A Phase II Study of Azacitidine, Venetoclax, and Trametinib in Relapsed or Refractory Acute Myeloid Leukemia Harboring RAS Pathway-Activating Mutations.

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.

• Authors: Sai Prasad Desikan, Farhad Ravandi, Naveen Pemmaraju, Marina Konopleva, Sanam Loghavi, Elias J Jabbour, Naval Daver, Nitin Jain, Kelly S Chien, Abhishek Maiti, Guillermo Montalban-Bravo, Tapan M Kadia, Walid Macaron, Ricardo DeLumpa, Monica Kwari, Gautam Borthakur, Nicholas J Short
• Journal: Acta haematologica (Acta Haematol) Vol. 145 Issue 5 Pg. 529-536 ( 2022) ISSN: 1421-9662 [Electronic] Switzerland
• PMID: 35717939 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: © 2022 S. Karger AG, Basel.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Pyridones
• Pyrimidinones
• Sulfonamides
• trametinib
• Mitogen-Activated Protein Kinase Kinases
• Azacitidine
• venetoclax

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Azacitidine (adverse effects)
• Bridged Bicyclo Compounds, Heterocyclic
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Mitogen-Activated Protein Kinase Kinases (genetics, therapeutic use)
• Mutation
• Pyridones
• Pyrimidinones
• Sulfonamides