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

• DOI: 10.1111/bjh.19007
• Publication Date: 2023-08-04T08:25:51Z
• Authors: Petya Apostolova; Stefanie Kreutmair; Cristina Toffalori; Marco Punta; Susanne Unger; Ann‐Cathrin Burk; Claudia Wehr; Kristina Maas‐Bauer; Wolfgang Melchinger; Eileen Haring; Rouven Hoefflin; Khalid Shoumariyeh; Valerie Hupfer; Eliza Maria Lauer; Sandra Duquesne; Theresa Lowinus; Nicolás Gonzalo N...; Chiara Alberti; Sara da Costa Per...; Carla Helena Merten; Laura Power; Matthias Weiss; Caroline Böke; Dietmar Pfeifer; Reinhard Marks; Hartmut Bertz; Ralph Wäsch; Gabriele Ihorst; Bernhard Gentner; Justus Duyster; Melanie Boerries; Geoffroy Andrieux; Juergen Finke; Burkhard Becher; Luca Vago; Robert Zeiser
• Keywords: AML; HCT; acute myeloid leukaemia; allogeneic haematopoietic cell transplantation; hypomethylating agent; immune checkpoint inhibition; immune phenotype; relapse; single-cell RNA-sequencing; single-cell immunomonitoring; 2720 Hematology; https://purl.org/becyt/ford/3.1; HMA; 610; 570 Life sciences; biology; 610 Medicine & health; Hematology; https://purl.org/becyt/ford/3; 10263 Institute of Experimental Immunology; 3. Good health

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.