Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantation—Immune signature correlates with response

Abstract

SummaryAcute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (allo‐HCT) is often driven by immune‐related mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graft‐versus‐leukaemia effect. Still, data about using this combination regimen after allo‐HCT are limited. We conducted a prospective, phase II, open‐label, single‐arm study in which we treated patients with haematological AML relapse after allo‐HCT with HMA plus the anti‐PD‐1 antibody nivolumab. The response was correlated with DNA‐, RNA‐ and protein‐based single‐cell technology assessments to identify biomarkers associated with therapeutic efficacy. Sixteen patients received a median number of 2 (range 1–7) nivolumab applications. The overall response rate (CR/PR) at day 42 was 25%, and another 25% of the patients achieved stable disease. The median overall survival was 15.6 months. High‐parametric cytometry documented a higher frequency of activated (ICOS+, HLA‐DR+), low senescence (KLRG1−, CD57−) CD8+ effector T cells in responders. We confirmed these findings in a preclinical model. Single‐cell transcriptomics revealed a pro‐inflammatory rewiring of the expression profile of T and myeloid cells in responders. In summary, the study indicates that the post‐allo‐HCT HMA/nivolumab combination induces anti‐AML immune responses in selected patients and could be considered as a bridging approach to a second allo‐HCT.Trial‐registration: EudraCT‐No. 2017‐002194‐18.

Single-cell genomics-based immune and disease monitoring in blood malignancies

“…Apostolova et al reported signatures of higher T cell activation and lower senescence in CD8 + T cells that distinguished responders from non-responders to combined decitabine/azacytidine and nivolumab treatment. 96 In one notable study participant, who maintained an incomplete remission (CRi) for 11 months after discontinuing nivolumab, scRNA-seq revealed signs of distinct immune activation with donor-derived monocytes which had high expression of HLA class II molecules. These observations provide evidence of nivolumab-induced immune activation as the driver for the observed reinvigorated GvL activity.…”