Type: Oral
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Commercially Available Therapy, excluding Transplantation I
Hematology Disease Topics & Pathways:
therapy sequence, Therapies, Combinations, Clinically relevant
Methods: We reviewed pts with newly diagnosed (ND) and relapsed/refractory (R/R) IDH1/IDH2 mutated AML treated with HMA+VEN at our institution between 2014 and present. A subset of these pts received IDH inhibitor (IDHi)-based regimens at alternate timepoints; these data were used for within-patient comparisons. Responses were defined by 2017 ELN criteria with the additional incorporation of measurable residual disease (MRD) assessment by flow cytometry (MRD-FC, sensitivity 10-3-10-4). Mutant IDH (mIDH) variant allele frequency (VAF) from amplicon-based next-generation sequencing (NGS) of bone marrow samples performed pre-treatment, at best response, and other available timepoints were analyzed for MRD by NGS (MRD-NGS, limit of detection 1-2%). OS was defined as the time from start of HMA + VEN to death or last follow up.
Results: Sixty-five pts (36 ND, 29 R/R; 45 mIDH2, 19 mIDH1, 1 both isotypes) received HMA+VEN; pre-treatment characteristics are shown in Figures A and B. Median age was 69 years; 45% percent had ELN adverse risk disease. Most frequent co-mutations (Figure C) were SRSF2 (42%), DNMT3A (38%), and NPM1 (28%). After a median of 1 cycle (range 1-5), ORR for HMA+VEN received as any line of therapy was 79% (CR 42%, CRi 26%, MLFS 11%, PR 0%). Ninety percent (36/40) of CR+CRi responses with evaluable MRD-FC were MRD negative. CR+CRi rates were 86% in ND pts and 100% in ND pts with mutated NPM1. Presence of a RAS-pathway and/or TP53 mutation was associated with a trend to lower likelihood of CR/CRi in R/R disease (35.7% vs. 53.3%, p=0.46). Fifty-two percent (23/44) of pts with available longitudinal mIDH VAF data were negative by MRD-NGS at time of best response (16 pts) or subsequently, the latter after a median of 4 (range 2-6) additional cycles of therapy. The median change in mIDH VAF from pre-treatment to time of best response or subsequent MRD-NGS negativity was -19%, corresponding to a median within-pt VAF reduction of 98%. MRD negativity by FC and mIDH NGS corresponded to quality of marrow response (Figure C). Median DOR was 17.0 months for all pts and 24.1 months when HMA+VEN was given frontline. Median OS was 42.2 months and is stratified by 2017 ELN risk in Figure D. Of the 65 pts treated with HMA+VEN, 34 pts received 37 different IDHi-containing regimens as separate lines of therapy. Most (35/37) IDHi regimens (monotherapy 32%, IDHi+HMA 32%, IDHi+HMA+VEN 27%, IDHi+ICT 8%) were given after progression/relapse on antecedent therapy. After a median of 4 cycles (range 1-23), ORR was 54% (CR 24%, CRi 19%, MLFS 8%, PR 3%); the highest CR+CRi rate (67%) was seen with the IDHi + HMA + VEN combination. The median change in mIDH VAF from pre-treatment to best response was -1%, corresponding to a median within-pt VAF reduction of 31%. Comparing within-patients, subsequent treatment with an IDHi-containing regimen after HMA+VEN led to a salvage response rate of 52%; 10/13 responses were CR/CRi, and 8/13 responses bridged the pt to SCT. In pts who instead received HMA+VEN after lack/loss of response to an IDHi regimen, the salvage response rate was higher at 72%; 6/8 responses were CR/CRi, 5/8 responses bridged the pt to SCT.
Conclusions: While not targeted therapy per se, we confirm that the combination of HMA+VEN leads to an impressive CR/CRi rate with longstanding DOR in IDH1/IDH2 mutated AML, particularly in the frontline setting and in NPM1 co-mutated disease. Although accompanying MRD negativity by flow cytometry is frequent, almost half of pts retain an IDH mutation detectable by NGS, suggesting a role for combination therapy with IDH inhibitors. Additionally, we identify excellent outcomes in the relapsed setting, although the presence of a RAS-pathway or TP53 mutation may confer treatment resistance. The high within-patient salvage response rates when switching between HMA+VEN and IDHi-containing regimens warrant further investigation of combination vs. sequential therapy approaches.
Disclosures: Konopleva: Cellectis: Research Funding; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Calithera: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; Agios: Research Funding; Kisoji: Consultancy; Forty-Seven: Consultancy, Research Funding. Kadia: BMS: Honoraria, Research Funding; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding. Daver: Bristol-Myers Squibb: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: 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; 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; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Issa: Celegene: Research Funding; Syndax: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Alvarado: Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; BerGenBio ASA: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Research Funding. Garcia-Manero: Celgene: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Novartis: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding. Borthakur: Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Research Funding; Incyte: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Novartis: Research Funding; PTC Therapeutics: Research Funding; GSK: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; BioTherix: Consultancy; Jannsen: Research Funding; FTC Therapeutics: Consultancy; Abbvie: Research Funding; BioLine Rx: Consultancy. Ravandi: Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding. Kantarjian: Delta Fly: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Adaptive biotechnologies: Honoraria. DiNardo: MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; Calithera: Research Funding; ImmuneOnc: Honoraria, Research Funding; Novartis: Consultancy.
OffLabel Disclosure: Combination therapy with IDH inhibitors for IDH-mutated AML.