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RNA BASED IMMUNE SIGNATURES MAY PREDICT RESPONSES TO PD-1 INHIBITION AND AZACITIDINE TREATMENT IN ACUTE MYELOID LEUKEMIA (AML): A SUBSET ANALYSIS OF A PHASE 2 STUDY

PF205

Abbas, H.1; Alfayez, M.1; Wang, F.1; Garcia-manero, G.1; Ravandi, F.1; Kadia, T.1; Jabbour, E.2; DiNardo, C.1; Mathews, J.1; Flores, W.1; Andreeff, M.1; Kornblau, S.1; Borthakur, G.1; Konopleva, M.1; Cortes, J.1; Neelapu, S.1; Kantarjian, H.1; Davis, R.1; Daver, N.1

doi: 10.1097/01.HS9.0000559036.39189.18
Poster Session I: Acute myeloid leukemia - Biology & translational research
Free

1University of Texas M D Anderson Cancer Center

2University of Texas M D Anderson, Houston, United States

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Background:

Combining PD-1/PD-L1 blockade with hypomethylating agents (HMA) showed encouraging efficacy in relapsed/refractory (R/R) AML, but immune biomarkers of response are needed to optimize patient selection.

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Aims:

Deciphering immune predictors of response to PD-1 blockade in AML.

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Methods:

We treated 70 R/R AML patients with azacitidine (AZA) (75 mg/m2 on Days 1 through 7) and nivolumab (Nivo) (3 mg/kg on Days 1 and 14 of a 28 to 35 day cycle) in a phase 2 clinical trial (DaverN et al Cancer Discovery 2018). Herein, we discuss results of 11 patients (5 responders and 6 non-responders) who had pretreatment bone marrow (BM) NanoString RNA expression profiling of 1468 immune-relevant genes. 17-color established immune panel flow cytometric analysis were performed at baseline and end of cycle (EOC)1, 2 and/or 4 treatments on BMs. Results were correlated with clinical, pathological and molecular data.

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Results:

11 patients with R/R AML, median age 65 years (range 47-73 years), 63% with adverse cytogenetics, 27% with TP53 mutation, 6/11 (55%) with prior hypomethylating agent-based therapy had indepth flow-cytometry and NanoString immune profiling.The median administered courses of AZA+Nivo was 3 (range 1-17). The CR/CRi rate was 45% (including 2 CR, 1 CRi, 1 CRn and 1 CRp), with a median time to response of 1.8 months (range 0.8-4.9 months). The median overall survival was 13 months with 27% patients alive at 1 year. We found significant positive correlations between proportions of T-effector cells in baseline BM, and CD3+, CD8+, and T-regulatory cells in EOC 1 BM (r>0.75, p < 0.01 for all). At EOC2, these correlations were no longer significant. However, there was a significant positive correlation between proportion of T-effector cells in baseline BM and T-regulatory cells (r = 1, p < 0.001) in EOC4 BM.

Using NanoString analysis on pretreatment BM samples, we found 133 differentially expressed genes (fold change = 2, q<0.1) between responders (5/11) and non-responders (NRs) (6/11). Pretreatment pathway analysis of differentially expressed BM genes between responders and non-responders demonstrated enrichment of innate immune response, cytokine activity, cell adhesion, and chemotaxis pathways (q<0.05) in responders. Hallmark signaling pathway analysis also demonstrated significant enrichment of IL2-STAT5, IL6-JAK-STAT3, IFN-aand TNF signaling pathways (q<0.05) in pretherapy BM in responders compared with NRs. We then utilized z-score distribution analysis to quantify the degree of activation of known immunologic pathways. We found signatures highly specific to neutrophils and macrophages were significantly (p < 0.05) upregulated in the pretreatment BMs of responders compared with NRs.

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Summary/Conclusion:

Immune regulatory signatures related to IL2, IL6, IFNa, chemotaxis, neutrophils and macrophages in pretreatment BMs may be associated with augmented clinical response to PD-1 based therapies in AML. Similar underlying pathways (primarily IL2-STAT5 and IFNa), have consistently predicted for responses to PD-1 inhibition in solid cancers. Further, responses to PD-1 based therapy was higher in patients with more active innate immune system as demonstrated by macrophage and neutrophil up-regulated signatures, suggesting a possible prerequisite of active innate immunity for optimal PD-1 blockade responses. Identifying such predictive signatures may help select AML patients most likely to benefit from PD-1 based approaches, further enhancing the benefit-risk ratio with such therapies.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.