Abstract LB-009: Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or nonintensive chemotherapy in patients with acute myeloid leukemia (AML)
Authors: Merchant Akil , Jamieson Catriona , Heuser Michael , Chan Geoffrey , Wang Panpan , Ching Keith A. , Johnson Jillian , O’Brien Thomas , Cortes Jorge E. 
Published: August 2019

Background: The Smoothened inhibitor glasdegib (GLAS) was recently approved in combination with low-dose cytarabine (LDAC) in adults with AML when intensive chemotherapy is not an option. GLAS in combination with intensive chemotherapy has also been well tolerated and shown clinical activity, and is undergoing further evaluation. This analysis aimed to identify molecular drivers that predict overall response (OR) and OS with GLAS.

Materials and Methods: We included AML patients receiving LDAC alone or with GLAS 100 mg QD (nonintensive arm) or GLAS 100 mg QD & 7+3 (intensive arm) from Phases 1b and 2 of a multicenter study (NCT01546038). We assessed correlation of OS/OR with mRNA expression of 19 genes, expression levels of 38 cytokines, and mutations in 109 genes. For correlation analyses, a cut-off &lt; or ≥ the median was used for gene expression and cytokine levels and mutated or not for gene mutations.

Results: Within the nonintensive arm (LDAC + GLAS, n=68; LDAC, n=30), improved OS with GLAS + LDAC correlated with lower FOXM1 and MSI2, and higher BCL2 and CCND2 expression. For cytokines, lower levels of 6CKINE, BAFF, ICAM-1, MIP-1α, MIP-1β and MMP-3 correlated with improved OS. The low number of responders in the LDAC arm (n=2) prevented correlation analysis of mRNA or cytokines; however, within the LDAC + GLAS arm, OR correlated with high PTCH1 levels, and high EOTAXIN but low BAFF levels. In the intensive arm (GLAS & 7+3, n=59), higher PTCH1 expression correlated with improved OS (median OS 10.8 vs 39.5 months) but no significant correlations were found with OR; no cytokines correlated with OS or with OR. For gene mutation, in the nonintensive arm (LDAC + GLAS, n=65; LDAC alone, n=25), OS differed with PLEKHH1 and STAG2 mutation status, but no genes correlated with OR. In the intensive arm (n=55), mutations in FLT3, TP53, CEP170, PHF6, and ANKRD26 correlated with OS. Patients in this arm with FLT3 mutations (including ITD) responded better vs wild type FLT3 (median OS 13.4 months vs unreached for FLT3 mutant). We also examined mRNA expression and cytokine levels at various times after starting treatment: statistically significant changes included modulation of SMO, BDNF, ITAC, and IL-23 levels in the nonintensive arm, and SMO, MYCN, CDKN1A, and a number of cytokines including IL-8, TNF-α and IL-5 in the intensive arm.

Conclusions: In this analysis, expression levels of a select number of genes and circulating cytokines implicated in AML appear to correlate with OS and OR. The improved response with FLT3 mutations and high PTCH1 expression levels in the intensive arm, along with the analysis appearing to indicate modulation of select genes (eg SMO) and cytokines in both arms while on treatment, deserves further investigation. These preliminary findings will need to be verified in larger randomized trials, which are on-going.

Citation Format: Akil Merchant, Catriona Jamieson, Michael Heuser, Geoffrey Chan, Panpan Wang, Keith A. Ching, Jillian Johnson, Thomas O’Brien, Jorge E. Cortes. Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or nonintensive chemotherapy in patients with acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-009.