Graft-versus-host disease prophylaxis: Pathophysiology-based review on current approaches and future directions.

Graft-versus-host disease (GvHD) was first described in 1959, since then major efforts have been made in order to understand its physiopathology and animal models have played a key role. Three steps, involving different pathways, have been recognised in either acute and chronic GvHD, identifying them as two distinct entities. In order to reduce GvHD incidence and severity, prophylactic measures were added to transplant protocols. The combination of a calcineurin inhibitor (CNI) plus an antimetabolite remains the standard of care. Better knowledge of GvHD pathophysiology has moved this field forward and nowadays different drugs are being used on a daily basis. Improving GvHD prophylaxis is a major goal as it would translate into less non-relapse mortality and better overall survival. As compared to CNI plus methotrexate the combination of CNI plus mycophenolate mophetil (MMF) allows us to obtain similar results in terms of GvHD incidence but a lower toxicity rate in terms of neutropenia or mucositis. The use of ATG has been related to a lower risk of acute and chronic GvHD in prospective randomized trials as well as the use of posttransplant Cyclophosphamide, with no or marginal impact on overall survival but with an improvement in GvHD-relapse free survival (GRFS). The use of sirolimus has been related to a lower risk of acute GvHD and significantly influenced overall survival in one prospective randomized trial. Other prospective trials have evaluated the use of receptors such as CCR5 or α4β7 to avoid T-cells trafficking into GvHD target organs, cytokine blockers or immune check point agonists. Also, epigenetic modifiers have shown promising results in phase II trials. Attention should be paid to graft-versus-leukemia, infections and immune recovery before bringing new prophylactic strategies to clinical practice. Although the list of novel agents for GvHD prophylaxis is growing, randomized trials are still lacking for many of them.