Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

The positive effects of physical and sports therapy for strain dependent physical practice and improved quality of life (QoL) are well known. Nevertheless, the available capacities and problem-oriented therapies in the setting of hematopoietic stem cell transplantation (HSCT) are limited. We conducted a prospective, randomized study among 42 HSCT recipients in order to investigate the influence of exergaming on Nintendo Wii or classical physiotherapy (PT) on physical fitness and psychological well-being. The trial included evaluation of muscle strength, endurance, physical activity, distress, QoL, anxiety, and depression. Within the first 2 weeks after HSCT endurance, muscle strength and physical well-being decreased, while the value of distress increased significantly in both groups. However, exergaming on Nintendo Wii resulted in a decrease of anxiety and depression and improved emotional well-being, while the PT group showed a contrariwise pattern of these features. Analysis of the FACT-BMT revealed a decline of QoL domains 2 and 4 weeks after HSCT and an improvement afterwards. The decrease of functional status after HSCT was accompanied by a drop of QoL and an increase of distress in both groups. However, our prospective study demonstrates that exergaming using the Nintendo Wii is feasible and well tolerated in HSCT recipients.

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