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

Author:

Apostolova Petya12ORCID,Kreutmair Stefanie23,Toffalori Cristina4,Punta Marco45,Unger Susanne3,Burk Ann‐Cathrin12,Wehr Claudia1,Maas‐Bauer Kristina1,Melchinger Wolfgang1,Haring Eileen12,Hoefflin Rouven1,Shoumariyeh Khalid12ORCID,Hupfer Valerie1,Lauer Eliza Maria1,Duquesne Sandra1,Lowinus Theresa1,Gonzalo Núñez Nicolás3,Alberti Chiara3,da Costa Pereira Sara3,Merten Carla Helena3,Power Laura3,Weiss Matthias1,Böke Caroline1,Pfeifer Dietmar1,Marks Reinhard1,Bertz Hartmut1,Wäsch Ralph1,Ihorst Gabriele6,Gentner Bernhard78,Duyster Justus1,Boerries Melanie29,Andrieux Geoffroy9,Finke Juergen1,Becher Burkhard3,Vago Luca41011,Zeiser Robert1212ORCID

Affiliation:

1. Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

2. German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ) Heidelberg Germany

3. Institute of Experimental Immunology University of Zurich Zurich Switzerland

4. Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease IRCCS San Raffaele Scientific Institute Milan Italy

5. Center for OMICS Sciences IRCCS San Raffaele Scientific Institute Milan Italy

6. Clinical Trials Unit, Medical Center—University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

7. Translational Stem Cell and Leukemia Unit, San Raffaele Telethon Institute for Gene Therapy IRCCS San Raffaele Scientific Institute Milan Italy

8. Ludwig Institute for Cancer Research and Department of Oncology University of Lausanne (UNIL) and Lausanne University Hospital (CHUV) Lausanne Switzerland

9. Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

10. Hematology and Bone Marrow Transplantation Unit IRCCS San Raffaele Scientific Institute Milan Italy

11. Vita‐Salute San Raffaele University Milan Italy

12. Signalling Research Centres BIOSS and CIBSS—Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany

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.

Funder

Associazione Italiana per la Ricerca sul Cancro

Fondazione Cariplo

Deutsche Forschungsgemeinschaft

Deutsche Krebshilfe

European Regional Development Fund

H2020 European Research Council

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Publisher

Wiley

Subject

Hematology

Reference65 articles.

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5. Genomic loss of patient-specific HLA in acute myeloid leukemia relapse after well-matched unrelated donor HSCT

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