A vision for the future of allogeneic hematopoietic stem cell transplantation in the next decade

The whole field of hematological malignancies has experienced a huge breakthrough during the past 40 years.Major methodological progress in cytogenetics(e.g.,fluorescence in situ hybridization,FISH),immunophenotyping(e.g.,multicolor flow cytometers),and molecular biology(with the discovery of numerous tumor molecular markers by polymerase chain reaction and,more recently,next-generation sequencing)has paved the way for the new concept of detecting and monitoring undetectable minimal residual disease(uMRD)and the engineering of multiple new targeted therapies,such as tyrosine kinase inhibitors and various immunotherapies,including monoclonal antibodies combined or not with antitumor agents,bispecific T-cell-engaging(BiTE)antibodies and chimeric antigen receptor T(CAR-T)cells(Supplementary Text 1 online).

How antithymocyte globulin,a polyclonal soup of the past century,when carefully dosed,has become crucial for hematopoietic stem cell transplantation with haplo-identical donors in the 21st century

Hematopoeitic stem cell transplantation(HSCT)using a haploidentical family donor(HAPLO)was long thought to be non-feasible,essentially because of HLA incompatibility leading to graft rejection,severe acute(aGVH)and chronic(cGVH)graft versus host disease(GVH),severe infections and unacceptable nonrelapse mortality(NRM).The group in Perugia in the last decade of the past century[1],was the first to be successful by initiating a positive selection of CD34+cells from peripheral blood stem cell(PBSC)collections,providing T cell depleted grafts with very high doses of CD34+cells to be infused.When combined with intensive conditioning regimen and profound immunosuppression,the Perugia group obtained the first demonstration of feasibility and efficacy.They later improved their results in acute myeloid leukemia(AML)by showing that a mismatch for natural killer(NK)cells in the killer-cell immunoglobulin-like receptor(KIR)-human leukocyte-antigen class I(HLA1)donor to recipient direction[2]decreased considerably the relapse incidence(RI).Unfortunately this approach was associated with severe infections,a high NRM and in addition was cumbersome and difficult to reproduce in other non-expert centers.