Global overview of post-HCT IR, pre- and post-HCT factors affecting IR and proposed strategies to optimize IR assessment. Pre-HCT factors affecting IR: IR kinetics are influenced by several modifiable and nonmodifiable factors, including the intensity and type of conditioning regimens; cell dose; graft composition; cell source (BM, PBSC, CB); degree and loci of HLA disparity; graft manipulation (eg, ex vivo or in vivo TCD); donor/recipient pairing; donor/recipient age; preparative regimens and drugs/serotherapy used for GVHD prophylaxis (including interindividual variability of pharmacogenomics, pharmacokinetics, and pharmacodynamics). Expanding tailored approaches beyond model-based dosing of ATG4-8 to other key variables, such as conditioning intensity, graft composition, and immune suppression strategies, could further optimize IR and improve transplant outcomes.4-8 Post-HCT factors affecting IR: after transplantation, several factors affect IR. Drugs used for GVHD prophylaxis or therapy, GVHD incidence, infections and viral reactivations can each negatively affect IR. Potential strategies to promote post-HCT IR may include adoptive cell therapies and immunotherapy or regenerative approaches. Immune cell compartments and reconstitution: initially, innate immune cells (blue) recover, followed by cells of the adaptive immune system (green). Posttransplant lymphocyte IR is posited to occur in 2 phases9,10: the earliest is a thymus-independent peripheral expansion (pink) of infused graft lymphocytes responding to host homeostatic cytokines.11 This is followed by a delayed, thymus-dependent, “regenerative” phase (orange) occurring months to years after HCT, wherein marrow-derived lymphocyte precursors mature to naïve T cells in the thymus. Thymopoiesis gives rise to a polyclonal TCR repertoire that confers full tolerance to host antigens. Strategies for harmonization, integration, analysis, and expected outcomes: development of shared standard operating procedures, flow cytometric antibody panels, and harmonization of timing of analysis, allows data comparison from different centers, integration in large databases, and potential applications of innovative machine learning/artificial intelligence tools. Together this effort will allow to establish functional thresholds for IR for stratification of patients and clinical management. AI, artificial intelligence; cAUC, cumulative area under the curve; CB, cord blood; CIBMTR, Center for International Blood and Marrow Transplant Research, EBMT, European Society for Blood and Marrow Transplantation; ML, machine learning; PBSC, peripheral blood stem cell; TBI, total body irradiation.
