ena-STUDY-MARTIN-LUTHER-UNIVERSITY HALLE-WITTENBERG, INSTITU-11-10-2021-07:06:29:172-146
Azacytidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients
Demethylating agents like azacytidine have been licensed for the treatment of patients with acute myeloid leukemia (AML) unlikely to benefit from chemotherapy because of disease- or patient-related factors. Biomarker-driven identification of azacytidine-responsive patients may facilitate the choice of treatment, especially in the challenging patient population between 60 and 70 years of age and borderline performance status. Since demethylating agents possess immunomodulatory functions that may constitute part of their anti-tumor effect, we set out to analyze the bone marrow immune environment by next-generation sequencing of T cell receptor repertoires in a patient population treated with a sequential azacytidine – chemotherapy protocol in the multicenter RAS-AZIC trial. We found that patients with elevated pre-treatment T cell diversity and those that showed a boost of T cell richness on day 15 after azacytidine treatment initiation had longer event-free and overall survival. Both pre-treatment and dynamic bone marrow T cell metrics proved to be better predictors of outcome than reduction of blasts or other established markers. The prognostically favorable broadening of the bone marrow T cell space appeared to be driven by antigen since patients with the boost in richness showed a significant skewing of TRBV gene usage with TRBV12-3, TRBV6-9, and TRBV5-7 overrepresented after azacytidine challenge. Taken together, our data suggest that only one course of azacytidine can cause reconstitution to a more physiological T cell bone marrow niche and that the bone marrow T cell space plays a so far underestimated prognostic role in AML.
Demethylating agents like azacytidine have been licensed for the treatment of patients with acute myeloid leukemia (AML) unlikely to benefit from chemotherapy because of disease- or patient-related factors. Biomarker-driven identification of azacytidine-responsive patients may facilitate the choice of treatment, especially in the challenging patient population between 60 and 70 years of age and borderline performance status. Since demethylating agents possess immunomodulatory functions that may constitute part of their anti-tumor effect, we set out to analyze the bone marrow immune environment by next-generation sequencing of T cell receptor repertoires in a patient population treated with a sequential azacytidine – chemotherapy protocol in the multicenter RAS-AZIC trial. We found that patients with elevated pre-treatment T cell diversity and those that showed a boost of T cell richness on day 15 after azacytidine treatment initiation had longer event-free and overall survival. Both pre-treatment and dynamic bone marrow T cell metrics proved to be better predictors of outcome than reduction of blasts or other established markers. The prognostically favorable broadening of the bone marrow T cell space appeared to be driven by antigen since patients with the boost in richness showed a significant skewing of TRBV gene usage with TRBV12-3, TRBV6-9, and TRBV5-7 overrepresented after azacytidine challenge. Taken together, our data suggest that only one course of azacytidine can cause reconstitution to a more physiological T cell bone marrow niche and that the bone marrow T cell space plays a so far underestimated prognostic role in AML.