Allogeneic hematopoietic cell transplantation (allo-HCT) is often the only curative treatment for patients with hematological malignancies. After conditioning, alloreactive donor T cells recognize and reject the residual malignant cells in affected patients. This powerful polyclonal response is called graft-versus-leukemia (GvL) and is critical to prevent relapses after allo-HCT. GvL occurs in primary and secondary lymphoid tissues, where hematologic malignant cells usually reside. However, graft-versus-host disease (GvHD) can be triggered by the same alloreactive donor T cells that migrate to peripheral organs, such as gastrointestinal tract, liver, and skin, where they cause clinically significant tissue damage, which is a major limiting factor for the successful outcome of allo-HCT.[1] Both, CD4+ and CD8+ T cells contribute to GvHD and GvL. The early phase of acute GvHD is predominantly mediated by CD4+ T helper 1 (Th1) and cytotoxic CD8+ T cells.[2] Blocking Th1 and Th17 differentiation by targeting the transcription factors T-Bet and ROR-γt has been shown to ameliorate GvHD while not suppressing GvL, suggesting Th1 and Th17 cells as main GvHD contributors.[3] Furthermore, Th17 cells are involved in the development of chronic GvHD.[4] The role of Th2 cells in GvHD pathophysiology is more controversial, as they exhibit a protective role when adoptively transferred, but can also be involved in acute GvHD development at later stages.[[5], [6], [7], [8]] Depletion of CD4+ or CD8+ T cells from the graft resulted in reduced GvHD but increased relapses.[9] The importance of both T cell subsets for GvL is further highlighted by data showing direct cell killing effects on tumor cells via Fas-mediated and perforin-mediated cytotoxicity by CD4 and CD8 T cells, respectively.[10] Moreover, cytokines secreted by CD4+ T cells can recruit additional cytotoxic and inflammatory immune cells, which additionally contribute to tumor killing. The sphingosine-1-phosphate receptor (S1PR) signaling plays a crucial role in lymphocyte trafficking, and pre-clinical and clinical data have shown that pharmacological modulation of S1PR redistributes lymphocytes resulting in reduced numbers of peripheral lymphocytes.[11] Pre-clinical evidence shows that inhibition of alloreactive T cell trafficking via S1PR modulation successfully prevents severe acute GvHD. At the same time, GvL is maintained as T cell function is not impaired by S1PR modulation.[[12], [13], [14], [15]] Mocravimod is a S1PR modulator and its administration blocks lymphocyte egress from lymphoid organs, thus resulting in reduced peripheral absolute lymphocyte counts and decreased donor T-cell infiltration in GvHD target organs.[[15], [16], [17], [18]]

We therefore hypothesized that higher T cell counts will be detected in the bone marrow (BM) from mocravimod-treated subjects compared to non-mocravimod treated patients.