Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells

Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival below 20%. We observed that sorafenib increased IL-15 production by FLT3-ITD+-leukemia cells, which synergized with the allogeneic CD8+T-cell response, leading to long-term survival in murine and humanized FLT3-ITD+AML models. Using IL-15 deficiency in recipient tissues or leukemia cells, IL-15 production upon sorafenib-treatment could be attributed to leukemia cells. Sorafenib treatment-related IL-15 production caused an increase in CD8+CD107a+IFN-+ T-cells with features of longevity (Bcl-2high/reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced ATF4 expression, thereby blocking negative regulation of IRF7-activation, which enhances IL-15 transcription. Consistent with the mouse data, IL-15 and pIRF7 levels increased in leukemic blasts of FLT3-ITD+AML patients upon sorafenib treatment. Analysis of 130 patients with FLT3-ITD-mutant AML relapsing after allo-HCT showed the highest complete remission-rate and median overall-survival-rate in the sorafenib/donor lymphocyte infusion (DLI) group compared to all other groups (chemotherapy, chemotherapy/DLI, sorafenib alone). Our findings indicate that the synergism of DLI and sorafenib is mediated via reduced ATF4 expression, causing activation of the pIRF7/IL-15-axis in leukemia cells. The sorafenib/DLI strategy therefore has the potential for an immune-mediated cure of FLT3-ITD-mutant AML- relapse, an otherwise fatal complication after allo-HCT.

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Mathew NR, Baumgartner F, Braun L, O'Sullivan D, Thomas S, Waterhouse M, Müller TA, Hanke K, Taromi S, Apostolova P, Illert AL, Melchinger W, Duquesne S, Schmitt-Graeff A, Osswald L, Yan KL, Weber A, Tugues S, Spath S, Pfeifer D, Follo M, Claus R, Lübbert M, Rummelt C, Bertz H, Wäsch R, Haag J, Schmidts A, Schultheiss M, Bettinger D, Thimme R, Ullrich E, Tanriver Y, Vuong GL, Arnold R, Hemmati P, Wolf D, Ditschkowski M, Jilg C, Wilhelm K, Leiber C, Gerull S, Halter J, Lengerke C, Pabst T, Schroeder T, Kobbe G, Rösler W, Doostkam S, Meckel S, Stabla K, Metzelder SK, Halbach S, Brummer T, Hu Z, Dengjel J, Hackanson B, Schmid C, Holtick U, Scheid C, Spyridonidis A, Stölzel F, Ordemann R, Müller LP, Sicre-de-Fontbrune F, Ihorst G, Kuball J, Ehlert JE, Feger D, Wagner EM, Cahn JY, Schnell J, Kuchenbauer F, Bunjes D, Chakraverty R, Richardson S, Gill S, Kröger N, Ayuk F, Vago L, Ciceri F, Müller AM, Kondo T, Teshima T, Klaeger S, Kuster B, Kim DDH, Weisdorf D, van der Velden W, Dörfel D, Bethge W, Hilgendorf I, Hochhaus A, Andrieux G, Börries M, Busch H, Magenau J, Reddy P, Labopin M, Antin JH, Henden AS, Hill GR, Kennedy GA, Bar M, Sarma A, McLornan D, Mufti G, Oran B, Rezvani K, Shah O, Negrin RS, Nagler A, Prinz M, Burchert A, Neubauer A, Beelen D, Mackensen A, von Bubnoff N, Herr W, Becher B, Socié G, Caligiuri MA, Ruggiero E, Bonini C, Häcker G, Duyster J, Finke J, Pearce E, Blazar BR, Zeiser R