Abstract CT069: Correlative biomarkers of clinical activity of the BCL-2 inhibitor, venetoclax (ABT-199/ GDC-0199), in acute myeloid leukemia patients
Authors: Popovic Relja , Daver Naval , Ruvolo Vivian , Chen Ken , Wang Zixing , Huang Xin , Mabry Mack , Potluri Jalaja , McKeegan Evelyn , Konopleva Marina , Chyla Brenda J. 
Published: July 2016

A phase 2 trial evaluated the efficacy and safety of venetoclax monotherapy in 32 patients (pts) with relapsed/refractory acute myeloid leukemia (AML) or those unfit for intensive therapy. Venetoclax demonstrated activity and a tolerable safety profile in these pts. We evaluated potential clinical biomarkers that correlated with venetoclax sensitivity and/or intrinsic/acquired resistance.

Given the selectivity of venetoclax to inhibit BCL-2, protein expression of BCL-2 family members BCL-2 and BCL-XL was determined by flow cytometry in tumor cells from peripheral blood collected at baseline (22 pts) and post venetoclax therapy (21 pts). Six pts had a sensitive protein index (?35% of blast expressing BCL-2 protein and &lt;40% blasts expressing BCL-XL) prior to therapy and the remaining 16 pts had a resistant protein index (7 pts had &lt;35% of blasts expressing BCL-2, 9 pts had ?40% blasts expressing BCL-XL). The median time on venetoclax therapy was 30 days for pts with a resistant index vs 104 days for pts with a sensitive index (P = 0.0381, Wilcoxon). AML blasts analyzed at relapse demonstrated a resistant BCL-2/BCL-XL protein index in 20 of 21 pts analyzed: 9 pts had &lt;35% blasts with BCL-2 expression and 11 pts had ?40% blasts with BCL-XL protein expression. All 6 pts with a sensitive protein index prior to therapy expressed a resistant protein index at relapse.

Occurrence of genetic mutations known to be associated with myeloid malignancies was investigated by next generation sequencing on blood and bone marrow specimens collected at baseline (32 pts) and relapse (20 pts). Biological activity defined as any measurable reduction in bone marrow blast counts after initiation of venetoclax therapy was observed in 17 pts. Eleven of 17 (65%) pts with biological activity had blasts containing mutations in the splicing factor genes SRSF2/ZRSR2, among them 6 pts also had blasts with mutations in IDH1/IDH2. Of the remaining 6 pts with biological activity, 1 pt had an IDH2 mutation and the remaining 5 pts were wild-type for SRSF2/ZRSR2/IDH1/IDH2. Six of 15 pts without biological response to venetoclax had blasts with either FLT3-ITD or PTPN11 mutation prior to therapy. Five of the 17 pts with initial biological response to venetoclax acquired a new FLT3-ITD or PTPN11 mutation at loss of response. Previous studies have shown that both these genetic alterations affect the expression of BCL-2 family members, suggesting that FLT3-ITD or PTPN11 mutations may be responsible for primary and acquired resistance to venetoclax in AML pts by deregulating anti-apoptotic proteins.

These findings suggest that BCL-2 protein expression patterns and/or presence of genetic mutations including splicing factors, IDH, PTPN11, and FLT3 may predict venetoclax monotherapy activity in pts with relapsed AML.

[R.P. and N.D. contributed equally to this work.]

Citation Format: Relja Popovic, Naval Daver, Vivian Ruvolo, Ken Chen, Zixing Wang, Xin Huang, Mack Mabry, Jalaja Potluri, Evelyn McKeegan, Marina Konopleva, Brenda J. Chyla. Correlative biomarkers of clinical activity of the BCL-2 inhibitor, venetoclax (ABT-199/ GDC-0199), in acute myeloid leukemia patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT069.