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Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL.272 consecutive allotransplanted AL or MDS patients in complete remission and off immunosuppression at day +120 were stratified according to the prior appearance of relevant GvHD (acute GvHD °II-IV or extensive chronic GvHD) as a clinical indicator for GvL. Escalating doses of unmodified proDLI were applied to 72/272 patients without prior relevant GvHD. Conversely, 157/272 patients with prior spontaneous GvHD did not receive proDLI, nor did 43/272 patients with contraindications (uncontrolled infections, patient refusal, DLI unavailability).By day 160-landmark analysis (median day of first DLI application), proDLI recipients had significantly higher five-year overall (OS) and disease free survival (DFS) (77% and 67%) than patients with spontaneous GvHD (54% and 53%) or with contraindications (46% and 45%) (p=0.003). Relapse incidence for patients with proDLI (30%) or spontaneous GvHD (29%) was significantly lower than in patients with contraindications (39%; p=0.021). With similar GvHD incidence beyond day +160, non-relapse mortality (NRM) was less with proDLI (5%) than without proDLI (18%; p=0.036).In conclusion, proDLI may be able to compensate for lack of GvL in alloSCT recipients with high risk AL or MDS., (© 2023. The Author(s).)

Identification of immune phenotypes linked to durable graft-versus-leukemia (GVL) response following donor lymphocyte infusions (DLI) is of high clinical relevance. In this prospective observational study of 13 AML relapse patients receiving therapeutic DLI, we longitudinally investigated changes in differentiation stages and exhaustion markers of T cell subsets using cluster analysis of 30-color spectral flow cytometry during 24 months follow-up. DLI cell products and patient samples after DLI were analyzed and correlated to the clinical outcome. Analysis of DLI cell products revealed heterogeneity in the proportions of naïve and antigen experienced T cells. Cell products containing lower levels of effector memory (eff/m) cells and higher amounts of naïve CD4 + and CD8 + T cells were associated with long-term remission. Furthermore, investigation of patient blood samples early after DLI showed that patients relapsing during the study period, had higher levels of CD4 + eff/m T cells and expressed a mosaic of surface molecules implying an exhausted functional state. Of note, this observation preceded the clinical diagnosis of relapse by five months. On the other hand, patients with continuous remission retained lower levels of exhausted CD4 + eff/m T cells more than four months post DLI. Moreover, lower frequencies of exhausted CD8 + eff/m T cells as well as higher amounts of CD4 + temra CD45RO + T cells were present in this group. These results imply the formation of functional long-term memory pool of T cells. Finally, unbiased sample analysis showed that DLI cell products with low levels of eff/m cells both in CD4 + and CD8 + T cell subpopulations associate with a lower relapse incidence. Additionally, competing risk analysis of patient samples taken early after DLI revealed that patients with high amounts of exhausted CD4 + eff/m T cells in their blood exhibited significantly higher rates of relapse. In conclusion, differentially activated T cell clusters, both in the DLI product and in patients post infusion, were associated with AML relapse after DLI. Our study suggests that differences in DLI cell product composition might influence GVL. In-depth monitoring of T cell dynamics post DLI might increase safety and efficacy of this immunotherapy, while further studies are needed to assess the functionality of T cells found in the DLI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Odak, Sikora, Riemann, Bayir, Beck, Drenker, Xiao, Schneider, Dammann, Stadler, Eder, Ganser, Förster, Koenecke and Schultze-Florey.)

Atrial fibrillation (AF) is the most common arrhythmia in adults but its impact on allogeneic stem cell transplantation (SCT) is not well characterized. We studied AF manifestation during the hospital stay for allogeneic SCT, referred to as AF in hospital (AFiH), and analyzed the incidence of, risk factors for, and clinical impact of AFiH on intensive care unit (ICU)-/hospital-/ and overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS). This retrospective matched cohort study comprised 553 consecutive SCT recipients at Hannover Medical School between January 2013 and October 2019. Patients with AFiH were compared with a non-AFiH control cohort matched for Hematopoietic Stem Cell-Specific Comorbidity Index (HCT-CI), European Group for Blood and Marrow Transplantation (EBMT) risk score, disease, conditioning regimen and availability of molecular genetic data for patients with myeloid diseases. AFiH occurred in 46 patients (8%) at a median of 2 days (interquartile range, 0 to 8 days) after SCT. Patient history of AF and elevated NT-proBNP and high-sensitivity troponin T levels, but not conventional echocardiographic parameters, were predictive for AFiH. AFiH occurred more often in patients with mutations in DNMT3A, TET2, and ASXL1 genes related to clonal hematopoiesis compared with patients with wild-type alleles, with the greatest impact from DMT3A mutations. ICU admission was significantly higher in the AFiH cohort (46% versus 7%), without significant differences in ICU or post-ICU hospital survival (62% versus 40% and 52% versus 40%, respectively). The main cause of death was sepsis. In terms of long-term outcomes, the incidences of relapse and grade II-IV acute GVHD did not differ significantly between the AFiH and the non-AFiH groups; however, OS was significantly shorter in the AFiH group (1 year OS, 39% versus 65%), owing to late noncardiac NRM (1 year NRM, 49% versus 27%). Although the underlying cellular and molecular mechanisms remain to be characterized in further detail, these data clearly demonstrate the impact of inpatient AF manifestation/AFiH on long-term outcomes of SCT recipients., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34(+) cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission.

Background: Delayed donor red blood cell chimerism (DRCC), pure red blood cell aplasia (PRCA), and autoimmune hemolytic anemia (AIHA) are poorly documented complications after hematopoietic cell transplantation (HCT). The clinical variable "prolonged isolated red blood cell transfusion requirement" (PRTR) was evaluated as a trigger for an extended diagnostic workup., Study Design and Methods: PRTR was defined as the need for red blood cell (RBC) transfusions beyond Day 60 after HCT. We analyzed 487 patients transplanted between 2000 and 2006. Median age was 37 years (range, 0-70 years). Peripheral blood stem cells (n = 344), marrow (n = 138), and cord blood (n = 5) from 278 unrelated and 209 family donors were used., Results: Univariate analysis identified age (incidence of 18.3% among elderly patients, 10.5% in adults, and 2.0% among children [p = 0.002]), ABO incompatibility (16.4% after major incompatible, 2.9% after minor incompatible, and 9.4% after ABO-compatible transplantations [p = 0.003]), conditioning (15.2% after reduced-intensity regimens vs. 7.3% after myeloablative conditioning; p = 0.006), donor type (13.2% after HLA-matched unrelated, 13.6% after mismatched unrelated, 5.7% after matched related, and 0.0% after mismatched related grafts; p = 0.026), and acute graft-versus-host disease (aGVHD; 7.1% with aGVHD vs. 12.5% without aGVHD; p = 0.046) as predisposing factors. In multivariate analysis minor ABO incompatibility (odds ratio [OR] = 0.2, p = 0.01), younger age (OR = 0.1, p = 0.02), and matched related HCT (OR = 0.4, p = 0.02) remained independent protective factors., Conclusions: PRTR could serve as a trigger for a standardized screening for DRCC, PRCA, and AIHA after HCT.