Allogeneic hematopoietic cell transplantation (HCT) effectively treats high-risk hematologic diseases but can entail HCT-specific complications, which may be minimized by appropriate patient management, supported by accurate, individual risk estimation. However, almost all HCT risk scores are limited to a single risk assessment before HCT without incorporation of additional data. We developed machine learning models that integrate both baseline patient data and time-dependent laboratory measurements to individually predict mortality and cytomegalovirus (CMV) reactivation after HCT at multiple time points per patient. These gradient boosting machine models provide well-calibrated, time-dependent risk predictions and achieved areas under the receiver-operating characteristic of 0.92 and 0.83 and areas under the precision-recall curve of 0.58 and 0.62 for prediction of mortality and CMV reactivation, respectively, in a 21-day time window. Both models were successfully validated in a prospective, non-interventional study and performed on par with expert hematologists in a pilot comparison.

Several studies suggest that harnessing natural killer (NK) cell reactivity mediated through killer cell immunoglobulin-like receptors (KIRs) could reduce the risk of relapse after allogeneic hematopoietic cell transplantation. Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or KIR-disadvantageous. This study was aimed at externally validating this model in unrelated donor hematopoietic cell transplantation. The impact of the predictor on overall survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, Karnofsky performance status, donor age, HLA match, sex match, cytomegalovirus match, conditioning intensity, type of T-cell depletion, and graft type. Data from 2222 patients with acute myeloid leukemia or myelodysplastic syndrome were analyzed. KIR genes were typed by using high-resolution amplicon-based next-generation sequencing. In univariable analyses and subgroup analyses, OS and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with a KIR-disadvantageous donor. The adjusted hazard ratio from the multivariable Cox regression model was 0.99 (Wald test, P = .93) for OS and 1.04 (Wald test, P = .78) for relapse incidence. We also tested the impact of activating donor KIR2DS1 and inhibition by KIR3DL1 separately but found no significant impact on OS and the risk of relapse. Thus, our study shows that the proposed model does not universally predict NK-mediated disease control. Deeper knowledge of NK-mediated alloreactivity is necessary to predict its contribution to graft-versus-leukemia reactions and to eventually use KIR genotype information for donor selection.

Prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT) remains challenging. Because prospective randomized trials of in-vivo T cell depletion using anti-T-lymphocyte globulin (ATLG) in addition to a calcineurin inhibitor and methotrexate (MTX) led to conflicting outcome results, we evaluated the impact of ATLG on clinical outcome, lymphocyte- and immune reconstitution survival models. In total, 1500 consecutive patients with hematologic malignancies received matched unrelated donor (MUD) HCT with cyclosporin and MTX (N = 723, 48%) or with additional ATLG (N = 777, 52%). In the ATLG cohort, grades III-IV acute (12% vs 23%) and extensive chronic GVHD (18% vs 34%) incidences were significantly reduced (P < .0001). Nonrelapse mortality (27% vs 45%) and relapse (30% vs 22%) differed also significantly. Event-free and overall survival estimates at 10 years were 44% and 51% with ATLG and 33% and 35% without ATLG (P < .002 and <.0001). A dose-dependent ATLG effect on lymphocyte- and neutrophil reconstitution was observed. At ATLG exposure, lymphocyte counts and survival associated through a logarithmically increasing function. In this survival model, the lymphocyte count optimum range at exposure was between 0.4 and 1.45/nL (P = .001). This study supports additional ATLG immune prophylaxis and is the first study to associate optimal lymphocyte counts with survival after MUD-HCT.

Considering the unsatisfactory results of salvage therapies for patients with relapsed/refractory acute myeloid leukaemia (R/R‐AML), their value before allogeneic haematopoietic stem cell transplantation (HSCT) remains questionable. However, direct allogeneic HSCT following established conditioning regimens applied in patients with R/R‐AML during active disease has been equally disappointing. In this retrospective observational study, high‐dose melphalan, as part of a sequential preparative regimen, followed by a total body irradiation (4 × 2 Gy)‐based or a treosulfan‐based dose‐adapted conditioning therapy for allogeneic HSCT was administered to 292 adult patients (median age 56 years, range 17–74) with primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). Overall survival rates at 3 years were 34%, 29% and 41%, respectively. Risk factors associated with an inferior survival were higher age, transplantation from a human leucocyte antigen‐mismatched donor and high disease burden. Patients transplanted with blast infiltration <20% showed a notable survival rate of 51% at 3 years. In particular, patients with primary refractory AML showed a more favourable outcome when transplanted early during their disease course. Thus, high‐dose melphalan‐based sequential conditioning chemotherapy followed by an allogeneic HSCT is feasible and enables long‐term remission to be achieved in a substantial proportion of patients with active R/R‐AML.

In patients with follicular lymphoma, secondary transformation to aggressive lymphoma (tFL) implies a poor prognosis. In principle, allogeneic haematopoietic cell transplantation (allo-HCT) offers a chance of cure for tFL but is rarely practiced. Aim of this retrospective multicenter study was to define the actual significance of allo-HCT in treatment of tFL.

Background: CMV reactivation is a major cause of severe complications in allogeneic hematopoietic stem cell transplant (HSCT) recipients. The risk of CMV reactivation depends on the serostatus (+/-) of the donor (D) and recipient (R). The reconstitution of CMV-specific T-cell responses after transplantation is crucial for the control of CMV reactivation. Objectives: The study aimed to determine the cellular immune status correlating with protection from high-level CMV viremia (> 5000 copies/ml) and disease. Study design: We monitored CMV-specific cellular immune responses in 9 high-risk (D-/R+), 14 intermediate risk (D+/R+) and 3 low risk individuals (D+/R-), and 8 CMV negative controls (D-/R-). Interferon-gamma (IFN-gamma) levels as a marker for the CD8+ T-cell response were determined by the QuantiFERON-CMV-assay and compared to viral loads determined by PCR. Results: Early CMV reactivation was detected in all high-risk and 13/14 intermediate risk individuals. High-level viremia was detected in 5/7 high and 7/14 intermediate risk patients. Reconstitution of the CMV-specific cellular immune response started from 3 months after transplantation and resulted in protection against CMV reactivation. Re-establishing of CMV-specific T-cell immune responses with IFN-gamma levels > 8.9 IU/ml is crucial for protection from high-level CMV viremia. Conclusions: Monitoring of HSCT-recipients with the QuantiFERON-CMV-assay might be of great benefit to optimize antiviral treatment.

Increasing donor-recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P < .002) and nonrelapse mortality (HR, .63; P < .001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [P < .02] and HR, 1.57 [P < .001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient-female donor), and cytomegalovirus (CMV) mismatching (positive recipient-negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P = .25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR, .89; P = .46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P = .04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity.

Background Previously, we demonstrated that the addition of anti-human-T-lymphocyte immunoglobulin (ATLG) to standard ciclosporin and methotrexate prophylaxis reduced graft-versus-host disease (GvHD) in adult patients treated with allogeneic haemopoietic cell transplantation from matched unrelated donors without negatively affecting relapse and survival. Since reports on long-term results from randomised trials testing anti-thymocyte globulin are scarce, we performed an extended follow-up of the trial.Methods Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation to receive ciclosporin and methotrexate with or without ATLG. 201 patients who underwent transplantation with peripheral blood (n= 164; 82%) or bone marrow (n= 37; 18%) grafts after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATLG n= 103, non-ATLG n= 98). We assessced chronic GvHD, non-relapse mortality, relapse, relapse mortality, disease-free survival, overall survival, severe GvHD-free (acute GvHD III-IV, and extensive chronic GvHD) and relapse-free survival, and time under immunosuppressive therapy after long-term follow-up. The trial is registered with the German Clinical Trials Register (DRKS00000002), ClinicalTrials. gov (NCT00655343), and EudraCT (2004-000232-91).Findings Median follow-up was 8 . 6 years (IQR 8 . 0-9 . 3). Only patients at risk for chronic GvHD (ie, patients who were alive and without a second transplant at 100 days) were included in the analyses of chronic GvHD (90 patients in the ATLG group, 80 patients in the non-ATLG group). At 8 years, the incidence of extensive chronic GvHD was 14% (95% CI 8-29) in the ATLG group versus 52% (42-64) in the non-ATLG group (adjusted hazard ratio [HR] 0 . 18, 95% CI 0 . 09-0 . 34; p < 0 . 0001). Non-relapse mortality was 21% (95% CI 14-30) versus 34% (26-45; adjusted HR 0 . 66, 95% CI 0 . 38-1 . 16; p= 0 . 15), incidence of relapse was 35% (95% CI 27-46) versus 30% (22-41; adjusted HR 1 . 17, 95% CI 0 . 71-1 . 93; p= 0 . 54), relapse mortality was 31% (95% CI 23-41) versus 29% (21-40; adjusted HR 1 . 03, 95% CI 0 . 61-1 . 76; p= 0 .90), disease-free survival was 44% (95% CI 35-54) versus 36% (27-46) (adjusted HR 0 . 91, 95% CI 0 . 63-1 . 31; p= 0 . 60), overall survival was 49% (95% CI 39-59) versus 37% (27-47; adjusted HR 0 . 82, 95% CI 0 . 56-1 . 20; p= 0 . 31), and severe GvHD-free and relapse-free survival was 34% (25-43) versus 13% (7-21) (adjusted HR 0 . 55, 95% CI 0 .39-0 .76; p= 0 . 0003). The probability of being alive and free of immunosuppressive therapy was 47% (95% 37-57) in the ATLG group and 11% (5-18) in the non-ATLG group at 8 years.Interpretation ATLG in addition to standard ciclosporin and methotrexate as GvHD prophylaxis improves severe GvHD-free and relapse-free survival in the long term. The use of ATLG in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression.

The role of HLA amino acid (AA) polymorphism for the outcome of hematopoietic cell transplantation (HCT) is controversial, in particular for HLA class II. Here, we investigated this question in nonpermissive HLA-DPB1 T-cell epitope (TCE) mismatches reflected by numerical functional distance (FD) scores, assignable to all HLA-DPB1 alleles based on the combined impact of 12 polymorphic AAs. We calculated the difference in FD scores (ΔFD) of mismatched HLA-DPB1 alleles in patients and their 10/10 HLA-matched unrelated donors of 379 HCTs performed at our center for acute leukemia or myelodysplastic syndrome. Receiver-operator curve-based stratification into 2 ΔFD subgroups showed a significantly higher percentage of nonpermissive TCE mismatches for ΔFD >2.665, compared with ΔFD ≤2.665 (88% vs 25%, P < .0001). In multivariate analysis, ΔFD >2.665 was significantly associated with overall survival (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.05-1.87; P < .021) and event-free survival (HR, 1.39; 95% CI, 1.05-1.82; P < .021), compared with ΔFD ≤2.665. These associations were stronger than those observed for TCE mismatches. There was a marked but not statistically significant increase in the hazards of relapse and nonrelapse mortality in the high ΔFD subgroup, whereas no differences were observed for acute and chronic graft-versus-host disease. Seven nonconservative AA substitutions in peptide-binding positions had a significantly stronger impact on ΔFD compared with 5 others (P = .0025), demonstrating qualitative differences in the relative impact of AA polymorphism in HLA-DPB1. The novel concept of ΔFD sheds new light onto nonpermissive HLA-DPB1 mismatches in unrelated HCT.

Summary Graft failure is a life‐threatening complication after allogeneic haematopoietic stem cell transplantation ( HSCT ). We report a cohort of 19 consecutive patients (median age: 8·5 years) with acute leukaemias ( n = 14) and non‐malignant diseases ( n = 5) who experienced graft failure after previous HSCT from matched ( n = 3) or haploidentical donors ( n = 16) between 2003 and 2012. After total nodal irradiation ( TNI )‐based reconditioning combined with fludarabine, thiotepa and anti‐T cell serotherapy, all patients received T cell‐depleted peripheral blood stem cell grafts from a second, haploidentical donor. Median time between graft failure and retransplantation was 14 d (range 7–40). Sustained engraftment (median: 10 d, range 9–32) and complete donor chimerism was observed in all evaluable patients. 5 patients additionally received donor lymphocyte infusions. Graft‐versus‐host disease (Gv HD ) grade II and III occurred in 1 patient each (22%); no Gv HD grade IV was observed. 2 patients had transient chronic Gv HD . The regimen was well tolerated with transient interstitial pneumonitis in one patient. Treatment‐related mortality after one year was 11%. Event‐free survival and overall survival 3 years after retransplantation were 63% and 68%. Thus, a TNI ‐based reconditioning regimen followed by transplantation of haploidentical stem cells is an option to rescue patients with graft failure within a short time span and with low toxicity.

Introduction Allogeneic stem cell transplantation (allo-SCT) is a curative treatment for several hematological diseases. Donor-recipient histo-incompatibility is associated with poorer outcome. Transplant outcome of CMV positive patients is reported to be poorer, if the unrelated donor is CMV negative (CMV-mismatch). Recent developments in transplant strategies including high resolution HLA-typing, toxicity-reduced conditioning regimens, CMV-monitoring, and improved supportive care have made transplants from HLA- as well as CMV- mismatched unrelated donors more feasible. We present a retrospective registry analysis from a large, and recent cohort of patients transplanted under these conditions. Patients and methods: We report data from adult recipients of allo-SCT treated between 2005 and 2013 in 10 transplant centers across Germany. Inclusion criteria were: 1.) consecutive patients from each center with AML or MDS as reported to the German Stem Cell Transplant Registry (DRST), 2) age >/= 18 years, 3) availability of high-resolution typing for HLA-A, -B, C, DRB1 and DQB1 in case of unrelated donor. Patients with ex-vivo T cell depletion were excluded. 3215 patients with AML (n = 2648) or MDS (n = 567) were included in the study. Donors were matched related (MRD, n =872), matched unrelated (MUD, n = 1553) or mismatched unrelated (9/10 MMUD, n= 620; 8/10 MMUD n = 137; Results: Kaplan-Meier estimates for OS at 3 years was similar after transplants from MRD = 55% (95%CI 51-59%) compared to MUD = 53% (95%CI 51-59%), p = 0.26. OS at 3 years was worse for 9/10 MMUD with 45% (95% CI 41-49%, p In recipients of unrelated donor transplants, multivariate cox regression analysis revealed significant negative impact of increasing patient age, increasing donor age, sex-mismatch (male patient/female donor), CMV-mismatch (patient pos/ donor neg), diagnosis of AML or sAML compared to MDS, lack of complete remission at transplant, abnormal cytogenetics and HLA-mismatching (table 1a). In a subgroup analysis restricted to patients transplanted from unrelated donors after myeloablative conditioning and T cell depletion, 3 years OS was better after 10/10 MUD: 60% (55-65%) compared to 9/10 MMUD: 49% (41-57%), p = 0.02. This was also true after reduced intensity conditioning and T cell depletion with ATG, with 3 year OS after 10/10 MUD: 49% (45-53) compared to 9/10 MMUD: 37% (31-43%), p = 0.001. Excluding HLA-DQB1-mismatches and HLA-C0303/0304-mismatches from the 9/10 MMUD group did not significantly alter results. Acknowledging the negative impact of both HLA and CMV-mismatching, we sought to determine which of these two parameters is of higher relevance for donor selection. For this purpose subgroup analyses were performed including only CMV-positive patients who received transplants from an unrelated donor (10/10 MUD or 9/10 MMUD). HLA-DQB1-mismatches and HLA-C0303/0304-mismatches were excluded. For this subgroup of n = 1167 patients multivariate cox regression analysis revealed better outcome after 10/10 MUD from CMV neg. donors compared to 9/10 MMUD from a CMV pos. donors (RR: 1.31, p = 0.04, table 1b and figure 2). Restricting the analysis only to patients who received T cell depletion with ATG did not significantly alter these findings. Conclusions: In this large multicenter cohort of recently transplanted patients, we find similar survival outcomes for matched related and fully matched unrelated donor transplants. We confirm the negative impact of HLA-mismatching on survival outcome, irrespective of conditioning intensity. Our results show that though CMV-mismatching is associated with poorer outcome, its relevance is secondary to HLA-mismatching. Acknowledgements: This work was supported by a research grant of the DKMS-Stiftung to FA and WB. Disclosures Stelljes:Pfizer: Consultancy. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Kroger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Background: Previously, in 201 adult patients with allogeneic hematopoietic cell transplantation from matched unrelated donors, we demonstrated that the addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control) significantly reduces acute and chronic GvHD without negatively affecting relapse and survival [1,2,3]. Methods: Now, we present final results after an extended follow-up (median 8.6, Q1 8.0, Q3 9.3 years) with regard to chronic GvHD, non-relapse mortality (NRM), relapse, relapse mortality, disease-free survival (DFS) and overall survival (OS). Additionally, we analyse the effect of ATG-F vs control on the composite endpoint severe GvHD (acute GvHD III-IV, extensive chronic GvHD) and relapse-free survival, and on time under immunosuppressive therapy. Since mortality within the first year after transplantation is usually high, we also analyse conditional survival, i.e. the OS probability after having survived 1 and 2 years after transplantation. Results: The incidence of extensive chronic GvHD after 8 years was 13.5% in the ATG-F group vs 51.8% in the control group (p ATG-F substantially increased the combined severe GvHD/relapse-free survival rate. The rates were 48.5% vs 20.4% after 1 year and 33.6% vs 13.0% after 8 years (p=0.0003), ATG-F vs control, respectively (see figure). The probability of being alive and free of immunosuppressive therapy was 46.8% in the ATG-F group and 11.2% in the control group at 8 years (p=0.0002). The survival probabilities increased when patients had survived the first year. The conditional 8 years-survival probability increased in the ATG-F group from 48.7% (unconditional) to 70.6% and 80.9% (conditional on having survived 1 and 2 years after transplantation), and in the control group from 36.8% (unconditional) to 58.5% and 71.7% (conditional on having survived 1 and 2 years after transplantation). Conclusion: The long-term follow-up of 8.6 years shows that ATG-F GvHD prophylaxis provides a sustained protective effect without increasing relapse and compromising survival. ATG-F in addition to standard cyclosporine, methotrexate as GvHD prophylaxis results in significantly improved severe GvHD/relapse-free survival. Furthermore, the stable results from our prospective trial after an extended long-term follow-up demonstrate that the choice to use ATG-F in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression. References: [1] Finke et al. Lancet Oncol 2009;10:855 [2] Socie et al. Blood 2011;117:6375 [3] Finke et al. Biol Blood Marrow Transplant 2012;18:1716 Disclosures Bertz:GILEAD Sciences: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding.

Background: We and others have previously shown that non-permissive T cell epitope (TCE) group mismatches at HLA-DPB1 are associated with the risks of mortality after hematopoietic cell transplantation (HCT) from 10/10 HLA-matched unrelated donors (Fleischhauer et al, Lancet Oncol 2012; Pidala et al, Blood 2014). Moreover, we recently reported that TCE groups are reflected by a numerical score assignable to each HLA-DPB1 allele based on the combined median impact of 12 naturally occurring amino acid substitutions (AAS) on allorecognition of HLA-DPB1*09:01 as reference, termed functional distance (FD) (Crivello et al, Biol Blood Marrow Transplant 2015). Here we studied the association between the Delta in FD scores of HLA-DPB1 alleles present in the patient and in the donor (Delta-FD), and the clinical outcome of unrelated HCT.

Abstract Background Chronic graft-versus-host disease (GVHD) is a major complication following allogeneic hematopoietic stem cell transplantation and is associated with a substantial morbidity and mortality. It is a systemic inflammatory disorder that reflects the lack of immune tolerance between donor-derived immune competent cells and host organs. Human chorionic gonadotropin hormone (hCG) is a natural occurring hormone during pregnancy secreted by syncytiotrophoblasts of the placenta. We had previously observed (Koldehoff et al; J Leukoc Biol 2011) that the rejection of transplanted skin was significantly delayed by hCG in a mouse skin transplant model and had also demonstrated that tryptophan-catabolizing enzyme, indoleamine-2,3-dioxygenase(IDO), interleukin-10 (IL 10) and T-regulatory cells (Tregs) increased significantly in females treated with hCG as preconditioning therapy for in-vitro-fertilization. Since all these factors are known to induce tolerance and given the low rate of adverse effects, we off-label used low dose of hCG to treat 20 patients as forth- or fifth-line therapy with steroid-refractory or intolerant severe-grade chronic GVHD. Patients Because all of these factors are known to induce tolerance and given the low rate of adverse effects in preconditioning therapy, we off-label used low dose of hCG (187 IU) to treat 8 male and 12 female patients (median age 48, r. 28-68) with moderate or severe grade of chronic GVHD according to the NIH criteria; all patients had been informed of the experimental state of this treatment and provided written consent. Results The median number of sites of chronic GVHD involvement per patient was 3 (range, 1-6). hCG therapy was started as 4 or 5th line-therapy together with preexisting medication with prednisone and a calcineurin inhibitor. Twelve of 20 patients (60%) had an objective partial response during 8 weeks of hCG treatment with at least 50% improvement according to the TSS score. Responses included softened skin and subcutaneous tissue; decreased erythema and extent of sclerodermatous, hidebound skin; improved joint mobility and gait; gastrointestinal improvements; and resolution of neuropathy. Nine patients had stable disease (6 with minor responses). Only one patient with previous ATG treatment showed progression of her liver GVHD (histologically proven) and died from GHVD. All other patients were well and alive. Daily low-dose hCG was well tolerated. Adverse events that were possibly related to hCG included reversible and asymptomatic CTCAE grade 4 hypertriglyceridemia (n=1), grade 2 constitutional symptoms (fever, malaise, fatigue; flush, breast enlargement). IDO expression increased up to 8 times and IL10-serum level up to 2 times after 3 weeks of hCG therapy (p<0.003 and p<0.04). T-regulatory cell expansion was documented in 3 patients. Conclusion This successful use of hCG in an immune disorder warrants further studies to assess its role as an immunosuppressant in GVHD and potentially other autoimmune disorders. Disclosures: Off Label Use: The off-label use of HCG will be presented here for the first tiem for treatment of chronic GVHD and will clearly marked as off-label use.

Abstract Abstract 5503 Introduction Early detection of inapparent replicative human cytomegalovirus (HCMV) infection together with its preemptive antiviral treatment has led to a marked reduction of life-threatening HCMV disease after allogeneic hematopoietic stem cell transplants (alloSCT). A new aspect of HCMV reactivation and pretransplant HCMV serostatus has recently emerged by an earlier retrospectively performed report from us showing that the occurrence of a HCMV-reactivation after transplant reduces the risk for relapse in patients with AML and NHL. This idea was supported by a study by Scheper and co-worker (Leukemia, 2013) reporting recently, that gamma-delta T cells elicited by HCMV reactivation after alloSCT cross-recognize HCMV and leukemia. Here we evaluate the potential impact of early HCMV replication in a prospectively performed observational study about the occurrence of a HCMV- reactivation after T cell repleted alloSCT on the risk for leukemic relapse in patients with AML (Registration Trial DRKS00004300). Patients and Method Between January 2012 and March 2013 we enrolled in this trial 83 patients with AML who were consecutively transplanted at the University Hospital of Essen. 48 of 83 patients received a myeloablative (TBI based conditioning n=27, chemotherapy based conditioning n=23) and 35 patients a RIC regimen. Patients were transplanted in 1.CR (n=40), 2.CR (n=23) or more progressive disease stages (n=20) from HLA-identical sibling donor (n=17) or HLA-identical unrelated donor (URD) (n=42) or mismatched unrelated donor (n=24). The median age of patients was 53 years (range 18-72) and that of the donors 38 years (range 12-61). GVHD prophylaxis was performed with MTX and CSA, or CSA and MMF with or without ATG (n=64) (30-60mg total dose). The incidence of acute GVHD grade 2-4 was statistically not different in both groups (78% versus 85%). Results HCMV status of recipient (R) or donors (D) were in 29% R-/D-, 8% R-/ D+; 34% D+/R- and 29% R+/D+. Patients with a documented HCMV-reactivation (HCMV-R) had an estimated relapse incidence (CIR) at 1-year after transplant of only 8% compared to 43% in patients without a HCMV-R (p=0.03). Patients in more progressive disease phase of AML (N=43) benefit more from a HCMV-R in regard of CIR than patients in 1.CR of AML (0% versus 55% estimate for relapse at 1-year after transplant for patients with HCMV-R compared to patients without HCMV –R, p=0.028). One-year overall survival was statistically not different in both groups. Non relapse mortality was greater in patients with HCMV reactivation 37.8% versus 12.5%, p=0.1) Conclusion The first result of this prospective study confirms an independent advantageous effect of early HCMV replication on the leukemic relapse risk in patients with AML after transplant, which was more pronounced in patients in progressive disease phase of AML than patients in 1.CR of AML. Disclosures: Off Label Use: The off-label use of HCG will be presented here for the first tiem for treatment of chronic GVHD and will clearly marked as off-label use.