Integrated Immune Landscape Analysis of RNA Splicing Factor-Mutant AML and Higher risk MDS Treated with Azacitidine ± Durvalumab

Jan Philipp Bewersdorf; Vanessa Hasle; Rory M Shallis; Ethan Thompson; Daniel Lopes de Menezes; Shelonitda Rose; Isaac Boss; Lourdes Mendez; Nikolai Podoltsev; Maximilian Stahl; Tariq Kewan; Stephanie Halene; Torsten Haferlach; Brian A Fox; Amer M Zeidan

doi:10.1177/20406207251347344

Integrated Immune Landscape Analysis of RNA Splicing Factor-Mutant AML and Higher risk MDS Treated with Azacitidine ± Durvalumab

Ther Adv Hematol. 2025 Jun 21:16:20406207251347344. doi: 10.1177/20406207251347344. eCollection 2025.

Authors

Affiliations

¹ Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, Yale University, New Haven, CT, USA.
² Bristol Myers Squibb, Princeton, NJ, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ MLL Munich Leukemia Laboratory, Munich, Germany.
⁵ Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, Yale University, 333 Cedar Street, PO Box 208028, New Haven, CT 06520-8028, USA.

Abstract

Background: RNA splicing factor (SF) mutations are associated with adverse outcomes in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes/neoplasms (HR-MDS). Preclinical data suggest that aberrant RNA splicing can lead to the generation of neoantigens, which renders these tumors more susceptible to immune checkpoint inhibitors. However, dedicated studies on immune checkpoint inhibitors in AML and MDS patients with SF mutations are limited.

Objectives: To characterize the immune and epigenetic landscape of AML and MDS patients with SF mutations.

Design: Post hoc analysis of the impact of RNA SF mutations (defined as any of SF3B1, SRSF2, U2AF1, and ZRSR2) on outcomes of newly diagnosed, older or intensive chemotherapy-ineligible patients with AML or HR-MDS treated with azacitidine ± the anti-PD-L1 antibody durvalumab as part of the randomized, phase II FUSION trial.

Methods: Primary endpoint was the overall response rate (ORR). Flow cytometry and gene expression profiling using bulk RNA sequencing were performed on pretreatment bone marrow aspirate samples.

Results: One hundred twenty-six patients with AML (51 SF-mutant and 75 wild type) and 79 patients with MDS (33 SF-mutant and 46 wild type) were included. ORR was independent of SF mutation status for both AML (SF-mutant: 35.3% vs wild-type: 33.3%; p = 0.47) and MDS patients (51.5% vs 56.5%; p = 0.63). Median overall survival was similar for SF-mutant and wild-type AML (14.9 months vs 12.2 months; p = 0.50) and MDS patients (23.5 months vs 10.6 months; p = 0.16). There were no differences in key cell populations from bone marrow aspirate flow cytometry samples. Gene expression analyses showed an increase in MKI-67 expression in SF wild-type patients, but no differences were observed in several immune-related genes including IL7R and PD-L1.

Conclusion: Addition of durvalumab to azacitidine did not improve ORR or OS among older patients with newly diagnosed AML and HR-MDS independent of SF mutation status.Trial registration: NCT02775903.

Keywords: AML; MDS; gene expression; immune phenotype; outcomes; splicing mutation.

Associated data

ClinicalTrials.gov/NCT02775903