H ly as the immune response against leukemic cells is stronger in NPM1mut compared to NPM1wt AML patients. 2 Thus, PD-1/PD-L1 inhibition in NPM1mut AML might further boost immune responses, which are possibly responsible for the high cure rate in this AML cohort. Moreover, immune responses induced by immune checkpoint molecules may result in the activated effector T cells being able to lyse not only NPM1-positive, but also NPM1-negative subclones, independent from their PD-1/PD-L1 status, due to a broader stimulation of these T cells. Markedly, genes with immunological functions seem to play an important role in the NPM1mut AML subtype, 5 and as such could also induce immune responses against subclones without NPM1 mutation. These facts might explain why the existence of NPM1mut clones could mirror the overall immunogenicity of a genetically unstable underlying disease.

In patients relapsing after allogeneic hematopoietic stem cell transplantation, reactivating the immune response via immune checkpoint has been demonstrated to produce a response, 10 as has treatment with hypomethylating agents which have the ability to enhance the expression of PD-1/PD-L1. 11 Thus, the combination of immunotherapies holds great promise to further improve the efficacy of T cells against cancer cells. 7, 12 A high number of immunotherapies are currently under investigation as part of combination therapies, eg, in combination with vaccination strategies. As mutated NPM1 is an immunogenic neoantigen with epitopes derived from the mutational region of NPM1 inducing specific immune responses in over 75% of patients, 1 it is an interesting immunogenic target structure, and NPM1mut-derived peptides might be used in combination with immune checkpoint inhibition to prevent AML relapse. Moreover, polyvalent immune responses of CTL against NPM1mut specific and known leukemia-associated antigens in NPM1mut AML might also be further exploited to achieve negativity for NPM1mut MRD. 13 Today, due to the good prognosis of most NPM1mut AML cases, the majority of NPM1mut patients do not receive an allogeneic stem cell transplantation in first complete remission. However, Röllig and colleagues demonstrated a very favorable clinical outcome for NPM1mut patients undergoing upfront allogeneic stem cell transplantation. 14 This approach further supports the positive effects of the immune system in NPM1mut leukemia eradication. In addition, Kuželová and colleagues noted that AML patients expressing certain groups of human leukocyte antigen alleles are predisposed to develop an efficient anti-AML immune response against the cytoplasmatic located NPM1mut protein. 15 In summary, we detected higher PD-L1 expression in NPM1mut patients, especially in the leukemic progenitor/stem cell compartment of NPM1mut AML patients. This observation further supports the hypothesis that NPM1-directed immune responses might play an important role in tumor cell rejection, which tumor cells try to escape via the expression of PD-L1. Therefore, in NPM1mut AML cases the immunogenicity of neoantigens derived from the NPM1 mutation and the higher CD274 expression constitute promising target structures for individualized immunotherapeutic approaches. PD-1/PD-L1-directed immune checkpoint inhibition approaches to enhance NPM1mut specific T-cell responses might be combined with antigen-directed immunotherapies eg, peptide vaccination against immunogenic NPM1 epitopes, in order to eradicate persisting MRD following conventional chemotherapy.