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Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2–2.5 mg/kg, N  = 44) or placebo ( N  = 47; N  = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66–4.32, P  = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group ( P  = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.

Background Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods We analyzed long-term outcomes in a cohort of 1423 AML patients, age ≥50 years, after SCT from HLA-matched siblings, during the years 1997–2005, median follow-up 8.3 years (0.1–17). Results The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27–35) and 32 % (28–35) after MAC and RIC, respectively ( P  = 0.57). The 10-year GVHD/ relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18–25) and 21 % (18–24), respectively ( P  = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65–76) and 73 % (67–78) after MAC and RIC, respectively ( P  = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.

Low aerobic capacity is associated with an increased mortality risk in allogenic stem-cell transplantation (alloSCT) patients, but currently used risk scores in the pre-transplantation workup are still underestimating physical activity as a prognostic factor. To examine the physical condition, muscle function, blood inflammation and training adherence of alloSCT patients during inpatient time to identify potential biomarkers associated with development of myopathy and sarcopenia. Patients undergoing alloSCT were examined at four time points (T0: before alloSCT; T : hospital admission; T1: engraftment; T2: inpatient discharge). T0 included cardiopulmonary performance, body composition, grip and knee strength, motor skill tests (One-leg stand/Tinetti/Chair-rising), blood sampling (blood cell profiling and inflammation targets (Kynurenin/high sensitivity C-reactive Protein (hsCRP)/Tumor necrosis factor alpha (TNF-alpha)/Musclin/Galectin-3) and quality of life, state of health, fatigue, muscle weakness and physical activity by questionnaires (IPAQ/BSA/SARC-F/Fatigue). At T1 and T2, blood samples, grip strength and motor skill tests were repeated. Glucocorticoid dose and daily physical activity were documented during inpatient stay. 26 of 35 included patients (4 females; age 55.58 ± 12.32 years; BMI 24.70 ± 3.27 kg/m ; VO 16.55 ± 4.06 ml/min/kg) could proceed to alloSCT. Grip strength and Tinetti decreased from T0 until T2, no difference in Chair-rising test, One-leg and Tandem stand. All patients engrafted after 24.9 days ± 3.9 days. HsCRP and Kynurenine increased from T0 to T1, decreased at T2. TNF-alpha (T0vsT2/T1vsT2) and Musclin (T0vsT1) decreased. At T2, Galectin-3 was higher compared to T0/T1. Correlation analysis of grip strength and inflammatory markers revealed a positive correlation with TNF-alpha at T2. 50% of patients documented physical activity and questionnaire and reported a 50%-reduction of daily endurance and strength training between T1 to T2. Allogeneic stem-cell transplantation is associated with immune system vulnerability due to conditioning, increased inflammation and fatigue, and loss of muscle strength and function. In addition to hsCRP, Kynurenine seems to be a reliable biomarker to monitor acute and regenerative inflammation status of alloSCT patients, while Musclin and Galectin-3 may be added to physiological assessment regarding myopathy and sarcopenia. Grip strength and daily activity level should be documented by professionals to identify risk patients early and support them with optimal (exercise) therapy.

Vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is approved and recommended for immunocompromised patients such as patients after allogeneic stem cell transplantation (allo-SCT). Since infections represent a relevant cause of transplant related mortality we analyzed the advent of immunization to SARS-CoV-2 vaccination in a bicentric population of allogeneic transplanted patients. We retrospectively analyzed data of allo-SCT recipients in two German transplantation centers for safety and serologic response after two and three SARS-CoV-2 vaccinations. Patients received mRNA vaccines or vector-based vaccines. All patients were monitored for antibodies against SARS-CoV2-spike protein (anti-S-IgG) with an IgG ELISA assay or an EIA Assay after two and three doses of vaccination. A total of 243 allo-SCT patients underwent SARS-CoV-2 vaccination. The median age was 59 years (range 22-81). While 85% of patients received two doses of mRNA vaccines, 10% had vector-based vaccines and 5% received a mixed vaccination. The two vaccine doses were well tolerated with only 3% patients developing a reactivation of graft versus host disease (GvHD). Overall, 72% of patients showed a humoral response after two vaccinations. In the multivariate analysis age at time of allo-SCT (p=0.0065), ongoing immunosuppressive therapy (p= 0.029) and lack of immune reconstitution (CD4-T-cell counts <200/μl, p< 0.001) were associated with no response. Sex, intensity of conditioning and the use of ATG showed no influence on seroconversion. Finally, 44 out of 69 patients that did not respond after the second dose received a booster and 57% (25/44) showed a seroconversion. We showed in our bicentric allo-SCT patient cohort, that a humoral response could be achieve after the regular approved schedule, especially for those patients who underwent immune reconstitution and were free from immunosuppressive drugs. In over 50% of the initial non-responders after 2-dose vaccination, a seroconversion can be achieved by boostering with a third dose.

Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14-1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05-1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01-1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01-1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15-1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91-1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08-0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11-0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13-0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26-5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.

Background Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively ( p  = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA ( p  = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology ( p  = 0.01; p  = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III–IV aGVHD ( p  = 0.02) and cGVHD ( p  = 0.006), with no influence on relapse. Conclusions In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.

Allogenic stem cell transplantation (aSCT) is the only potentially curative treatment for high-risk hematological diseases. Despite advancements in supportive measures, aSCT outcome is still affected by considerable transplant-related mortality. We implemented a new sarcopenia assessment prior to aSCT to evaluate its predictive capability for all-cause and non-relapse mortality. Therefore all patients initially scheduled for aSCT within a 25-month period were screened during pre-transplantation-routine for muscle mass, grip strength, and aerobic capacity (AC) by measuring peak oxygen uptake (VO2peak). Patients were assigned to one of five groups adapted according current sarcopenia guidelines. Primary endpoints were all-cause and non-relapse mortality within a follow up time of up to 12 months. A total of 178 patients were included and rated as normal (n = 48), impaired aerobic capacity (n = 56), pre-sarcopenic (n = 26), sarcopenic (n = 27), and severe sarcopenic (n = 22) without significant age-differences between groups. Patients presenting with sarcopenia showed a significant three-fold increase in all-cause and non-relapse mortality compared to patients with normal screening results. AC showed to be the strongest single predictor with a more than two-fold increase of mortality for low AC. We conclude that risk stratification based on combination of muscle mass, grip strength, and AC allowed identifying a subgroup with increased risk for complications in patients undergoing aSCT.

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.

Background Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. Methods The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors ( n  = 660) versus unrelated donors ( n  = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. Conclusions HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients’ outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated.

Background Nilotinib is a tyrosine kinase inhibitor with high target specificity. Here, we characterized the effects of nilotinib for the first time on CD4 + CD25 + regulatory T cells (Tregs) which regulate anti-tumor/leukemia immune responses. Design and Methods Carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2-deoxy -uridine (BrdU) were used to assess the proliferation and cell cycle distribution of Tregs. The expression of the transcription factor forkhead box P3 (FoxP3) and the glucocorticoid-induced tumor necrosis factor receptor (GITR) were measured by flow cytometry. Western blotting analysis was used to detect the effects of nilotinib on the signal transduction cascade of T-cell receptor (TCR) in Tregs. Results Nilotinib inhibited the proliferation and suppressive capacity of Tregs in a dose-dependent manner. However, the production of cytokines secreted by Tregs and CD4 + CD25 - T cells was only inhibited at high concentrations of nilotinib exceeding the mean therapeutic serum concentrations of the drug in patients. Only high doses of nilotinib arrested both Tregs and CD4 + CD25 - T cells in the G 0 /G 1 phase and down-regulated the expression of FoxP3 and GITR. In western blotting analysis, nilotinib did not show significant inhibitory effects on TCR signaling events in Tregs and CD4 + CD25 - T cells. Conclusions These findings indicate that nilotinib does not hamper the function of Tregs at clinical relevant doses, while long-term administration of nilotinib still needs to be investigated.