Background:IDH1 mutations are found in 6-10% of acute myeloid leukemia (AML) cases. Ivosidenib (IVO), an oral mIDH1 inhibitor, is approved for newly diagnosed mIDH1 AML in patients (pts) aged ≥75 years or unfit for intensive chemotherapy as monotherapy (US), based on the results of the AG120-C-001 study (Roboz, Blood, 2020, median overall survival (mOS) 12.6 months) or with azacitidine (AZA) (US and Europe) based on the results of the AGILE study (Montesinos, NEJM, 2022, mOS 29.3 months). However, data available on IVO+/-AZA in real-life are limited.

Method: This retrospective study (IVOOBS, NCT06377579)included pts treated in France between 01/2017 and 02/2024 through a compassionate use program with IVO+/-AZA for mIDH1 AML, front-line or at time of relapse or for a refractory disease. Here we focused only on newly diagnosed pts. The primary objective was OS and secondary objectives included response rate (ELN-2022 criteria) and toxicity.

Results: 49 pts from 17 centers were included; 16 (33%) received IVO alone (IVO-mono cohort) and 33 (67%) the combination (IVO+AZA cohort).

IVO-mono cohort (n=16): The median age was 72 yo (IQR: 60 - 83.25), 62.5% were male. Most of the pts were unfit (PS > 2 in 92%) with high-risk disease (secondary AML n=14, including 8 pts who have already received AZA for prior hematologic disease; adverse (adv)-risk according to ELN-2022 classification n=7, 43%, intermediate (int)-risk n= 9, 57%). The median white blood count (WBC) was 2.67 Giga/L. The majority of pts started IVO at the recommended dose of 500 mg/day (d) (n=13, 81%), while 3 started at 250 mg/d (concomitant prescription of azole). Median duration of IVO treatment was short (3.25 months, IQR: 1.6-7.07) as 77% % (n=10) of IVO discontinuations occurred within 4 months (3 allo-HCT, 3 progressions, 2 differentiation syndrome (DS), 1 QT prolongation (QTp), 1 death). Any grades of DS and QTp were reported in 25% (n=4) and 7% (n=1) of pts, respectively, while grade 3-4 hepatic, infection and hematologic adverse events (AE) occurred in 0, 4 and 3 pts, respectively. Two deaths were linked to IVO (DS). Mortality at D30 and D60 was 6% and 25%, respectively. Composite complete remission (CCR) (CR/CRh/CRi) rate was 37% (31%/6%/0%), with no MLFS and 44% of non-responders (19% of pts not assessed (NA)). For pts receiving IVO at 500mg/d, CCR was 46% (38%/8%/0%). At 250mg/d, 2 pts did not respond and 1 was NA. Four pts (3 in CR, 1 in no response) received an allo-HCT after IVO. Among responders (n=6), 1 pt relapsed at 10.8 months. With a median follow-up (mFU) of 4.5 months, mOS was 4.5 months (95% CI: 2.07-not reached (NR)) and 2y OS 31.25% (95% CI: 15.11-64.64).

IVO+AZA cohort (n=33): The median age was 78 yo (IQR: 75 – 80), 60% were male. The majority of pts were unfit (PS > 2 in 93%) and classified as int-risk (83%) according to ELN-2022 classification (adv-risk 17%). However, according to ELN-2024 classification, most pts had favourable-risk (n=22, 67%) (adv-risk n=2, NA n=9). The median WBC was 2.15 Giga/L. Nine pts (27%) had a secondary AML. The majority of pts started IVO at the dose of 500 mg/d (n=27, 82%), while 6 pts started at 250 mg/d (concomitant prescription of azole (n=5), previous cardiac history (n=1)). Median number of AZA cycles was 6 (range: 1; 28). Median duration of IVO treatment was 13.1 months (IQR: 8.4-18.4) and 26% (n=5) of IVO discontinuations occurred within 4 months (3 progressions, 2 deaths). Mortality at D30 and D60 was 3% and 9%, respectively. DS was reported in 3 pts (9%) and QTp in 2 (7%), any grades, while grade 3-4 hepatic, infection and hematologic AE occurred in 0, 5 and 8 pts, respectively. No death was linked to IVO. CCR was 73% (55%/12%/6%), 3% showed MLFS, 21% were non-responders and 3% NA. CCR was 78% (56%/15%/7%) and 50% (50%/0%/0%) for those receiving IVO at 500 mg/d and 250mg/d, respectively. Among responders (n=24), only 1 pt was consolidated with an allo-HCT and 8 (33%) relapsed at a median of 11.4 months. At relapse, 4 were treated with AZA+BCL2 inhibitor and 1 obtained CR. With a mFU of 16.6 months, mOS was NR (95% CI: 16.62-NR) and 2y OS 52% (95% CI: 35.55-76.56).

Conclusion: This retrospective real-life study shows the reproducibility of the results of the AGILE study (IVO+AZA). Pts receiving IVO mono had poorer outcome compared to those of the AG120-C-001 study, likely because pts were at higher risk. The dose of 500 mg/d should also be preferred questioning the role of azole prophylaxis.

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2025
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