Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 201, Issue 6, Pages 1129-1143Publisher
WILEY
DOI: 10.1111/bjh.18783
Keywords
acute leukaemia; AML; chemotherapy; immunophenotyping; measurable residual disease; T cells
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Oral azacitidine (Oral-AZA) maintenance therapy improves relapse-free (RFS) and overall survival (OS) for AML patients in remission after intensive chemotherapy (IC). Immune profiling reveals that increased levels of lymphocytes, monocytes, T cells, and CD34+ CD117+ BM cells are prognostic for RFS. Oral-AZA modulates T-cell activity, reverses T-cell exhaustion, and is associated with improved clinical outcomes.
Oral azacitidine (Oral-AZA) maintenance therapy improved relapse-free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML-001 study. Immune profiling was performed on the bone marrow (BM) at remission and on-treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on-treatment immune effects by Oral-AZA with clinical outcomes. Post-IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T-cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD-L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD-L2+. High co-expression of T-cell exhaustion markers PD-1 and TIM-3 was associated with inferior outcomes. Oral-AZA augmented T-cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T-cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T-cell content and expression of T-cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral-AZA modulates T-cell activity in the maintenance setting of AML, and these immune-mediated responses are associated with clinical outcomes.
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