Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations

Abstract

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML).

Patients and methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle).

Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group.

Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719.

Figure 1.

Study design and molecular classification. *Two patients had both IDH1/2 mutations. **One patient had both IDH1/2 mutations. Ven, venetoclax; Aza, azacitidine.

Figure 2.

A, Remission rates in patients with IDH1/2 mutations and IDH1/2 wild-type by treatment groups. B, Remission rates in patients with IDH1 mutations in the venetoclax and azacitidine group. C, Remission rates in patients with IDH2 mutations in the venetoclax and azacitidine group.

Figure 3.

Kaplan–Meier curves for OS (A) patients with IDH1/2 mutation treated with venetoclax (Ven) and azacitidine (Aza) versus azacitidine groups, patients with IDH1 mutation by treatment groups (B); patients with IDH2 mutated by treatment groups (C); and patients with IDH1/2 wild-type by treatment groups (D).

Figure 4.

Kaplan–Meier curves for overall survival (A) patients with IDH1/2 mutated and IDH1/2 wild-type and treated with venetoclax and azacitidine; patients with IDH1/2 mutation treated with venetoclax and azacitidine and stratified by NCCN risk categories for AML (B); patients with IDH1/2 wild-type treated with venetoclax and azacitidine and stratified by NCCN cytogenetic risk categories (B); Venn diagrams showing co-mutations of NPM1, FLT3, and TP3 with IDH1/2 in patients treated with venetoclax and azacitidine (C); patients with IDH1/2 and NPM1-mutant or wild-type in the venetoclax and azacitidine group (D); patients with IDH1/2- and FLT3-mutant or wild-type in the venetoclax and azacitidine group (E).