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

Petya ApostolovaStefanie KreutmairCristina ToffaloriMarco PuntaSusanne UngerAnn-Cathrin BurkClaudia WehrKristina Maas-BauerWolfgang MelchingerEileen HaringRouven HoefflinKhalid ShoumariyehValerie HupferEliza Maria LauerSandra DuquesneTheresa LowinusNicolás Gonzalo NúñezChiara AlbertiSara da Costa PereiraCarla Helena MertenLaura PowerMatthias WeissCaroline BökeDietmar PfeiferReinhard MarksHartmut BertzRalph WäschGabriele IhorstBernhard GentnerJustus DuysterMelanie BoerriesGeoffroy AndrieuxJuergen FinkeBurkhard BecherLuca VagoRobert Zeiser
Published in: British journal of haematology (2023)
Acute 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.
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