Immune and Epigenetic Landscape of TP53-mutated Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes (HR-MDS)

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.3371-3371
• Main Authors: Zeidan, Amer M., Bewersdorf, Jan Philipp Philipp, Hasle, Vanessa, Thompson, Ethan G., Lopes de Menezes, Daniel, Rose, Shelonitda, Boss, Isaac, Fox, Brian
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-146329

Introduction: Mutations in TP53 occur in 10% of patients (pts) with AML and HR-MDS and have been associated with worse outcomes and an immunosuppressive phenotype. To define the immune and epigenetic landscape in TP53-M advanced myeloid neoplasms (MN), we compared data from 61 pts with HR-MDS or AML with TP53 mutations (TP53-M) to 143 TP53 wildtype (TP53-WT) pts who were followed prospectively with serial samples in a well-annotated clinical trial in which all pts received hypomethylating agent (HMA)-based therapy. Methods: The FUSION trial (NCT02775903) was a large, randomized phase 2 study comparing azacitidine (AZA) monotherapy with AZA + anti-PD-L1 antibody durvalumab in 2 separate cohorts of previously untreated unfit AML and HR-MDS pts (Zeidan A et al, ASH 2019). Responses were classified by IWG 2003 and 2006 criteria for AML and MDS, respectively. Survival was estimated using Kaplan-Meier techniques. Samples from peripheral blood (PB) and bone marrow (BM) were obtained at baseline and serially on trial. A 38-targeted mutation analysis was performed at Munich Leukemia Laboratory. Only level 1 pathogenic TP53 mutations with variant allele frequency (VAF) ≥2% were included. DNA methylation was assessed using Illumina's Infinium Human Methylation EPIC methylation array. Immunophenotyping and immune checkpoint expression was performed using flow cytometry. Gene expression profiles were studied by RNA-sequencing. Results: Of 129 AML and 84 HR-MDS pts enrolled in FUSION trial, 37 had TP53-M AML, 88 TP53-WT AML, 24 TP53-M HR-MDS, and 55 TP53-WT HR-MDS pts. The average VAF for TP53 mutations were 37%, and 90% had ≥10% VAF. TP53-M AML pts were more likely to have poor-risk cytogenetics, therapy-related disease, and lower BM blast percentage compared to TP53-WT AML pts. TP53-M HR-MDS were more likely to have secondary MDS, very poor risk cytogenetics by IPSS-R, and very high risk IPSS-R score. There were no statistically significant differences in overall response rate (ORR) between TP53-M and TP53-WT pts (AML cohort: ORR: 35.1% [95% CI: 21%-53%] vs. 34.1% [CI: 26%-45%]; HR-MDS cohort: ORR: 41.7% [CI: 23%-63%] vs. 60% [CI: 46%-73%]). Median OS was 8.1 [95% CI: 5.4 - 13] months (mos) among TP53-M AML pts and 16.6 [95% CI: 13 - 21] mos for TP53-WT AML pts [Figure 1A]. Median OS was 9.8 [95% CI: 9.3 - 20+] mos for TP53-M HR-MDS pts and 23.5 [95% CI: 12 - 25+] mos for TP53-WT HR-MDS pts [Figure 1B]. Global DNA methylation was independent of TP53 mutation status in