PURPOSE:Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT.PATIENTS AND METHODS:In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first.RESULTS:With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib.CONCLUSION:Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.

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.

Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry-based matched-pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair-matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion. Eighty-nine pairs were identified (median follow-up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high-risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high-risk AML.

Abstract Introduction: Most patients with FLT3-ITD-positive AML, who relapse after allogenic stem cell transplantation (allo-SCT) die from their disease. Whether prophylactic FLT3-ITD inhibition with sorafenib can prevent AML relapse and improve outcome of patients in complete hematological remission (CHR) after allo-SCT is unknown and was tested in the SORMAIN trial. Methods: This randomized, double blind, placebo-controlled study was done at 14 centers in Germany and Austria. Patients with FLT3-ITD+ AML, aged 18 years or older, who had undergone allogenic stem cell transplantation from a HLA-matched sibling donor, 10/10 or 9/10 HLA-matched unrelated donor, and who were in confirmed CHR at the time of screening between day +30 and day +100 post allo-SCT, were included. Patients were randomly assigned (1:1) to receive either sorafenib (starting dose: 2 x 1 tbl. [2 x 200mg] qd, increasing every 14d to up to 2 x 2 tbl. [2 x 400mg] qd according to tolerability) or placebo (2 x 1 or 2 tbl. qd) for up to 24 months. Randomization was done centrally. In case of drug related adverse events, study medication could be interrupted, stepwise reduced to a minimum of 2 x 1 tbl. qd, temporarily withheld and recommenced at a lower dose level. FLT3-ITD diagnostics was done centrally at baseline and at time of relapse. In relapsing patients, off-label compassionate use of sorafenib was possible. The primary endpoint was relapse-free survival (RFS) as defined by either hematological relapse or death from any cause. The secondary endpoint was overall survival (OS). We here report the final RFS analysis. The OS results will be unblinded only prior to the ASH meeting and will be reported there. The SORMAIN study was terminated prior to full recruitment because of slow accrual. SORMAIN was registered with the European Clinical Trials Database (EudraCT 2010-018539-16) and the German Clinical Trials Register (DRKS00000591). Results: Between October 29, 2010, and May 17, 2016, 83 patients (41 males, 42 females) were randomized and included in the primary analysis (placebo, n=40; sorafenib, n=43). Median age was 54 years (IQR 47.75 - 61.33) for the entire study population and not significantly different between sorafenib and placebo groups. With a median follow up of 41.8 months after randomization (IQR 24.1 - 42.5), median RFS was 30.9 months (lower bound of 95% CI 5.2 months) in the placebo group versus not reached in the sorafenib group, corresponding to a 2-year RFS of 53,3 % (95% CI 36.5-67.5) in the placebo versus 85.0 % (69.5-93.0) in the sorafenib group (hazard ratio [HR] 0.39, 95% CI; 0.18 -0.85; P=0.0135) (Fig. 1). Overall, sorafenib was well tolerated. The most common grade 3-4 adverse event in both groups was acute GvHD (seven [ 17.5%] in the placebo group vs. nine [20.9%] in the sorafenib group. Conclusion: Sorafenib maintenance therapy after allo-SCT is feasible and significantly reduces the risk of relapse or death in patients with FLT3-ITD positive AML. OS results will be presented at the meeting. Figure 1. Figure 1. Disclosures Burchert: Bristol Myers Squibb: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; AOP Orphan: Honoraria, Research Funding; Novartis: Research Funding. Bug:Amgen: Honoraria; Neovii: Other: Travel Grant; Novartis Pharma: Honoraria, Research Funding; Astellas Pharma: Other: Travel Grant; Jazz Pharmaceuticals: Other: Travel Grant; Celgene: Honoraria; Janssen: Other: Travel Grant. Finke:Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Rollig:Bayer: Research Funding; Janssen: Research Funding. Wäsch:Pfizer: Honoraria. Lang:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Serve:Bayer: Research Funding. Kroeger:Neovii: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding. Schmid:Jazz Pharma: Honoraria, Other: Travel grant, Speakers Bureau. Wolf:BMS: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.

Allogeneic stem cell transplantation (HSCT) is a curative treatment for adult patients with hematologic malignancies, but is limited by severe, life-threatening complications such as acute graft-versus-host disease (aGvHD). We have developed a proteomic urine pattern “aGvHD_MS17”, consisting of 17 differentially excreted peptides, capable to predict aGvHD grade II or more (1, 2). In 2008, a multicenter, randomized, placebo-controlled, double blind clinical trial (Pre-GvHD) was initiated testing aGvHD_MS17 for prediction of aGvHD and to initiate pre-emptive therapy using prednisolone 2-2.5mg/kg.

No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation (P<0.001), advanced disease (P=0.001), older age (P=0.007), unrelated donor (P=0.008) and acute graft-versus-host disease before relapse (P<0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation (P<0.001) and younger age (P=0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation (P<0.001), complete remission at second transplant (P=0.008), no prior chronic graft-versus-host disease (P<0.001) and change to a new donor (P=0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials.

Introduction: Allogeneic stem cell transplantation (SCT) remains a treatment option for patients with chronic myeloid leukemia (CML) that fail to respond to tyrosine kinase inhibitors (TKI). While the use of Imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second generation TKI (2GTKI). We present the results of a prospective non-interventional study (NIS) performed by the European Group for Blood and Marrow Transplantation (EBMT) of all consecutive allogeneic SCT for patients diagnosed with CML from 2009 to 2013.

Background: Patients (pts) relapsing with CML after allogeneic hematopoietic stem cell transplantation (alloHSCT) may be treated with tyrosine kinase inhibitors (TKI) and/or donor lymphocyte infusions (DLI). As nowadays the majority of CML patients would have received at least imatinib prior to transplantation, we were interested in analizing a) the type of TKI used after alloHSCT, b) the indication for TKI treatment, c) the outcome of this treatment and d) the temporal relationship with DLI if given.

In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% (P = .01) and 46% (P = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS.

Background: Relapse is the most frequent cause of failure after alloSCT for acute leukemia (AL). Unlike in CML, infusion of donor lymphocytes (DLI) is of limited efficacy in overt hematological relapse. Hence, it may be preferable to give DLI in complete hematological remission (CHR) after alloSCT, to exploit the allogeneic graft-versus-leukemia (GvL) effect either as maintenance in high risk patients (prophylactic DLI, proDLI), or as early intervention to prevent hematological recurrence in case of decreasing donor chimerism or minimal residual disease (preemptive DLI, preDLI). However, no systematic analysis of this strategy is available so far, neither concerning the optimal way of application, nor with respect to safety and clinical efficacy. Here, the Acute Leukemia Working Party of the EBMT presents results from a registry-based survey on 343 patients with AML (n=266) or ALL (n=77), who received DLI in CHR after alloSCT. Patients: Median age was 48y, 64% of patients had received alloSCT from a matched sibling, 36% from an 8/8 matched unrelated donor. Disease status at time of alloSCT was CR1/CR2/advanced in 68%/14%/17% of cases, respectively. Patients had received standard/reduced intensity conditioning in 53%/47% of cases. Before alloSCT, 55% had received in vivo T-cell depletion (TCD), 16% ex vivo TCD, 10% in vivo plus ex vivo, and 19% no TCD. Reasons for preDLI were persisting mixed or decreasing donor cells chimerism (n=167, 49%) and persisting or recurrent minimal residual disease (MRD; n=32, 9%). ProDLI without any sign of leukemia was given to 144 patients (42%) with high risk disease Results: Median follow up from DLI1 was 6.5 years (range, 1.1-14.5). Median interval from alloSCT to first DLI (DLI1) was 180 days (range, 15-1178). Patients received a median of 2 infusions with the median CD3+ cell dose at DLI1 being 1x106/kg (range, 0.1-163). Reasons to discontinue DLI were: number of planned infusions reached (56%), GvHD (17%), disease progression (13%), and documented improvement of donor chimerism (6%). At 5y from DLI1, cumulative incidence of leukemia relapse was 43% and 28% in patients receiving preDLI for MRD and mixed chimerism, and 28% among recipients of proDLI given for maintenance in high risk disease. The corresponding 5y OS rates were 55%, 66% and 64%, 5y-LFS rates were 52%, 57% and 58%. Efficacy of preDLI could be directly demonstrated by decreasing MRD in 71% (15/21) and by improvement of donor chimerism in 68% (110/163) of informative patients. Furthermore, hematologic improvement was observed in 13 patients following proDLI. Cumulative incidences of acute GvHD grade II-IV and chronic GvHD after DLI were 13% and 32%, respectively. A multivariate model identified a history of aGvHD ≥grade II after alloSCT (p=0.009, HR 2.1, 95% CI 1.2-3.7), an interval from alloSCT to DLI <6 months (p=0.003, HR 0.997, 95% CI 0.006-0.999), and a CD3+ cell count >1 x 106/kg at DLI1 (p=0.024, HR 1.011, 95% CI 1.001-1.021) as risk factors for induction of GvHD after DLI in CHR. One hundred and thirty three patients (39%) had died at last follow-up, with relapse still being the most frequent cause of death (n=87). Sixteen patients (5% of the entire cohort) died from DLI-induced GvHD, and 29 patients died from other courses. In summary, in this large cohort of patients receiving DLI for AL in CHR after alloSCT, efficacy of preemptive DLI cells could be demonstrated in 69% of patients. About half of patients with MRD, and >70% of patients with mixed chimerism did not experience hematological relapse during a follow up period of >5 years, suggesting a clinically meaningful effect of preDLI in AL. GvHD was the most devastating complication, leading to death in 5% of patients. The identification of risk factors for GvHD may influence the selection of candidates for prophylactic and preemptive DLI in general, and may help to refine the use of DLI in this context with respect to cell dose and timing. Disclosures Schmid: Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Bug:Celgene, Novartis: Research Funding; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; TEVA Oncology, Astellas: Other: Travel Grant. Tischer:Sanofi-Aventis: Other: advisory board. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Based on molecular aberrations, in particular the NPM1 mutation (NPM1mut) and the FLT3 internal tandem duplication (Flt3-ITD), prognostic subgroups have been defined among patients with acute myeloid leukemia with normal karyotype. Whereas these subgroups are known to play an important role in outcome in first complete remission, and also in the indication for allogeneic stem cell transplantation, data are limited on their role after transplantation in advanced disease. To evaluate the role of molecular subgroups of acute myeloid leukemia with normal karyotype after allogeneic stem cell transplantation beyond first complete remission, we analyzed the data from 141 consecutive adults (median age: 51.0 years, range 18.4-69.3 years) who had received an allogeneic transplant either in primary induction failure or beyond first complete remission. A sequential regimen of cytoreductive chemotherapy (fludarabine, high-dose AraC, amsacrine) followed by reduced intensity conditioning (FLAMSA-RIC), was uniformly used for conditioning. After a median follow up of three years, overall survival from transplantation was 64±4%, 53±4% and 44±5% at one, two and four years, respectively. Forty patients transplanted in primary induction failure achieved an encouraging 2-year survival of 69%. Among 101 patients transplanted beyond first complete remission, 2-year survival was 81% among patients with the NPM1mut/FLT3wt genotype in contrast to 43% in other genotypes. Higher numbers of transfused CD34+ cells (hazard ratio 2.155, 95% confidence interval 0.263-0.964, P=0.039) and favorable genotype (hazard ratio 0.142, 95% confidence interval: 0.19-0.898, P=0.048) were associated with superior overall survival in multivariate analysis. In conclusion, patients with acute myeloid leukemia with normal karyotype can frequently be rescued after primary induction failure by allogeneic transplantation following FLAMSA-RIC. The prognostic role of NPM1mut/FLT3-ITD based subgroups was carried through after allogeneic stem cell transplantation beyond first complete remission.

Transplant activity for acute leukemia continues to increase worldwide. In the ALWP registry more than 85000 transplant procedures for AML and ALL (auto and allo-HSCT) were registered thus far. The ALWP objectives are: (i) to organize high level accredited educational activities pertinent to acute leukemia (latest symposiums: Nantes in 2008, Barcelona in 2009, Milan in 2010, Warsaw in 2011, and Milan in 2012); (ii) to design and support prospective clinical trials in the fi eld of acute leukemia across member centres (the pan-european elderly AML randomized trial is currently recruiting patients: ClinicalTrials.gov Identifi er: NCT00766779); (iii) to generate high quality retrospective studies addressing diff erent issues related to acute leukemia management and therapy; (iv) to increase within the EBMT registry the quality of data pertinent to HSCT for acute leukemia; and (v) to generate guidelines pertinent to the management of acute leukemia. Currently, the ALWP activities are organized and structured within 6 subcommittees (SC) focused on specifi c fi elds of interest: autologous HSCT SC, Immunotherapy SC, Alternative donors SC, RIC SC, Molecular markers SC, and the Developing centers SC. The ALWP is currently chaired by M. Mohty (France) and the secretary is S. Giebel (Poland) and includes representatives/members from most EBMT centres/countries, with expertise in both auto and allogeneic HSCT for AML and ALL. The ALWP meets twice a year to discuss ongoing studies and new study proposals and review manuscript preparation. All EBMT members are encouraged to submit study proposals (registry-based studies) to the ALWP. After a quick feasibility assessment performed by the ALWP offi ce, projects will be discussed during the ALWP winter (usually October or November) and spring (during the EBMT annual meeting) business meetings.

To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience.

Acute and chronic graft-versus-host disease (GVHD) are potentially lethal complications after stem cell transplantation (SCT). Steroids are the appropriate first-line treatment for both. However, if patients do not adequately benefit from steroid therapy, mortality is high and standardized treatment algorithms are lacking. This is mainly because of limited data from prospective, randomized clinical trials. In addition, most of the available treatment options only induce clinical benefits in a limited proportion of patients. Thus, there is an urgent clinical need to develop more potent immunosuppressive treatment strategies for patients suffering from acute or chronic steroid-refractory GVHD while maintaining the graft versus tumor effect to avoid a potential rise in relapse-related mortality. The increasing knowledge about host- as well as donor-derived variables favoring GVHD development and the increasing armamentarium of immune-modulatory agents entering preclinical and clinical research will probably allow more effective treatment of GVHD in the future. This review describes novel developments in the treatment of steroid-refractory GVHD, with a special focus on the rationale behind promising pharmacologic compounds or up-coming cellular therapies.

This retrospective study analyzes 34 patients with severe sclerodermatous chronic graft-versus-host disease (cGVHD) treated with inhibitors of the mammalian target of rapamycin (mTOR-I). Twelve patients received mTOR-I as monotherapy and 22 a combination therapy. Four patients also received extracorporal photopheresis. mTOR-I were applied as first-line therapy (n = 15) or in refractory disease (n = 19). Drug doses were adjusted to low therapeutical levels (3-8 ng/mL). Six and 20 patients had a complete and a partial response, respectively, with an overall response rate of 76%. Two additional patients had stable disease. Six refractory patients required alternative therapy. Comedication, especially steroids, could be tapered and stopped in a significant number of patients. No difference in response was observed in everolimus- and sirolimus-treated patients. Major adverse events possibly related to mTOR-I were hyperlipidemia and impaired wound healing. Two patients developed thrombotic microangiopathy. Eight patients died, 5 of the nonresponders (cGVHD; n = 3, infection; n = 2) and 3 of the responders (relapse of the underlying malignancy; n = 1, secondary malignancy; n = 1, unknown cause; n = 1). Twenty-six of the 34 patients remain alive, 18 still on therapy with mTOR-I. Median follow-up for surviving patients is 723 days (range 88-1621). The overall survival at 3 years since mTOR-I is 72%. In conclusion, mTOR-I seem to be an effective and well-tolerated treatment option for patients with sclerodermatous cGVHD. Biol Blood Marrow Transplant 17: 657-663 (2011) (C) 2011 American Society for Blood and Marrow Transplantation

Abstract Abstract 1209 Poster Board I-231 Background: The prognosis of patients with cytogenetically normal acute myeloid leukemia (CN-AML) ranges from relatively favorable to extremely poor. Recently, based on the presence or absence of well defined mutations, molecular subgroups have been identified, which allow an estimate of a patient's prognosis at the time of diagnosis. Allogeneic stem cell transplantation (SCT) is the only curative treatment for the majority of these patients. However, only limited data is available to describe the role of alloSCT in different molecular subgroups of CN-AML, particularly in advanced stages of the disease. Methods: We retrospectively analyzed the data on 247 patients with CN-AML, who uniformly had received the FLAMSA-RIC conditioning regimen for alloSCT in 14 European centers between 1996 and 2008. Results: Patients suffered from de novo AML (76%), sAML/MDS (21%), and tAML (4%). Median age was 52.1 (19-71) years. Donors were matched or mismatched family, and matched or mismatched unrelated donors in 30%, 2%, 50% and 18%, respectively. SCT was performed in untreated disease (6%), after primary induction failure (PIF, median time from diagnosis to transplantation 134 days; 23%), in first complete remission (CR1, 14%), and beyond CR1 (57%). Median follow-up of survivors was 19 months. Overall survival (OS) and leukemia-free-survival (LFS) of the entire cohort at 2 years from SCT was 51% and 47%, respectively. The disease stage at transplant was the most important variable for outcome (p=.001 for OS, <.001 for LFS): Encouraging results were achieved in patients transplanted in CR1 (2y OS and LFS: 76%), and in patients with PIF (2y OS and LFS: 69%), whereas results were inferior after transplantation in previously untreated disease (2y OS and LFS: 34%), or beyond CR1 (2y OS: 42%, LFS: 34%). Age, sex, de novo vs. secondary leukemia, donor type and CD34+ cell counts showed no influence on outcome. Information on molecular markers was available in 183 patients (74%). As suggested by Schlenk et al. (NEJM 2008), analysis was based on two subgroups: 22 patients with isolated NPM1 mutation (NPM1mut), and 161 patients with other genotypes (FLT3 internal tandem duplication [FLT3-ITD], n=66; or wildtype FLT3/wildtype NMP1 [FLT3wt/NPM1wt], n=95). Patients with NPM1mut had a 4y OS/LFS of 75/63%. Results were not significantly different, when these patients were transplanted in PIF, CR1, or beyond CR1. Patients with other genotypes showed an OS/LFS of 51%/48% at 2y and of 40%/39% at 4y, without differences among patients with FLT-ITD and FLT3wt/NPM1wt. However, in this subgroup, outcome was highly dependent on the disease stage at SCT, with excellent results after transplantation in PIF (2y OS/LFS: 75%/74%) or in CR1 (2y OS and LFS: 76%), but inferior outcome after transplantation beyond CR1 (2y OS/LFS 38%/33%; p=.004 for OS and .001 for LFS). Conclusion: Allogeneic SCT following the FLAMSA-RIC conditioning produces excellent survival rates in patients with CN-AML, particularly when performed in CR1. Encouraging results in PIF support an early transplant, regardless of molecular subgroup, when CR is not reached after double induction therapy. In patients with an NPM1 mutation, transplantation in advanced disease achieved identical results as in early stage, which supports the strategy not to transplant these patients in CR1, but to delay alloSCT until relapse has occurred. In contrast, patients with FLT3-ITD or FLT3wt/NPM1wt achieved significantly worse results when transplanted beyond first relapse, arguing in favor of transplantation in CR1 for this molecular subgroup. Disclosures: Mayer: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Fresenius: Consultancy; Roche: Research Funding; Pfizer: Research Funding.

Abstract 347 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many hematologic malignancies or hematopoietic dysfunction syndromes, but the application is still limited due to major complications, such as severe graft versus host disease (GvHD) and infectious complications. Diagnosis GvHD is based on clinical features and biopsies, a non invasive, unbiased laboratory test does not exist. To date the proteomic pattern specific for aGvHD was evaluated blindly on 961 samples collected from 345 patients undergoing allo-HSCT at MHH and 7 additional clinics, including the University of Michigan. The majority of the patients included were transplanted for hematological malignancies (n=329), 16 for hematopoietic failure syndromes, mainly severe aplastic anemia. Conditioning regimens included dose reduced conditioning regimens (FLAMSA and ClaraC for the majority of the patients of MHH), as well as standard conditioning regimens (TBI+Cy or Busulfan+Cy) for about 35% of the patients. GvHD-prophylaxis was cyclosporine A (CSA) and mycophenolate (MMF) or CSA metothrexate (MTX) as appropriate. In addition, about 80% percent of the patients received ATG (antithymocyte globulin) prior to HSCT. A peptide pattern of 31 peptides - either absent/decreased (15) or present /increased (16) - was previously published (Weissinger et al. 2007). Prospective and blinded evaluation of the patients included in this diagnostic analysis for early recognition of patients at risk for aGvHD development revealed the correct classification of patients developing aGvHD about 7 days prior to the development of clinical symptoms for aGVHD with a sensitivity 76% and specificity of about 85% (fig.1). Additional data obtained from patients transplanted until September 2009 will be reported. Based on these data a pre-emptive therapy multicenter trial, administering steroids upon positivity of the proteomic pattern has been initiated now in 10 German centers, testing the efficacy of the pre-emptive therapy on incidence and severity of aGvHD and a possible benefit on overall survival of the patients. Disclosures: Krons: mosaiques-diagnostics GmbH: Employment. Metzger: mosaiques-diagnostics GmbH: Employment.

Abstract Abstract 2254 Poster Board II-231 Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in hematopoietic transplant recipients. The mammalian target of rapamycin inhibitors (mTOR-I) sirolimus and everolimus are immunosuppressants that have activity in the prevention and treatment of acute GVHD. Sirolimus in combination with calcineurininhibitors (CNI) has also been shown to have activity in chronic GVHD, however at the cost of considerable toxicity. Since mTOR-I exert their action by blocking interleukin 2 receptor signaling and thus arresting the cells at G1 phase they are promising candidates for tolerance induction. In addition, they also have antiangiogenic and antiproliferative activity. We hypothesized that treatment of cGVHD with mTOR-I and without CNI would be more effective in inducing tolerance than the combination of both and would have a lower toxicity profile. In this retrospective analysis we report 31 consecutive patients (pts) with severe cGVHD according to the NIH consensus, in whom treatment with mTOR-I (everolimus n=20; sirolimus n=11) was initiated between 2004 and 2006, with a median follow-up after initiation of mTOR-I therapy for surviving pts of 46.5 months. Three pts terminated treatment prematurely (within 3 months after starting therapy) because of adverse events (1xsevere cough; 1xhypertriglyceridemia; 1xmouth ulcers) and they were excluded from further analysis. Of the remaining, 12 pts had de novo or quiescent cGVHD, 5 progressive cGVHD developing from acute GVHD and 11 had cGVHD following donor lymphocyte transfusions. Organ involvement included skin (scleroderma) in 21, lungs in 12, mucous membranes in 9, liver in 6, gut in 2 and eyes in 4 pts. Eighteen pts received mTOR-I in combination with steroids, three received a monotherapy and 7 pts received additional immunomodulatory drugs, no CNI however. To further reduce the risk of adverse events drug trough levels were monitored and the dosing was adjusted to low therapeutical levels (3-8 ng/ml). Eleven pts each had a complete and partial response, respectively, with an overall response rate of 78%. At the time of analysis 6 of the 15 surviving pts were complete off immunosuppression and steroids could be tapered and stopped in 5 additional pts. Best responses were seen in pts with de novo or quiescent cGvHD. Thirteen pts have died. Causes of death were: progressive cGvHD (n=5) relapse of the underlying disease (n=4), infections (n=2), secondary malignancy (n=1), unknown (n=1). No difference was observed in everolimus- and sirolimus-treated pts. With a median treatment time of 24 months (range 3 – 54 mo) the major adverse events possibly related to mTOR-I were hyperlipidaemia and impaired wound healing, especially in pts with ulcerative lesions of skin or mucous membranes. Only one of the pts developed thrombotic microangiopathy (TMA) and infectious complications were rare. In pts treated in combination with steroids frequently a shortened prothrombin time has been observed, suggesting an increased risk for thomboembolic events. Controlled trials comparing this approach with alternative strategies are warranted. Disclosures: Off Label Use:Everolimus and Sirolimus for the treatment of chronic GVHD. Jedlickova:Wyeth: Research Funding.

Abstract Abstract 1164 Poster Board I-186 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many hematologic malignancies or hematopoietic dysfunction syndromes, but the application is still limited due to major complications, such as severe graft versus host disease (GvHD) and infectious complications. Diagnosis chronic GvHD is based on clinical features and biopsies, a non invasive, unbiased laboratory test does not exist. We used the urine collected from 20 patients (10 with limited cGvHD, 10 with extensive cGvHD) to establish a proteomic pattern that allowed the diagnosis of cGvHD development and tested the resulting set of polypeptide markers (27 differentially excreted peptides) on more than 200 patients prospectively and blinded for the correct classification of cGvHD samples. The majority of the patients included were transplanted for hematological malignancies (n=209), 6 for hematopoietic failure syndromes. Conditioning regimens included dose reduced conditioning regimens (FLAMSA and ClaraC for the majority of the patients of MHH), as well as standard conditioning regimens (TBI+Cy or Busulfan+Cy) for about 35% of the patients, with GvHD-prophylaxis including cyclosporine A and mycophenolate (MMF) or metothrexate (MTX) as appropriate. Eighty percent of the patients received ATG (antithymocyte globulin) prior to HSCT. A peptide pattern of 27 peptides, differentiating chronic from acute GvHD was developed. Controls were patients at least 100 days post HSCT, with no GvHD in the history, no infections and without relapse at the time of sampling. Prospective and blinded evaluation of the patients revealed the correct classification of patients developing cGvHD with a sensitivity of 85% and specificity of 95%.Further evaluation of the cGvHD patterns specific for particular organ manifestations of cGvHD are currently ongoing. Interestingly, the cGvHD pattern seems to be predictive for GvHD developing post DLI, while the aGvHD-specific proteomic pattern only predicts GvHD of the intestine, which may be more similar to “late acute GvHD”. Disclosures Krons: mosaiques-diagnostics GmbH: Employment. Metzger:mosaiques-diagnostics GmbH: Employment.

Adjuvant transfusion of donor lymphocytes (aDLT) may reduce the risk of relapse after allogeneic stem cell transplantation. We report our data on aDLT in high-risk AML. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and aDLT. For aDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression and free of GvHD. 30% of patients (n=46) alive at day +120 fulfilled the criteria for aDLT. They had been transplanted for refractory (n=11) or relapsed leukemia (n=24) or in CR1 because of unfavourable cytogenetics (n=7) or other unfavourable criteria (n=2) or in CR2 with unfavourable cytogenetics (n=2). 24 patients had an unfavourable karyotype, 10 with complex aberrations. Thirty-one patients with similar disease characteristics and fulfilling similar selection criteria (being alive in CR at d +120, no cGVHD and no history of aGVHD> II°) transplanted during the same time period served as control. Of these, 10 pts. were transplanted at a different center not using aDLT and 21 at the center in Wiesbaden during 2000 and 2002 prior to the introduction of the protocol at this center. The median time from transplant to first aDLT was 160 days (range 71–303). Median follow up of the surviving transfused patients is 3.6 years (range 1.8–7.8). Seven patients received 1, 15 patients received 2, and 24 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at aDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or patient’s refusal. Induction of GvHD was the main complication; grade II/III acute GvHD developed in 4, and chronic GvHD in 8 patients. So far, 9 (19.6%) patients have relapsed despite aDLT, as compared to 52.9% in the control group (Fisher-exact: p=0.004). Of these, 8 pts. finally died despite adoptive immunotherapy and only one patient is now surviving more than 3 years after relapse was treated by a second transplantation. Non relapse mortality post DLT was low with patients dying from infection, severe cGvHD, and secondary solid tumour one each. At the time of analysis, 35/46 patients are alive and all are in CR at a median of 3.2 years post first DLT. The actuarial overall survival four years after transplant is 79% as compared to 34% in the control group and at six years 63% vs. 31%, respectively (p=0.000). In conclusion, aDLT is safe, when given in escalating doses and to a selected group of patients. Results are encouraging, and improved long term leukemia-free survival can be achieved.