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The prognostic significance of soluble immune checkpoint molecule TIM-3 and its ligands in the plasma has been illustrated in various solid tumors, but such study in newly diagnosed acute myeloid leukemia (AML) remains absent. Soluble TIM-3, Gal-9, and CEACAM1 levels in bone marrow plasma samples collected from 90 adult AML patients at diagnosis and 12 healthy donors were measured by enzyme-linked immunosorbent assays, and 16 AML patients were simultaneously tested cell membrane TIM-3 expression by multicolor flow cytometry. AML patients had significantly elevated soluble TIM-3 levels and similar soluble Gal-9 and CEACAM1 levels compared with healthy donors (P = 0.0003, 0.26, and 0.96, respectively). In the whole cohort, a high soluble TIM-3 level was the sole independent adverse prognostic factor for relapse-free survival (RFS) (P = 0.0060), and together with adverse European LeukemiaNet genetic risk they were independent poor prognostic factors for event-free survival (P = 0.0030 and 0.0040, respectively). A high soluble CEACAM1 level was significantly related to lower RFS (P = 0.028). In addition, a high soluble Gal-9 level had a significant association with lower RFS in patients receiving allogeneic hematopoietic stem cell transplantation at the first complete remission (P = 0.037). Furthermore, soluble TIM-3 level tended to have positive correlation with the percentage of nonblast myeloid TIM-3+ cells in nucleated cells in AML (r = 0.48, P = 0.073). Therefore, the high soluble TIM-3 level in the diagnostic BM plasma predicted poor outcome in adult AML patients, and a high sGal-9 level was associated with relapse after allogeneic hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: Compared to other immune checkpoint molecules, T cell immunoglobulin domain and mucin domain-3 (TIM-3) is highly expressed on natural killer (NK) cells, but its functional role and prognostic significance in acute myeloid leukemia (AML) remains unclear. This study aims to evaluate the role of TIM-3 expression on the cytotoxic and killing capacity of NK cells and its prognostic significance in AML. Methods: AML public single-cell RNA sequencing (scRNAseq) data were used to analyze the correlation of transcript levels between HAVCR2 (encoding TIM-3) and cytotoxic molecules in NK cells. NK cells from the bone marrows of seven newly diagnosed AML patients and five healthy donors (HDs) were stimulated in vitro and cell-killing activity was evaluated. A total of one hundred and five newly diagnosed adult AML patients and seven HDs were tested the expression of TIM-3 and cytotoxic molecules on the bone marrow NK cells by multi-parameter flow cytometry (MFC). Results: Both scRNAseq and MFC analysis demonstrated that TIM-3 expression on NK cells was positively related to the levels of perforin (PFP) and granzyme B (GZMB) (all p < 0.05) in AML. It was PFP and GZMB but not the TIM-3 level that was related to NK-cell-killing activity against K562 cells (p = 0.027, 0.042 and 0.55). A high frequency of TIM-3+ NK cells predicted poorer relapse-free survival (RFS) and event-free survival (EFS) (p = 0.013 and 0.0074), but was not an independent prognostic factor, whereas low GZMB levels in TIM-3+ NK cells independently predicted poorer RFS (p = 0.0032). Conclusions: TIM-3 expression on NK cells is positively related to PFP and GZMB levels but has no relation to cell-killing activity in AML, and low GZMB levels in TIM-3+ NK cells in the diagnostic bone marrows predicts poor outcomes. This study lays a theoretical foundation for the clinical application of immune checkpoint inhibitor treatment. [ABSTRACT FROM AUTHOR]

Background: The effect of the expression of the newly identified immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) on NK cells in core binding factor-acute myeloid leukemia (CBF-AML) remains to be investigated. Methods: Fresh bone marrow samples from a total of 39 newly diagnosed CBF-AML patients and 25 healthy donors (HDs) were collected for testing the phenotype and function state of total NK, CD56bright, and CD56dim NK cell subsets after in vitro stimulation. Results: The frequencies of TIGIT+ cells in total NK, CD56bright, and CD56dim NK cell subsets had no significant difference between patients and HDs. TNF-α and INF-γ levels were uniformly lower in TIGIT+ cells than the corresponding TIGIT− cells in all HDs, whereas those for TIGIT+ to TIGIT− cells in patients were highly heterogenous; TIGIT expression was not related to PFP and GZMB expression in HDs, whereas it was related to higher intracellular PFP and GZMB levels in patients. Patients' TIGIT+ NK cells displayed lower K562 cell-killing activity than their TIGIT− NK cells. In addition, high frequencies of TIGIT+ cells in total NK and CD56dim NK cells were associated with poor RFS. Conclusions: TIGIT expression affected the diagnostic bone marrow-sited NK cell function and had prognostic significance in CBF-AML patients. [ABSTRACT FROM AUTHOR]

Introduction: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo‐geneic hematopoiesis stem cell transplantation (allo‐HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. Methods: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF‐normal (CSF−) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. Results: Compared to those in the CSF‐negative group, the conventional cytology positive and MFC+ groups had comparable 8‐year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia‐free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. Conclusion: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients. [ABSTRACT FROM AUTHOR]

Introduction: Immune microenvironment plays an important role in the occurrence and development of acute myeloid leukemia (AML). Studies assessing the prognostic significance of bone marrow (BM) lymphocyte subsets' frequencies at diagnosis in patients with AML were limited. Methods: Fresh BM samples collected from 97 adult AML patients at diagnosis were tested for lymphocyte, T, CD4+T, CD8+T, γδT, NK, and B cell frequencies using multi‐parameter flow cytometry. Results: Low frequencies of lymphocytes, T, CD4+T, and CD8+T cells were associated with significantly lower rates of one‐course complete remission (CR) (all p < 0.05). Moreover, the frequency of CD4+T cells independently predicted one‐course CR achievement (p = 0.021). Low frequencies of T and CD8+T cells were significantly associated with lower relapse‐free survival (RFS) rates (p = 0.032; 0.034), respectively, and a low frequency of CD8+T cells was associated with a significantly lower overall survival (OS) rate (p = 0.028). Combination of frequency of CD8+T cells and ELN risk stratification showed that patients with ELN‐intermediate/adverse risk + high CD8+T cell frequency had a similar RFS rate to those with ELN‐favorable risk + high CD8+T cell frequency and those with ELN‐favorable risk + low CD8+T cell frequency (p = 0.88; 0.76), respectively. The RFS rate of patients with ELN intermediate/adverse risk + low CD8+T cell frequency was significantly lower than that of all aforementioned patients (p = 0.021; 0.0007; 0.028), respectively. Conclusion: The frequencies of BM lymphocyte subsets at diagnosis predicted clinical outcomes and could help improve risk stratification in AML. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease and needs to be stratified. Both, cancer cells and immune cells participate in tumor initiation, growth and progression and might affect clinical outcomes. TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3), an immune checkpoint molecule, is expressed not only on immune cells but also on leukemic stem cells (LSCs) in AML. This prompted us to investigate the prognostic significance of TIM-3 in t(8;21) AML. A total of 47 t(8;21) AML patients were tested for TIM-3 expression by multi-parameter flow cytometry at diagnosis. 35 of these, who received chemotherapy alone or along with allogeneic hematopoietic stem cell transplantation were followed up. The expression pattern of TIM-3 on T-cells and NK (natural killer) cells as a whole (T + NK) and LSCs were evaluated independently. High percentage of T + NK − TIM-3+ and CD34+CD38−TIM-3+ cells were significantly associated with a high 2-year cumulative incidence of relapse (CIR) (p = 0.028, 0.016). Further, concurrent high frequencies of T + NK-TIM-3+ and CD34+CD38-TIM-3+ cells at diagnosis were significantly associated with a high 2-year CIR (p < 0.0001) and this together with c-KIT D816 mutation were the independent adverse prognostic factors for relapse (hazard ratio (HR)=2.5, [95% confidence interval (CI), 1.1–6.0], p = 0.04; HR = 46.5, [95% CI, 2.7–811.5], p = 0.009). In conclusion, the expression pattern of TIM-3 on both T and NK cells and LSCs at diagnosis had prognostic significance in t (8;21) AML. [ABSTRACT FROM AUTHOR]