Desikan S.P.a· Ravandi F.a· Pemmaraju N.a· Konopleva M.a· Loghavi S.b· Jabbour E.J.a· Daver N.a· Jain N.a· Chien K.S.a· Maiti A.a· Montalban-Bravo G.a· Kadia T.M.a· Macaron W.a· DeLumpa R.a· Kwari M.a· Borthakur G.a· Short N.J.a

Author affiliations

aDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
bDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Article / Publication Details

First-Page Preview

Received: March 11, 2022
Accepted: May 14, 2022
Published online: June 17, 2022

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 3

ISSN: 0001-5792 (Print)
eISSN: 1421-9662 (Online)

For additional information: https://www.karger.com/AHA

Abstract

Introduction: RAS pathway mutations are common mechanisms of resistance to acute myeloid leukemia (AML) therapies. Trametinib, an oral MEK inhibitor, has been shown to have single-agent activity in relapsed/refractory AML and preclinical synergy with venetoclax. Methods: We conducted a single-center, open-label, phase 2 trial of the combination of azacitidine, venetoclax, and trametinib in patients with relapsed or refractory AML harboring a RAS pathway-activating mutation. Results: Sixteen patients were treated. The patients were heavily pretreated with a median number of 4 prior therapies; 13 (81%) had received a prior hypomethylating agent (HMA) with venetoclax, and 8 (50%) had undergone prior stem cell transplant. Four patients (25%) responded (CR, n = 1; CRi, n = 1; MLFS, n = 2). Two of the 3 patients (67%) who had not previously received HMA plus venetoclax responded; in contrast, only 2 of the 13 patients (15%) who had previously received HMA plus venetoclax responded. The median OS was 2.4 months, and the 6-month OS rate was 31%. Related grade 3–4 adverse events occurred in 50% of patients, and 50% of patients required a dose adjustment of trametinib. Conclusions: The combination of azacitidine, venetoclax, and trametinib had only modest activity in patients with relapsed/refractory AML, with a response rate that was similar to previous reports of trametinib monotherapy. Substantial toxicity was observed with this combination. Given the established role of RAS pathway mutations in mediating resistance to AML therapies, future studies of better tolerated, more active inhibitors of this pathway are still needed.

© 2022 S. Karger AG, Basel

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First-Page Preview

Received: March 11, 2022
Accepted: May 14, 2022
Published online: June 17, 2022

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 3

ISSN: 0001-5792 (Print)
eISSN: 1421-9662 (Online)

For additional information: https://www.karger.com/AHA

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