Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML

Abstract

Tosedostat is an orally administered metalloenzyme inhibitor with antiproliferative and antiangiogenic activity against hematological and solid human cancers. Clinical activity has been demonstrated in relapsed acute myeloid leukemia (AML). Thirty-three elderly patients with AML (median age, 75 years) received 120 mg tosedostat orally once daily combined with subcutaneous low-dose cytarabine (20 mg twice per day for 10 days, up to 8 cycles), until disease progression. Induction mortality was 12%. According to an intention-to-treat analysis, the complete remission (CR) rate was 48.5%, and thus the primary end point of the study was reached (expected CR, 25%). The partial remission rate was 6.1%, with an overall response rate of 54.5%. Furthermore, 4 of 33 patients had stable disease (median: 286 days). The median progression-free survival and overall survival (OS) were 203 days and 222 days, respectively. Responding patients had a longer median OS than nonresponding patients (P = .001). A microarray analysis performed in 29 of 33 patients identified 188 genes associated with clinical response (CR vs no CR). Three of them (CD93, GORASP1, CXCL16) were validated by quantitative polymerase chain reaction, which correctly classified 83% of the patients. Specifically, CR achievement was efficiently predicted by the gene expression patterns, with an overall accuracy exceeding 90%. Finally, a negative predictive value of 100% was validated in an independent series, thus representing the first molecular predictor for clinical response to a specific combination drug treatment for AML. This trial has been registered at the European Medicines Agency and on the European Clinical Trials Database (https://www.clinicaltrialsregister.eu) as #2012-000334-19.

Graphical abstract

Figure 1.

Survival in all patients according to intent to treat. PFS (A) and OS (B) in all patients. (C) OS according to response (CR vs no CR).

Figure 2.

GEP enables a clear distinction of cases based on clinical response. (A) Volcano plot indicating genes differentially expressed in the 2 groups (CR [red] vs NR [gray]). (B) Hierarchical clustering based on the expression of 188 differentially expressed probe sets (corresponding to 140 genes), distinguishing CR vs NR cases.

Figure 3.

Gene Set Enrichment Analysis of genes differentially expressed in the 2 groups defined by the clinical response, CR vs NR. (A) Gene Ontology biological processes. (B) Curated gene sets. (C) Oncogenic signatures. The size of each group in the pie charts corresponds to the number of genes found in each category.

Figure 4.

Validation of gene expression analysis by qPCR. (A-C) Single gene expression from the 10th to 90th percentiles plotted in the box. (D) Heat map showing the expression of the 3 genes.

Figure 5.

Expression of the 3 genes in an independent data set of patients with AML treated with conventional chemotherapy (GSE6891). No significant differences were recorded, suggesting the specificity of the identified signature in discriminating patients likely to respond to the tosedostat-araC combination only.