AbstractIntroductionAcute Myeloid Leukemia Patients Research Articles

Quantity and Functional Exhaustion of Mucosal-Associated Invariant T Cells in Acute Myeloid Leukemia: Friends or Foes?

Abstract Introduction Acute Myeloid Leukemia (AML) is a hematological malignancy affecting hematopoietic progenitor cell differentiation, proliferation, and cell cycle progression, possibly involving disturbances in host immune function. Comprehensive understanding of the immune system composition and function in AML patients is crucial for developing novel immunotherapeutic strategies. Mucosa-Associated Invariant T cells (MAITs), as a subset of unconventional T cells, bridge innate and adaptive immunity and have been predominantly studied in the context of mucosa-related cancers. However, their role in AML remains largely unexplored. Investigating the association between MAITs and AML is of significant importance for understanding the immune escape mechanisms in AML, developing novel immunotherapeutic approaches, and predicting patient prognosis. Methods This study aimed to delineate the longitudinal immune profile of MAITs during AML pathogenesis and treatment, which may contribute to understanding immunological changes of MAITs in AML and predicting patient prognosis. In this prospective study, we collected peripheral blood or bone marrow samples from 131 AML patients, including 99 newly diagnosed cases, 18 in remission, and 14 in relapse, as well as 69 healthy controls. We performed multi-parameter flow cytometry for phenotypic and functional analysis of MAITs and explored their relationship with disease features, progression, and prognosis. Results We initially demonstrated that MAITs reflected immunological defects in AML patients. MAITs showed signs of depletion in both frequency and absolute count at initial diagnosis (p<0.0001) (Fig. 1A), especially in the CD8 + MAITs subset. The frequency of MAITs reflected AML cell genetics, tumor burden, disease status, and treatment responsiveness (Fig. 1B). AML patients exhibited reduced frequency of effector memory MAITs (p<0.0001) and increased frequency of terminal differentiated MAITs (p<0.0001) in peripheral blood (Fig. 1C), indicating altered reactivity of MAIT cells to antigen stimulation. MAITs displayed a state of high activation and even exhaustion, as evidenced by upregulated PD-1 expression. Impaired secretion of Th1-type cytokines and increased secretion of Th17-type cytokines (Fig. 1D), granzyme B, and perforin were observed in MAITs, while MAITs also shifted towards secreting tumor-promoting cytokines such as IL-8. Lower frequency of MAITs was correlated with inferior Overall Survival (OS) and Progression-Free Survival (PFS) (Fig. 1E). Multivariate analysis identified MAITs frequency <2.12% as an independent prognostic factor affecting OS. Conclusion Our study highlights the role of MAITs in immunological defects in Acute Myeloid Leukemia and reveals their functional impairment and enhanced tumor-promoting effects. The frequency of MAITs in peripheral blood reflects the genetic features, tumor burden, disease status, and treatment responsiveness of AML patients. Lower frequency of MAITs is associated with inferior OS and PFS, serving as a prognostic indicator for AML.

87 Epidemiology Study of Elderly Patients with Acute Myeloid Leukaemia at a Haematological Tertiary Referral Centre

Abstract Introduction Acute Myeloid Leukemia (AML) is a rare disease with a high incidence in the elderly. Our aim is to report the incidence of elderly patients with AML at a haematological tertiary referral centre. Method We have collected data from 2007 till 2017 from the main Malaysian haematological tertiary referral centre involving all the 1225 AML patients. Out of those, 182 elderly patients aged 65 and above with AML were examined. The patients had at least 2 years follow-up. Results The elderly represented 14.9% of the 1225 patients who presented with acute myeloid leukemia to the centre. There were 182 elderly patients with AML which were subdivided to the unspecified AML of 154 patients, 1 patient with M1, 4 patients with M2, 6 patients with M3, 5 patients with M4, 8 patients with M5, 2 patients with M6 and 2 patients with M7. There were 109 males and 73 females. The majority of the patients were Chinese (n=85) representing 46.7% of the patients, followed by the Malay (n=76), Indian (n=19) and lastly others (n=2). The average age at diagnosis was 71 years. There were 136 deaths and the mortality rate was 74.7%. The average age of the patients who had passed away (n=136) was 71.4 years. The average age of the patients who are still living (n=42) was 76.5 years. Conclusion The incidence of elderly AML is increasing. The younger patients with AML are known to have better survival rate in comparison to the elderly. More research is needed to explore the reasons for the higher mortality in the elderly and the ways to improve the outcome of this elderly population as our lifespan increases and Malaysia heads towards an ageing nation.

Abstract 1340: High NK cell number predicts poor overall survival in de novo treatment naive acute myeloid leukemia

Abstract Introduction Acute myeloid leukemia (AML) is a deadly disease associated with high mortality and morbidity. Previous studies report defects in NK cell maturation and function in AML patients leading to innate immune evasion. Considering that the number of NK cells may be an important indicator of innate immune regulation of AML, our group sought to understand the prognostic significance of NK cell number in de novo AML patients. Methods Patient samples were obtained from the Oregon Health and Science University (OHSU) Pathology Department between September 2010 and March 2016. This cohort study includes 82 newly diagnosed adult AML patients who had a bone marrow biopsy that was subjected to flow cytometry and a targeted-NGS panel within 30 days prior to induction treatment. Patients were excluded if they had antecedent hematological diseases or therapy-related AML. Bone marrow immunophenotyping was performed using the Ion Torrent PGM platform. Absolute numbers of NK cells were estimated from flow cytometric analysis of the bone marrow samples whereby lymphocytes were identified based on CD45 staining and light side scatter and NK cells were defined as CD3-/CD56+. Results This retrospective cohort of 82 newly diagnosed AML patients were 53.7% male with a median age of 61 years (range 18 - 83). Using 2017 ELN risk stratification guidelines, 36.6% of patients were classified as favorable, 26.8% as intermediate, and 36.6% as adverse. Absolute NK cell numbers in the bone marrow ranged from 1 to 896 cells/μl with a median of 98. When stratifying NK cells by staining intensity to identify subpopulations, the number of CD56 bright NK cells ranged from 0 to 69 cells/μl (median 3) and the number of CD56 dim NK cells ranged from 1 to 585 cells/μl (median 77). Overall survival (OS) was measured from diagnosis to date of death or last contact and varied from 1 day to 5.7 years (median 20.5 months). There were 3 deaths in the first week after diagnosis. Separate Cox proportional hazards regression models were applied to each NK cell group in both the univariable and multivariable settings, with the latter models accounting for patient age and ELN risk. Higher absolute numbers of NK cells (CD3-/CD56+) were significantly correlated with worse OS in both model settings, with a multivariable p-value of 0.001. The number of bright NK cells was a significant predictor of OS in the univariable model but lost significance when controlling for other variables. However, similar to the number of all NK cells and contrary to previous reports, higher counts of dim NK cells were significantly associated with shorter survival times, with a multivariable p-value of 0.001. Conclusions In this study, we show that higher NK cell numbers at diagnosis are associated with worse OS and thus play an important role in prognostication for AML patients. This association with survival is most evident in patients at least 60 years old or those with intermediate or adverse ELN risk. Citation Format: Weiwei Wang, Guang Fan, Andy Kaempf, evan Lind, Tomi Mori, Byung Park, Jennifer Saultz. High NK cell number predicts poor overall survival in de novo treatment naive acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1340.

Decreased CD4+-Th/CD8+-Tc ratio in Bone marrow at diagnosis of acute myeloid leukemia Predicts Increased Risk of Graft-Versus-Host-Disease in Transplant Patients

Abstract Introduction Acute myeloid leukemia (AML) is an aggressive disease with high morbidity and mortality. Transplant is one of the most important treatments for AML. However, graft-versus-host-disease (GVHD) remains one of major problems in transplant patients. Since immune repertoire plays an important role in the GVHD occurrence, we investigate the relationship between lymphocyte subsets and the risk of GVHD. Methods 60 initial diagnostic flow data of AML transplant patients were reviewed (Oregon Health and Science University 2010 to 2016, 30 females and 30 males, with a median age of 51.417 years, range 13–72). 36 patients with GVHD including acute and chronic GVHD while 24 patients without GVHD. The lymphocyte subsets were analyzed including CD3+T-cells, CD3+CD4+Th, CD3+CD8+Tc, CD4/CD8 ratio, CD19+CD20+B, CD19+CD5+B1, CD3+CD56+NKT, CD3−CD56+NK, and three NK subsets (CD56brightNK, CD56normalNK, CD56dimNK). Results As to the overall survival (OS), there’s no statistic difference between age<60 years old or age ≥60 years. Compared with non-GVHD group, decreased percentage (%) of Th, increased % of Tc & low Th/Tc ratio were observed in GVHD group (P=0.0281, P=0.0394, P=0.0340 accordingly). Receiver operating characteristic (ROC) analysis indicates that low Th/Tc ratio predicts increased risk of GVHD (P=0.0231, AUC=0.663, 95% Confidence Interval is 0.530 to 0.780). There’re no statistic differences between GVHD and non-GVHD for all other lymphocyte subsets percentage (P>0.05). Conclusions AML patients with GVHD post transplant have a lower Th cell percentage and higher Tc cell percentage at diagnosis. This is to say, decreased Th/Tc ratio in BM of initial diagnosed AML patients may predict a high risk of GVHD post transplant.