Harnessing the power of alloreactivity without triggering graft-versus-host disease: how non-engrafting alloreactive cellular therapy might change the landscape of acute myeloid leukemia treatment

Human leukocyte antigen-mismatched leukocyte infusions outside of the context of transplantation are a promising strategy for acute myeloid leukemia. Recent studies using such non-engrafting alloreactive cellular therapy (NEACT) revealed that survival of elderly patients increased from 10% to 39% when NEACT was given following chemotherapy, and that durable complete remissions were achieved in about a third of patients with relapsed or chemorefractory disease. We review the clinical reports of different NEACT approaches to date and describe how although T-cell and NK alloreactivity could generate immediate anti-leukemic effects, long-term disease control may be achieved by stimulating recipient-derived T-cell responses against tumor-associated antigens. Other variables likely impacting NEACT such as the release of pro-inflammatory cytokines from donor-host bidirectional alloreactivity and the choice of chemotherapeutics as well as future avenues for improving NEACT, such as optimizing the cell dose and potential synergies with adjuvant pharmacologic immune checkpoint blockade, are discussed.