Therapeutic interventions to counteract genomic loss of the mismatched HLA haplotype after allo-HCT. Schematic representation of the genomic HLA loss relapse modality and of available therapeutic strategies to restore donor T-cell recognition of leukemia. Genomic loss of one HLA haplotype by CN-LOH under allo-immune pressure leads to leukemia immune evasion from donor T cells (in red) and subsequently to relapse (leukemia at diagnosis in gray, relapse in violet). To counteract HLA loss relapse, one of the therapies available is a second allo-HCT using an alternative, partially HLA-incompatible donor. A different haploidentical donor is, in fact, expected to have T cells (in blue) alloreactive against the haplotype conserved and duplicated by the relapsed leukemic blasts. Other potential approaches that are gaining increased attention include non-HLA restricted immunotherapies, including NK cells or CD1c-restricted lymphocytes, and redirection of T cells from the stem cell donor through bispecific antibodies or transgenic receptors.