An Immune Risk Score Predicts Survival of Patients with Acute Myeloid Leukemia Receiving Chemotherapy

Abstract

Purpose: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML.Experimental Design: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model.Results: Six flow cytometry-validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P ¼ 0.041), 44% versus 24% (P ¼ 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P ¼ 0.005), 2.12 (P ¼ 0.004), 2.02 (P ¼ 0.034), 1.66 (P ¼ 0.019), and 1.59 (P ¼ 0.001) in the training and validation cohorts, respectively.Conclusions: Our immune risk score complements current AML prediction models.

Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward

“…Although the prognostic significance of most immune cell types in AML remains to be elucidated, a similar trend has been seen in recent studies on adult AML [42][43][44]. For instance, for adult AML patients treated with chemotherapy, a relatively high proportion of T-and NK-cells in the bone marrow at diagnosis has been associated with improved survival, while the proportion of Tregs has been associated with poor prognosis [42][43][44]. For pediatric AML, such data are not available in literature yet.…”

“…Accordingly, cytotoxic T-cells, memory T-cells, T-helper 1 cells, follicular helper T-cells, NK-cells, B-cells, and M1-macrophages have been associated with prolonged survival, while high densities of regulatory T-cells (Tregs), M2-macrophages, myeloid-derived suppressor cells, and neutrophils have been correlated with poor prognosis [23,[39][40][41]. Although the prognostic significance of most immune cell types in AML remains to be elucidated, a similar trend has been seen in recent studies on adult AML [42][43][44]. For instance, for adult AML patients treated with chemotherapy, a relatively high proportion of T-and NK-cells in the bone marrow at diagnosis has been associated with improved survival, while the proportion of Tregs has been associated with poor prognosis [42][43][44].…”

“…In contrast, a small study that used flow cytometry in children with AML (n = 28) revealed a significantly lower fraction of T-cells out of all mononuclear cells in the bone marrow (4%) [44]. Phenotypically, both CD4+ and CD8+ T-cells expressed higher levels of the inhibitory checkpoints LAG3 and PD-1, in comparison to healthy donors [47].…”

Ferroptosis-related gene signature predicts the clinical outcome in pediatric acute myeloid leukemia patients and refines the 2017 ELN classification system

“…There are also numerous existing models for adult AML early prediction or risk stratification, which have been compared to the FGL model corresponding to different aspects of modeling ( Supplementary Table S8 ). For the immune risk score model proposed for adult AML ( Wang Y. et al, 2021 ), we did not succeed in validating it in the TARGET dataset (data not shown). The inconsistency might be induced by the differences in the immune microenvironment of AML tumors between adults and children.…”

Editorial: The Biological Landscape of Immunotherapy in AML

“…In AML, the current riskassessment classification 1 and prognostication are still predominantly focused on cytogenetic and molecular alterations, which are historically known to influence the sensitivity of leukemic cells to conventional chemotherapy. However, based on the compelling preclinical data regarding the fundamental impact of tolerogenic tumor microenvironment mechanisms in dysregulating patients' immune response, the prognostic significance of the immune landscape is recognized as being increasingly important in AML, revealing that immune-related genes may predict survival (10). Based on these premises, it is time to move in the direction of a paradigm shift with the ambition to refine stratification and prognostication of AML patients that incorporates an immunological-driven biological approaches.…”