieved MRD(-) CR with dual therapy. The 4 remaining pts did not respond to concurrent treatment. Two pts (17%) were effectively bridged to HCT following dual therapy. Five pts (42%) remain alive.
In this retrospective analysis, a notable proportion of pts benefitted from concurrent FLT3i and IDHi therapy. Composite remission rate was 33%, and overall response rate (CR+CRi+MLFS) was 42% among a largely R/R patient cohort, the majority of whom had received IDHi or FLT3i monotherapy in a prior line of treatment. An additional pt in MRD(+) CR cleared MRD following concurrent treatment. Concurrent therapy appeared to be largely well-tolerated. These response rates are particularly intriguing, given the presence ofFLT3/ITDmutations, alterations thought to confer resistance to IDHi monotherapy. Larger, prospective studies are needed to fully assess the promise of concurrent FLT3i and IDHi therapy in co-mutated pts with AML.

Disclosures
Fathi: Amphivena:Consultancy;Astellas:Consultancy;Trillium:Consultancy;Amgen:Consultancy;Seattle Genetics:Consultancy, Research Funding;Abbvie:Consultancy;Pfizer:Consultancy;Newlink Genetics:Consultancy;Forty Seven:Consultancy;Trovagene:Consultancy;Kite:Consultancy;BMS/Celgene:Consultancy, Research Funding;Novartis:Consultancy;Daiichi Sankyo:Consultancy;Kura Oncology:Consultancy;Blueprint:Consultancy;PTC Therapeutics:Consultancy;Agios:Consultancy, Research Funding;Takeda:Consultancy, Research Funding;Jazz:Consultancy;Boston Biomedical:Consultancy.Perl:Arog Pharmaceuticals Inc:Other: uncompensated consulting, travel costs for meetings;Astellas:Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding;AbbVie Inc:Consultancy, Honoraria, Other, Research Funding;Syndax:Consultancy, Honoraria;Takeda:Honoraria, Other: Travel costs for meeting;Leukemia & Lymphoma Society, Beat AML:Consultancy;Novartis:Honoraria, Other, Research Funding;Actinium Pharmaceuticals Inc:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding;FUJIFILM Pharmaceuticals USA, Inc:Research Funding;New Link Genetics:Honoraria, Other;Bayer HealthCare Pharmaceuticals:Research Funding;Biomed Valley Discoveries:Research Funding;Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company:Consultancy, Honoraria, Other;Jazz:Honoraria, Other;Agios:Consultancy, Honoraria, Other;FORMA Therapeutics:Consultancy, Honoraria, Other.Levis:Menarini:Honoraria;Amgen:Honoraria;FujiFilm:Honoraria, Research Funding;Daiichi-Sankyo:Honoraria;Astellas:Honoraria, Research Funding.Smith:Daiichi Sanyko:Consultancy, Honoraria;Abbvie:Other: Research Support, Research Funding;FujiFilm:Other: Research support, Research Funding;Astellas Pharma:Honoraria, Other: Research Support, Research Funding;Revolution Medicines:Other: Research Support, Research Funding;Sanofi:Honoraria.Brunner:Forty-Seven Inc:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Research Funding;Takeda:Research Funding;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis:Research Funding;Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Amrein:Amgen:Research Funding;AstraZeneca:Consultancy, Research Funding;Takeda:Research Funding.Hobbs:Merck:Research Funding;Constellation:Honoraria, Research Funding;Incyte:Research Funding;Bayer:Research Funding;Celgene/BMS:Honoraria;Novartis:Honoraria;Jazz:Honoraria.Narayan:Sanofi-Genzyme:Other: Current Spouse employment ;Takeda:Other: Prior Spouse employment within 24 months;Genentech:Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months.Daver:Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Karyopharm:Research Funding;Servier:Research Funding;Daiichi Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech:Research Funding;AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Astellas:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novimmune:Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Trovagene:Research Funding;Fate Therapeutics:Research Funding;ImmunoGen:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Jazz:Consultancy, Membership on an entity's Board of Directors or advisory committees;Trillium:Consultancy, Membership on an entity's Board of Directors or advisory committees;Syndax:Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen:Consultancy, Membership on an entity's Board of Directors or advisory committees;KITE:Consultancy, Membership on an entity's Board of Directors or advisory committees;Agios:Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.DiNardo:Calithera:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Agios:Consultancy, Honoraria, Research Funding;Syros:Honoraria;Daiichi Sankyo:Consultancy, Honoraria, Research Funding;Notable Labs:Membership on an entity's Board of Directors or advisory committees;Jazz:Honoraria;ImmuneOnc:Honoraria;Takeda:Honoraria;MedImmune:Honoraria;Novartis:Consultancy;AbbVie:Consultancy, Honoraria, Research Funding.

OffLabel Disclosure:
Midostaurin for relapsed/refractory AML Sorafenib for relapsed/refractory AML