TY - JOUR A1 - Eckardt, Jan-Niklas A1 - Stasik, Sebastian A1 - Kramer, Michael A1 - Röllig, Christoph A1 - Krämer, Alwin A1 - Scholl, Sebastian A1 - Hochhaus, Andreas A1 - Crysandt, Martina A1 - Brümmendorf, Tim H. A1 - Naumann, Ralph A1 - Steffen, Björn A1 - Kunzmann, Volker A1 - Einsele, Hermann A1 - Schaich, Markus A1 - Burchert, Andreas A1 - Neubauer, Andreas A1 - Schäfer-Eckart, Kerstin A1 - Schliemann, Christoph A1 - Krause, Stefan W. A1 - Herbst, Regina A1 - Hänel, Mathias A1 - Frickhofen, Norbert A1 - Noppeney, Richard A1 - Kaiser, Ulrich A1 - Baldus, Claudia D. A1 - Kaufmann, Martin A1 - Rácil, Zdenek A1 - Platzbecker, Uwe A1 - Berdel, Wolfgang E. A1 - Mayer, Jiří A1 - Serve, Hubert A1 - Müller-Tidow, Carsten A1 - Ehninger, Gerhard A1 - Stölzel, Friedrich A1 - Kroschinsky, Frank A1 - Schetelig, Johannes A1 - Bornhäuser, Martin A1 - Thiede, Christian A1 - Middeke, Jan Moritz T1 - Loss-of-function mutations of BCOR are an independent marker of adverse outcomes in intensively treated patients with acute myeloid leukemia JF - Cancers N2 - Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation. KW - acute myeloid leukemia KW - BCOR KW - BCORL1 KW - loss-of-function KW - risk stratification KW - survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236735 SN - 2072-6694 VL - 13 IS - 9 ER - TY - JOUR A1 - Danhof, Sophia A1 - Rasche, Leo A1 - Mottok, Anja A1 - Steinmüller, Tabea A1 - Zhou, Xiang A1 - Schreder, Martin A1 - Kilian, Teresa A1 - Strifler, Susanne A1 - Rosenwald, Andreas A1 - Hudecek, Michael A1 - Einsele, Hermann A1 - Gerhard-Hartmann, Elena T1 - Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns JF - Annals of Hematology N2 - Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells. KW - plasma cells KW - extramedullary disease KW - monoclonal antibody KW - CD319 KW - CS1 KW - antigen loss Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266468 SN - 1432-0584 VL - 100 IS - 6 ER - TY - JOUR A1 - Garitano-Trojaola, Andoni A1 - Sancho, Ana A1 - Götz, Ralph A1 - Eiring, Patrick A1 - Walz, Susanne A1 - Jetani, Hardikkumar A1 - Gil-Pulido, Jesus A1 - Da Via, Matteo Claudio A1 - Teufel, Eva A1 - Rhodes, Nadine A1 - Haertle, Larissa A1 - Arellano-Viera, Estibaliz A1 - Tibes, Raoul A1 - Rosenwald, Andreas A1 - Rasche, Leo A1 - Hudecek, Michael A1 - Sauer, Markus A1 - Groll, Jürgen A1 - Einsele, Hermann A1 - Kraus, Sabrina A1 - Kortüm, Martin K. T1 - Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia JF - Communications Biology N2 - The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML. KW - actin KW - acute myeloid leukaemia Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260709 VL - 4 IS - 1 ER - TY - JOUR A1 - Bäuerlein, Carina A. A1 - Qureischi, Musga A1 - Mokhtari, Zeinab A1 - Tabares, Paula A1 - Brede, Christian A1 - Jordán Garrote, Ana-Laura A1 - Riedel, Simone S. A1 - Chopra, Martin A1 - Reu, Simone A1 - Mottok, Anja A1 - Arellano-Viera, Estibaliz A1 - Graf, Carolin A1 - Kurzwart, Miriam A1 - Schmiedgen, Katharina A1 - Einsele, Hermann A1 - Wölfl, Matthias A1 - Schlegel, Paul-Gerhardt A1 - Beilhack, Andreas T1 - A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease JF - Frontiers in Immunology N2 - Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT. KW - acute graft-versus-host disease KW - alloreactive T cells KW - transplantation KW - prediction KW - mouse models Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224290 SN - 1664-3224 VL - 11 ER -