Introduction Ivosidenib (IVO) is approved as monotherapy and in combination with azacitidine for frontline treatment of patients (pts) with mIDH1 acute myeloid leukemia (AML) unfit for intensive chemotherapy (chemo). In this ph 1 study IVO was combined with intensive induction and consolidation chemo in fit pts with ND mIDH1 AML (NCT02632708). The regimen was as well tolerated as induction/consolidation chemo alone. There were no new safety signals compared with IVO monotherapy (Stein, Blood 2021). The rate of complete remission (CR)+CR with partial hematologic recovery (CRh) was 77%. We present long-term follow-up response/safety data.

Methods This multicenter, open label ph 1 study was previously described (Stein, Blood2021). Pts with ND mIDH1 AML received induction therapy: cytarabine 200 mg/m2/d × 7 d and either daunorubicin 60 mg/m2/d or idarubicin 12 mg/m2/d × 3 d (up to 2 cycles of induction were permitted) and IVO 500 mg once daily starting on d 1 of induction therapy. Pts with at least partial remission at end of induction could receive ≤4 cycles of consolidation chemo while continuing IVO 500 mg daily. Those completing, or ineligible for, consolidation could receive maintenance with IVO 500 mg daily until relapse, unacceptable toxicity or allogeneic hematopoietic stem cell transplantation (HSCT). Pts could proceed to HSCT at any point.

Results From Jan 2016–Jul 2018, 60 pts received IVO. Median age was 62.5 yr (range 24–76); 30 (50%) were female. Of 60 pts who received induction therapy, 9 (15%) received 2 induction cycles, 35 (58%) proceeded to consolidation, and 19 (32%) received IVO maintenance. At the data cutoff date of 16 Jan 2025, 3/19 pts who received IVO maintenance were still in maintenance and 16 had discontinued treatment due to: HSCT (n=2), adverse event (n=1), progressive disease (n=4), pt/physician decision (n=6), and other reasons (n=3). A total of 29 (48%) underwent HSCT in CR1: 13 (22%) after induction, 14 (40%) after consolidation, and 2 (11%) during maintenance. Ten pts are still in survival follow-up. Overall, CR was 70% (42/60; 95% CI: 57, 81); CR+CRh was 77% (46/60; 95% CI: 64, 87). Median time to CR was 34 d (range 23–246); 34 d to CR+CRh (range 22–246). Median duration of CR was 24.9 mo (95% CI: 16.0, 41.6) and of CR+CRh was 25.1 mo (95% CI: 8.3, 41.6). After the 1st induction cycle, absolute neutrophil count (ANC) recovery rate (ANC >500/µL) was 95.1% (39/41 pts eligible for analysis) and platelet count recovery rate (>50,000/µL) was 97.6% (40/41); median duration to recovery was 28 days for both. After the first consolidation cycle, ANC recovery rate was 90% (9/10 eligible pts for analysis) and platelet count recovery rate was 80% (8/10); median duration to recovery was 32 days and 26 days, respectively. Durable responses were noted across all comutations, including TP53. Median overall survival (OS) was not reached (NR; 95% CI: 39.4 mo, NR); OS rate at 3/5 yr was 67/61%. For 4 TP53 mutation positive pts, OS ranged from 18 to 66 mo; 1 pt had OS of 0.8 mo. Treatment-emergent adverse events (TEAEs) during induction and consolidation were consistent with previously reported TEAEs (Stein, Blood 2021). Incidence of G≥3 thrombocytopenia, leukopenia, and neutropenia after IVO-based induction was 62% (37/60), 33% (20/60), and 18% (11/60), respectively; after IVO-based consolidation, incidence was 43% (15/35), 26% (9/35), and 17% (6/35). G≥3 QT prolongation was reported in 7 (12%) pts during induction, 1 (33%) during consolidation, and 0 pts during maintenance. Median duration of IVO treatment in maintenance was 589 d (range 12–2871). During maintenance, at least 1 TEAE was reported in 17/19 (90%) pts, and G≥3 TEAEs were reported in 6 pts (32%), including acute renal failure and neutropenia in 1 pt each (5%). TEAEs leading to treatment interruption during maintenance were reported in 6 pts (32%), and discontinuation in 1 pt (5%); no TEAE-related deaths were reported.

Conclusions Addition of IVO to intensive induction and consolidation chemo followed by single-agent IVO maintenance produces long-term responses with an acceptable safety profile and can serve as bridge to HSCT if needed. IVO maintenance has an acceptable safety profile, is associated with stable normalization of blood counts, and results in durable responses and long-term survival across comutational profiles. The benefit of this frontline regimen is being assessed in a phase 3 randomized, blinded trial (NCT03839771).

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2025
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