Abstract P195: Omacetaxine mepessucinate plus venetoclax show strong synergistic anti-leukemic activity in nucleophosmin (NPM1)-mutated AML patient-derived xenograft (PDX) models to support a phase 1 clinical trial
Authors: Mezzasoma Federica , Cardinali Valeria , Gionfriddo Ilaria , Milano Francesca , Sciabolacci Sofia , Ferrari Alessio , Sabino Marcella , Silvestri Serenella , Donini Serena , Tini Valentina , Spinozzi Giulio , Falini Brunangelo , Martelli Maria Paola 
Published: December 2021

Abstract
Despite different novel targeted drugs against specific genetic lesions have been developed for acute myeloid leukemia (AML) treatment, therapy in many AML subtypes should still rely on drugs possibly targetting alternative pathways essential for leukemia survival. Different biological and clinical evidences point to nucleophosmin (NPM1) gene mutations (the most frequent genetic lesion in AML) among strong predictors of sensitivity to venetoclax, a small molecule drug inhibitor of the B-cell leukemia/lymphoma-2 (Bcl-2) anti-apoptotic protein, highly expressed in most AML. Venetoclax appeared to be extremely efficacious in combination with hypomethylating agents (HMA) as first-line therapy, particularly in NPM1-mutated AML. Omacetaxine mepessucinate is a synthetic form of the plant cephalotaxine alkaloid homoharringtonine (HHT). HHT binds to the A-site cleft of ribosomes preventing the initial elongation step of protein synthesis and leading to a transient but profound inhibition of protein synthesis especially of those with a short half-life, including the antiapoptotic protein myeloid cell leukemia-1 Mcl-1, acting as mechanism of resistance following Bcl-2 inhibition. Besides its action as ‘Mcl-1 inhibitor’ (targeting its protein levels), we focused on HHT because i) it is a FDA-approved drug, in the setting of chronic myeloid leukemia (CML); ii) it showed some activity in clinical trials in AML; iii) it was shown to be a safe treatment, when evaluated also in association with chemotherapy, either standard intensive or low-dose regimen, in AML; iv) it is administered subcutaneously in its FDA-approved formulation; v) it has never been used in combination with venetoclax. Here, we sought to explore the therapeutic potential of omacetaxine mepessucinate and venetoclax in pre-clinical in vivo models, and used 2 different NPM1-mutated AML PDX (one, NPM1/FLT3-ITD double mutant; the other, DNMT3A/NPM1/FLT3-ITD triple mutant) edited to express luciferase allowing to track the disease by in vivo bioluminescence imaging (BLI) during treatment and evaluate drug response. HHT was given at 1 mg/Kg by subcutaneous administration for 2 consecutive weeks (5 days/week) and venetoclax at 100 mg/kg by gavage for 4 weeks (5 days/week), in cycles of 28 days. The anti-leukemic activity of the treatment was measured by evaluating AML growth/tissue infiltration on sacrificed animals by immunohistochemistry or flow cytometry and in vivo by BLI. Strikingly, on overt disease combinatorial HHT and venetoclax treatment resulted in a strong and synergic anti-leukemic effect with no leukemia detection in a cohort of mice sacrificed and analyzed after the first cycle, and in a significant advantage in a cohort analyzed for survival compared with single-drug or vehicle-treated animals. These data gave the support to design a pilot phase 1 clinical trial aimed at assessing safety and preliminary efficacy of omacetaxine mepessucinate plus venetoclax in relapsed/refractory NPM1-mutated AML patients. The trial is now open to patients accrual at our Hematology department.
Citation Format: Federica Mezzasoma, Valeria Cardinali, Ilaria Gionfriddo, Francesca Milano, Sofia Sciabolacci, Alessio Ferrari, Marcella Sabino, Serenella Silvestri, Serena Donini, Valentina Tini, Giulio Spinozzi, Brunangelo Falini, Maria Paola Martelli. Omacetaxine mepessucinate plus venetoclax show strong synergistic anti-leukemic activity in nucleophosmin (NPM1)-mutated AML patient-derived xenograft (PDX) models to support a phase 1 clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P195.