All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit Know AML.
The AML Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the AML Hub cannot guarantee the accuracy of translated content. The AML Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
Isocitrate dehydrogenase-1 (IDH1) mutations are present in 6–10% of cases of acute myeloid leukemia (AML) and are associated with oncogenesis. Recent research has investigated the role of the potent oral IDH1 inhibitor ivosidenib (Ivo), particularly in patients who are ineligible for intensive chemotherapy. Below we summarize three poster presentations from the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, which covered safety data on Ivo + venetoclax (Ven) with or without azacitidine (Aza) in IDH1-mutated hematologic malignancies, as well as further analysis of the phase III AGILE trial, supporting the U.S. Food and Drug Administration (FDA) approval of Ivo + Aza.
Curtis Andrew Lachowiez et al.1 investigated a combination of Ivo + Ven in 31 patients across four dosing levels (Figure 1).
Figure 1. Study design*
AML, acute myeloid leukemia; Aza, azacitidine; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance score; EFS, event-free survival; GvHD, graft-versus-host disease; Ivo, ivosidenib; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; MTD, median tolerated dose; ND, newly diagnosed; ORR, overall response rate; OS, overall survival; PK, pharmacokinetic; RP2D, recommended phase II dose; R/R, relapsed/refractory; Ven, venetoclax.
*Adapted from Lachowiez et al.1
†ORR includes complete response (CR) + complete response with incomplete count recovery (CRi) + complete response with incomplete hematologic recovery (CRh) + partial response (PR) + morphological leukemia-free state (MLFS).
Patient characteristics are summarized in Table 1. Almost half of all patients (48%) received prior treatment. Two-thirds of the cohort had AML, and over half of patients had adverse cytogenetics using the European LeukemiaNet (ELN) 2017 criteria.
Table 1. Patient characteristics*
Characteristic |
N = 31 |
---|---|
Median age, years (range) |
67 (44–84) |
Male, % |
65 |
Median baseline BM blasts, % (range) |
23 (1–80) |
ECOG PS, % |
|
0 |
27 |
1 |
60 |
2 |
13 |
Disease type, % |
|
MDS/MPN |
29 |
ND-AML |
45 |
R/R AML |
26 |
2017 ELN risk group |
|
Favorable |
26 |
Intermediate |
19 |
Adverse |
55 |
Received prior treatment, % |
48 |
AML, acute myeloid leukemia; BM, bone marrow; ECOG PS, Eastern Cooperative Oncology Group performance score; ELN, European LeukemiaNet; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; ND, newly diagnosed; R/R, relapsed/refractory. |
In summary, Ivo + Ven with and without azacitidine resulted in deep responses across several hematologic malignancies, with an expected and tolerable safety profile. Responses appeared to deepen over time, with the majority of patients who received ≥5 treatment cycles achieving IDH1-mutated clone clearance.
Botton et al.2 presented findings from the AGILE study (NCT03173248), in which 500 mg Ivo + 75 mg/m2 Aza was compared with placebo + Aza in patients with newly diagnosed IDH1-mutated AML who were ineligible for intensive chemotherapy. We previously summarized key efficacy and safety findings from this trial in a visual abstract. Botton et al.2 presented the molecular analysis of bone marrow and peripheral blood mononuclear cells, as of the March 18, 2021 data cutoff, as well as the IDH1 mutation clearance analysis using BEAMing digital PCR, and a co-mutation analysis using next-generation sequencing (NGS).
Figure 2. CR + CRh based on baseline mutation status*
Aza, azacitidine; CR, complete remission; CRh, complete remission with incomplete hematologic recovery; Ivo, ivosidenib; Pbo, placebo.
*Adapted from Botton et al.2
In summary, molecular analysis of data from the AGILE trial demonstrated improved IDH1 mutation clearance and deeper responses with Ivo + Aza versus Aza + placebo. Mutations in the DNMT3A, RUNX1, SRSF2, and RTK pathways were associated with improved CR/CRh; further investigations are necessary to determine if the combination Ivo + Aza overcomes the resistance to Ivo alone previously noted with the RTK pathway.
Hartmut Döhner presented further results from the AGILE trial, where rates of blood count recovery and transfusion independence were assessed in patients receiving Ivo + Aza versus Aza + placebo.
In summary, these results demonstrated faster recovery of blood counts with Ivo + Aza vs Aza + placebo, and improved rates of transfusion independence.
These novel data confirm the potential of Ivo in IDH1-mutated AML, in doublet combination with Aza, and as a triplet with Ven.1 Further analysis of the AGILE trial revealed benefits on blood count recoveries and transfusion independence,3 and molecular evaluation found specific mutations which may particularly benefit from these therapies.2
Subscribe to get the best content related to AML delivered to your inbox