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Mesenchymal stromal cells (MSCs) are used as salvage therapy to treat steroid-refractory acute graft-versus-host disease (aGvHD). We studied the immunological response to MSC treatment in 16 aGvHD patients by assessing lymphocyte profiles and three proposed aGvHD serum markers during the MSC treatment. Surprisingly, there were no obvious differences in the lymphocyte profiles between the responders and non-responders. The numbers of T, B, and NK cells were below the normal reference interval in all patients. CD4+ T helper (Th) cell levels remained particularly low throughout the follow-up period. The relative proportion of Th1 cells decreased, while regulatory T cells remained unaltered, and only very few Th2 and Th17 cells could be detected. Serum concentrations of regenerating islet-derived protein 3-alpha, cytokeratin-18 fragments (CK18F), and elafin were significantly elevated in patient samples compared with healthy controls, but only CK18F showed any potential in the prediction of patients’ response to MSCs. No obvious markers for MSC therapy response were revealed in this study, but the results suggest that allogeneic MSCs do not provoke overt T cell-mediated immune responses at least in immunosuppressed aGvHD patients. The results advocate for the safety of MSC therapy and bring new insights in MSC immunomodulation mechanisms., Graphical Abstract

Background Measurable residual disease (MRD) status pre- transplantation (alloSCT) predicts transplant outcome. Nonetheless, the impact of MRD persistence (MRD+) might be modulated by the use of anti thymocyte globulin (ATG) to prevent graft versus host disease (GVHD). Since GVHD is usually associated with the graft versus leukemia effect (GVL), there is a concern that ATG may increase relapse incidence (RI) in patients (pts) with a higher risk of relapse. We therefore investigated whether MRD status pre-alloSCT could impact the outcome in AML patients receiving alloSCT with ATG in CR1. Methods Study included adult AML pts undergoing alloSCT in CR1 during 2005-2016 period. First, we assessed the impact of MRD status, cytogenetics, FLT3-ITD and ATG in the whole population. Then, we studied the impact of ATG in relation to the MRD status at time of alloSCT. Results 1509 pts (1083 MRD negative (MRD-) and 426 MRD+) were included. In the MRD- group, 552 (48%) pts did not receive ATG (MRD− /no ATG) and 561 (52%) received ATG (MRD−/ATG), whereas within MRD+ cohort, 187 (44%) received no ATG (MRD+/no ATG) and 239 (58%) received ATG (MRD+/ATG). Median age was 51 (range 18-73) years, 51% were females. Acute GVHD grade III-IV and cGVHD were significantly lower in pts who received ATG in comparison to those who did not, translating into better GVHD-free, relapse-free survival (GRFS). Non-relapse mortality (NRM), RI, LFS and OS did not differ statistically. Focusing on the influence of MRD status, the overall RI was higher in MRD+ patients prior to alloSCT (38.7% vs. 22.8%, p Conclusions ATG reduces acute and cGVHD incidence and severity in AML pts undergoing alloSCT in CR1, resulting in improved GRFS. AML relapse risk remained unmodified by ATG use, even in the high risk subset of MRD+ patients' pre-alloSCT. Therefore, the use of ATG is not detrimental, and can allow for a significant clinical benefit in all CR1 AML patients who are candidate for alloSCT.

Introduction Baseline karyotype at diagnosis remains the pivotal determinant of outcome in patients with acute myeloid leukemia (AML). The Medical Research Council (MRC) prognostic model is currently the benchmark for risk assessment in this patient population. However, the prognostic role of the complete spectrum of chromosomal abnormalities in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) is currently unknown. Furthermore, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Methods Using the Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation multicenter database a retrospective analysis was performed to assess the clinical outcomes of AML patients undergoing allo-SCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-SCT in first remission from either a matched sibling or a matched unrelated donor in 2006-2016. Results Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Del (9q), trisomy 14, and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Conclusion Our analysis endorses the prognostic significance of the MRC predictive model in patients undergoing allo-SCT in CR1 with some specific modifications. Furthermore, consideration of FLT3-ITD and karyotypic complexity improved the projective capacity of the MRC model in transplanted patients.

Background Acute myeloid leukemia (AML) secondary to another haematological neoplasia or malignant disease (sAML) is thought to have an inferior prognosis than de novo AML. However, the role of this difference for allogeneic stem cell transplantation (SCT) is unclear. A registry-based analysis was performed to compare results after SCT for sAML versus AML. Methods Inclusion criteria were age ≥18y and SCT for de novo or sAML from a matched related, unrelated or T-cell replete haploidentical donor between 2000 and 2016. A multivariate Cox model was performed for risk factors for outcome. It was stratified for different stages at SCT. Further, a matched pair analysis of de novo versus sAML was done, using age (+/-3 years), stage at SCT, Karnofsky performance score (KPS), conditioning, in vivo/ex vivo T cell depletion, donor, donor/recipient sex and CMV-status combination, cytogenetics, and graft source as matching criteria. Results 11439 patients (pts) with de novo and 1325 with sAML were identified. Median follow-up was 36 and 33 months. After SCT in first complete remission (CR1), 3Y cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 28.5%/16.4% for de novo (n=7691), and 35%/23.4% for sAML (n=909). 3Y overall survival (OS), leukemia-free survival (LFS) and GvHD/relapse free survival (GRFS) were 60.8%, 55.1% and 38.6% for de novo and 46.7%, 41.6% and 28.4% for sAML. In a multivariate Cox model focusing on SCT in CR1, sAML was associated with higher NRM (HR=1.32; p 80, p=0.003) and donor (UD 10/10 match, p=0.007; UD 9/10 match, p=10-5; haplo, p=0.002). When focusing on pts transplanted for primary refractory (de novo, n=607, sAML, n=199) or relapsed AML (de novo, n=1009, sAML, n=124), results were generally inferior. However, Cox models did not identify sAML as a relevant factor. Instead, outcome was determined by age, cytogenetics and KPS. The matched pair analysis was performed on 877 pairs and confirmed the above findings: Over all, sAML was associated with higher NRM (p=0.004), and lower LFS (p=0.004), OS (p=0.008) and GRFS (p=0.04). However, when the analysis was stratified by stage at SCT, again differences were only seen among pts transplanted in CR1, but not after SCT in advanced disease. Conclusion Our large-scale, registry-based analysis identified sAML as independent risk factor for outcome after SCT in first CR1. In primary refractory and relapsed AML, other factors such as age, cytogenetics and performance status were of higher relevance. This data may help to improve risk stratification and prognostic estimates after SCT for sAML.