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

Daniel A Pollyea, Courtney D DiNardo, Martha L Arellano, Arnaud Pigneux, Walter Fiedler, Marina Konopleva, David A Rizzieri, B Douglas Smith, Atsushi Shinagawa, Roberto M Lemoli, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L Miller, Hagop M Kantarjian, Daniel A Pollyea, Courtney D DiNardo, Martha L Arellano, Arnaud Pigneux, Walter Fiedler, Marina Konopleva, David A Rizzieri, B Douglas Smith, Atsushi Shinagawa, Roberto M Lemoli, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L Miller, Hagop M Kantarjian

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.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
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.
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.
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.
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).

References

    1. Marando L, Huntly BJP. Molecular landscape of acute myeloid leukemia: prognostic and therapeutic implications. Curr Oncol Rep 2020;22:61.
    1. Papaemmanuil E, Dohner H, Campbell PJ. Genomic classification in acute myeloid leukemia. N Engl J Med 2016;375:900–1.
    1. Lagunas-Rangel FA, Chávez-Valencia V, Gómez-Guijosa MÁ, Cortes-Penagos C. Acute myeloid leukemia-genetic alterations and their clinical prognosis. Int J Hematol Oncol Stem Cell Res 2017;11:328–39.
    1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med 2015;373:1136–52.
    1. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. . The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010;17:225–34.
    1. DiNardo CD, Ravandi F, Agresta S, Konopleva M, Takahashi K, Kadia T, et al. . Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol 2015;90:732–6.
    1. Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. . Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 2015;21:178–84.
    1. Montalban-Bravo G, DiNardo CD. The role of IDH mutations in acute myeloid leukemia. Future Oncol 2018;14:979–93.
    1. Marcucci G, Maharry K, Wu Y-Z, Radmacher MD, Mrózek K, Margeson D, et al. . IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010;28:2348–55.
    1. Thol F, Damm F, Wagner K, Göhring G, Schlegelberger B, Hoelzer D, et al. . Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 2010;116:614–6.
    1. Duchmann M, Micol J-B, Duployez N, Raffoux E, Thomas X, Marolleau J-P, et al. . Prognostic significance of concurrent gene mutations in intensively treated patients with IDH-mutated AML: an ALFA study. Blood 2021;137:2827–37.
    1. Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. . Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 2020;135:463–71.
    1. DiNardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, et al. . Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol 2021;39:57–65.
    1. Dinardo CD, Stein AS, Stein EM, Fathi AT, Schuh AC, Fernández PM, et al. . Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML). J Clin Oncol 2018;36:7042.
    1. Pollyea DA, Tallman MS, de Botton S, Kantarjian HM, Collins R, Stein AS, et al. . Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia 2019;33:2575–84.
    1. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. . Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019;133:7–17.
    1. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. . Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020;383:617–29.
    1. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. . Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003;21:4642–9.
    1. US Department of Health and Human Services. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Available from: .
    1. National Comprehensive Cancer Network. NCCN Guidelines for patients with Acute Myeloid Leukemia, Version 3.2021; 2021.
    1. DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S, et al. . Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol 2021;22:1597–608.
    1. Lachowiez CA, Borthakur G, Loghavi S, Zeng Z, Kadia TM, Masarova L, et al. . A phase Ib/II study of ivosidenib with venetoclax ± azacitidine in IDH1-mutated myeloid malignancies. J Clin Oncol 2021;39:7012-.
    1. DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, et al. . Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood 2020;135:791–803.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner