Defective T-cell response to COVID-19 vaccination in acute myeloid leukaemia and myelodysplastic syndromes.

Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.

Machine learning of COVID-19 clinical data identifies population structures with therapeutic potential.

Clinical outcomes for patients with COVID-19 are heterogeneous and there is interest in defining subgroups for prognostic modeling and development of treatment algorithms. We obtained 28 demographic and laboratory variables in patients admitted to hospital with COVID-19. These comprised a training cohort (n = 6099) and two validation cohorts during the first and second waves of the pandemic (n = 996; n = 1011). Uniform manifold approximation and projection (UMAP) dimension reduction and Gaussian mixture model (GMM) analysis was used to define patient clusters. 29 clusters were defined in the training cohort and associated with markedly different mortality rates, which were predictive within confirmation datasets. Deconvolution of clinical features within clusters identified unexpected relationships between variables. Integration of large datasets using UMAP-assisted clustering can therefore identify patient subgroups with prognostic information and uncovers unexpected interactions between clinical variables. This application of machine learning represents a powerful approach for delineating disease pathogenesis and potential therapeutic interventions.

Very early lineage-specific chimerism after reduced intensity stem cell transplantation is highly predictive of clinical outcome for patients with myeloid disease.

BACKGROUND: The importance of chimerism status in the very early period after hematopoietic stem cell transplantation is unclear. We determined PBMC and T-cell donor chimerism 50 days after transplantation and related this to disease relapse and overall survival. METHODS: 144 sequential patients underwent transplantation of which 90 had AML/MDS and 54 had lymphoma. 'Full donor chimerism' was defined as ≥99% donor cells and three patient groups were defined: 40% with full donor chimerism (FC) in both PBMC and T-cells; 25% with mixed chimerism (MC) within both compartments and 35% with 'split' chimerism (SC) characterised by full donor chimerism within PBMC and mixed chimerism within T-cells. RESULTS: In patients with myeloid disease a pattern of mixed chimerism (MC) was associated with a one year relapse rate of 45% and a five year overall survival of 40% compared to values of 8% and 75%, and 17% and 60%, for those with SC or FC respectively. The pattern of chimerism had no impact on clinical outcome for lymphoma. CONCLUSION: The pattern of lineage-specific chimerism at 50 days after transplantation is highly predictive of clinical outcome for patients with myeloid malignancy and may help to guide subsequent clinical management.

Progression of mycosis fungoides occurs through divergence of tumor immunophenotype by differential expression of HLA-DR.

Immunotherapy is a valuable treatment for many cancer patients, and there is considerable interest in understanding the mechanisms of immune evasion to guide appropriate management. Mycosis fungoides (MF) is a malignant disorder of skin-homing CD4+ T cells, and it exhibits a highly variable clinical course during which the tumor-specific immune response may be an important determinant. An unusual feature of MF is that tumor-infiltrating lymphocytes (TILs) must attempt to control a malignant cell from within their own lineage. We obtained skin biopsies and blood from 43 patients with CD4+ MF and undertook a detailed phenotypic and functional analysis of CD4+ and CD8+ T cells. Clonotypic TCRBV staining allowed delineation of malignant and reactive CD4+ subsets. CD4+ and CD8+ TILs displayed a comparable "exhausted" phenotype that was characterized by expression of PD-1 and TIGIT but retained cytotoxic activity and production of interferon-γ and interleukin-17 in early-stage disease. In contrast, tumor cells were much more heterogeneous and were divided into 3 discrete subsets based on differential expression of HLA-DR: "cold" (DR-), "exhausted" (DR+ PD-1+), and "evasive" (DR++ PD-L1+) phenotypes. Disease progression was associated with increasing divergence of the tumor phenotype away from that of TILs and reduced functional activity within TILs. These observations reveal that the phenotype and function of TIL populations are constrained at all stages of disease, whereas the tumor evolves discrete phenotypic profiles of escape during clinical progression. The findings should help to direct appropriate immunotherapeutic interventions for individual patients.

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT.

The graft-versus-leukemia (GVL) effect of allogeneic hemopoietic stem cell transplantation (allo-HSCT) is mediated by the donor immune system and acts to decrease the rate of disease relapse. Although studies of posttransplant immune reconstitution have identified correlates of clinical outcome, the number and profile of mature immune cells infused with the stem cell graft is also likely to be an important determinant and has been relatively poorly studied. We characterized immune cells within the stem cell graft of 107 patients who underwent T-cell-depleted allo-HSCT and related this to clinical outcome. The number of natural killer (NK) cells and T cells that were infused varied markedly between patients, but T-cell dose was not an important factor in subsequent outcome. In contrast, the number of NK cells was a powerful determinant of the risk of disease relapse. Patients who received an NK cell dose below the median level of 6.3 × 106 cells per kg had a relapse rate of 40% at 2 years posttransplant compared with only 6% for those whose stem cell graft contained a dose above this value. Analysis of NK subsets showed that this effect was mediated primarily by the CD56dim population of mature effector cells and that high-level expression of the activatory protein DNAM on donor NK cells was also strongly protective. These observations offer important insights into the mechanism of GVL and suggest that optimization studies of the number of NK cells within the stem cell graft should be considered as a means to reduce disease relapse.

National Emergency Department Overcrowding Study tool is not useful in an Australian emergency department.

OBJECTIVE: To determine the accuracy and usefulness of the National Emergency Department Overcrowding Study (NEDOCS) tool in an urban hospital ED in Australia by direct comparison with subjective assessment by senior ED staff. METHOD: A sample of simultaneous subjective and objective data pairs were collected six times a day for a period of 3 weeks. All senior medical staff in the ED answered a brief questionnaire along with the senior charge nurse for the ED. Simultaneously, the senior charge nurse also documented the total number of patients in the ED, the number of patients awaiting admission, the number of patients on ventilators, the longest time waited by an ED patient for ward bed, and the waiting time for the last patient from the Waiting Room placed on a trolley. The objective indicators were entered into a Web-based NEDOCS tool and transformed scores were compared with the averaged and transformed subjective scores for each sample time. Bland-Altmann and Kappa statistics were used to test the agreement between the objective and subjective measuring methods. RESULTS: The mean difference between the subjective and objective methods was small (3.5 [95% confidence interval -0.875-7.878] ); however, the 95% limits of agreement was wide (-46.52-53.43). The Kappa statistic used to assess the extent of reproducibility between categorical variables was 0.31 (95% confidence interval 0.17-0.45). CONCLUSION: The present study suggests that NEDOCS method of processing the objective overcrowding data does not accurately reflect the subjective assessment of the senior staff working at that time in the ED. This might be because the assumptions of the original NEDOCS study are flawed.