Azacitidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients

Abstract

Hypomethylating agents (HMA) like azacitidine are licensed for the treatment of acute myeloid leukemia (AML) patients ineligible for allogeneic hematopoietic stem cell transplantation. Biomarker-driven identification of HMA-responsive patients may facilitate the choice of treatment, especially in the challenging subgroup above 60 years of age. Since HMA possesses immunomodulatory functions that constitute part of their anti-tumor effect, we set out to analyze the bone marrow (BM) immune environment by next-generation sequencing of T cell receptor beta (TRB) repertoires in 51 AML patients treated within the RAS-AZIC trial. Patients with elevated pretreatment T cell diversity (11 out of 41 patients) and those with a boost of TRB richness on day 15 after azacitidine treatment (12 out of 46 patients) had longer event-free and overall survival. Both pretreatment and dynamic BM T cell metrics proved to be better predictors of outcome than other established risk factors. The favorable broadening of the BM T cell space appeared to be driven by antigen since these patients showed significant skewing of TRBV gene usage. Our data suggest that one course of AZA can cause reconstitution to a more physiological T cell BM niche and that the T cell space plays an underestimated prognostic role in AML.Trial registration: DRKS identifier: DRKS00004519

Oral azacitidine modulates the bone marrow microenvironment in patients with acute myeloid leukaemia in remission: A subanalysis from the QUAZAR AML‐001 trial

“…The association between MRD negativity and high BM T cells suggests that high T-cell numbers may contribute to the magnitude of the MRD response (Figure 7), consistent with T-cell reconstitution and effective eradication of leukaemic cells in the allogeneic haematological stem cell transplant setting. 32,33 In accordance with these observations, Oral-AZA appeared to augment the kinetics of T-cell recovery after IC. Nevertheless, in a small subset of patients, despite achieving or exceeding T-cell reconstitution after Oral-AZA treatment, residual AML blasts (MRD+) were still observed and were associated with poor outcomes (Figures 1, 7, and Figure S5).…”

“…Overall, 63% of patients exhibited MRD negativity after IC (Table 1). The association between MRD negativity and high BM T cells suggests that high T‐cell numbers may contribute to the magnitude of the MRD response (Figure 7), consistent with T‐cell reconstitution and effective eradication of leukaemic cells in the allogeneic haematological stem cell transplant setting 32,33 . In accordance with these observations, Oral‐AZA appeared to augment the kinetics of T‐cell recovery after IC.…”

Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities

“…For instance, increased IFN-γ-producing cells and increased T-cell cytotoxicity following decitabine treatment predicted improved therapeutic responses and survival in clinical patients [ 144 ]. In addition, AML patients with elevated pretreatment T cell diversity and those with an increased T cell receptor beta repertoire richness after azacitidine treatment had longer event-free and overall survival [ 147 ]. These data highlight the importance of TIME in dictating the effects of DNMTi on MDS/AML.…”

Curse and blessing: upregulation of oncogenes upon treatment with hypomethylating agents in myelodysplastic syndrome

“…Our group and others have previously demonstrated that HMAs possess potent immunomodulatory functions which could mediate disease control in patients treated with azacitidine. 5 …”

“…Our group and others have previously demonstrated that HMAs possess potent immunomodulatory functions which could mediate disease control in patients treated with azacitidine. 5 The study of Liu et al makes an important step towards a better understanding of the molecular mechanism underlying HMA treatment. It could also pave the way for novel therapeutic concepts tackling resistance to these drugs.…”