Background: Prognosis is dismal for older patients (pts) with R/R AML, especially if multiple lines of AML treatment (Tx) have failed. Attaining response is more difficult after each Tx failure, and many pts cannot tolerate high-intensity salvage chemotherapy regimens. IDH2 mutations occur in ~8-19% of pts with AML. ENA is an oral IDH2 inhibitor approved for Tx of adult pts with m IDH2 R/R AML. The phase 3, randomized IDHentify trial compared ENA monotherapy vs. conventional care regimens (CCR)-intermediate-dose cytarabine (IDAC), low-dose cytarabine (LDAC), azacitidine (AZA), or best supportive care (BSC) only-in older pts with late-stage m IDH2 R/R AML who had received multiple prior AML Tx. Reported here are clinical outcomes for pts in IDHentify who were preselected to one of the lower-intensity CCR options (LDAC, AZA, or BSC only) before randomization to ENA or CCR.

Methods: This international, multicenter, open-label trial enrolled pts aged ≥60 yrs with ECOG PS ≤2 and m IDH2 AML R/R to 2-3 prior AML Tx. Before randomization, pts were preselected to AZA 75 mg/m 2/day (d) ×7d, IDAC 0.5-1.5 g/m 2 ×3-6d, LDAC 20 mg BID ×10d, or BSC only. Pts were then randomized 1:1 to receive ENA (100 mg QD) or CCR in repeated 28d Tx cycles; pts randomized to CCR received their preselected Tx. All pts could receive BSC. These post hoc analyses include pts preselected to lower-intensity AZA, LDAC, or BSC only.

Endpoints included overall response rate (ORR: complete remission [CR], CR with incomplete recovery [CRi/CRp], partial response [PR], or morphologic leukemia-free state [MLFS], per IWG 2003 AML response criteria), rates of hematologic improvement (HI) and transfusion independence (TI) (IWG 2006 MDS criteria), overall survival (OS), event-free survival (EFS), and time to Tx failure (TTF). OS was assessed in the intent-to-treat (ITT) population and among efficacy-evaluable (E-E) pts who received ≥1 study drug dose and had ≥1 response evaluation on-Tx.

Results: In all, 267 (84%) of 319 enrolled pts were preselected to a lower-intensity Tx regimen and then randomized 1:1 to receive ENA (n = 139) or their preselected CCR (n = 128: AZA 69, LDAC 37, BSC 22). At data cutoff (17-Mar 2020), 10 ENA pts and 4 CCR pts continued to receive their assigned Tx. Median Tx durations were 143d (range 3-1270) in the ENA arm and 49d (1-1166) in the CCR arm; 15 CCR pts (12%) and 1 ENA pt discontinued before receiving assigned Tx. After discontinuing Tx, 43 ENA pts (31%) and 52 CCR pts (41%) received subsequent AML Tx, including 12 CCR pts (9%) who received commercially available ENA. Baseline (BL) characteristics were generally similar between Tx arms. Median age overall was 72 yrs (range 60-86), 80% of pts had received 2 prior AML Tx, 61% had ELN adverse-risk AML, 41% had primary refractory AML (ie, never attained CR/CRi/CRp), and 63% and 51% of pts were RBC and platelet transfusion-dependent (TD), respectively.

Among all pts preselected to a lower-intensity Tx (ITT), ORR was substantially greater with ENA vs CCR (41% vs 11%, respectively), as were rates of CR (26% vs 3%) and HI (41% vs 13%) (P < 0.001, all comparisons) (Table), and proportionally more pts in the ENA arm achieved or sustained RBC and platelet TI (Table). OS was prolonged with ENA vs CCR (HR 0.74 [95% CI 0.56, 0.97]; P = 0.029), with a late separation of the curves after median OS had been reached (median OS 6.8 vs 6.2 mo, respectively), and 1-yr survival rates were 41% vs 26% (∆15.0% [3.4%, 26.6%]). Among E-E pts (ENA, n = 133; CCR, n = 110), OS was improved with ENA (HR 0.70 [0.53, 0.93]; P = 0.013): median OS was 6.9 mo, vs 5.7 mo with CCR. EFS and TTF in the ITT population were also prolonged with ENA vs CCR (Table).

The safety of ENA in this pt subgroup was similar to that for all ENA-randomized pts and consistent with previous findings (Stein 2019). ENA-related differentiation syndrome occurred in 13% of pts and hyperbilirubinemia in 26% of pts.

Conclusions: In pts with late-stage m IDH2 R/R AML, ENA was associated with clinically meaningful improvements in morphologic response, HI, RBC and platelet TI, and survival compared with conventional lower-intensity Tx options. OS outcomes were potentially confounded by the substantial number of pts randomized to CCR who did not receive Tx or discontinued Tx early, and by extensive use of subsequent Tx (including ENA) during follow-up. These clinical benefits support use of ENA as an appropriate oral outpatient Tx for pts with m IDH2 R/R AML who are not candidates for intensive therapies.

Figure 1
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Disclosures

DiNardo: Forma: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceutical: Consultancy; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Schuh: Kite/Gilead: Research Funding; GlycoMimetics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, 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; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Papayannidis: AbbVie: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Vyas: AbbVie: Consultancy, Honoraria; Novartis: Honoraria; Daiichi Sankyo: Honoraria; Jazz: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Astellas: Consultancy, Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Honoraria. Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. Zeidan: Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BeyondSpring: Consultancy; Pfizer: Other: Travel support, Research Funding; Agios: Consultancy; Jazz: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Ionis: Consultancy; Aprea: Consultancy, Research Funding; Astellas: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Jasper: Consultancy; Astex: Research Funding; Incyte: Consultancy, Research Funding. Bluemmert: Bristol Myers Squibb: Current Employment. Yu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hasan: Bristol Myers Squibb: Current Employment. Martin-Regueira: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. de Botton: Pfizer: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Daiichi: Consultancy; Abbvie: Consultancy; Astellas: Consultancy; Forma: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Celgene: Consultancy.

Author notes

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© 2021 by The American Society of Hematology
2021
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