ALBERT

Description: The currently observed Arctic warming will increase permafrost degradation followed by mineralization of formerly frozen organic matter to carbon dioxide (CO 2 ) and methane (CH 4 ). Despite increasing awareness of permafrost carbon vulnerability the potential long-term formation of trace gases from thawing permafrost remains unclear. The objective of the current study is to quantify the potential long-term release of trace gases from permafrost organic matter. Therefore, Holocene and Pleistocene permafrost deposits were sampled in the Lena River Delta, Northeast Siberia. The sampled permafrost contained between 0.6 and 12.4% organic carbon. CO 2 and CH 4 production was measured for 1200 days in aerobic and anaerobic incubations at 4°C. The derived fluxes were used to estimate parameters of a two pool carbon degradation model. Total CO 2 production was similar in Holocene permafrost (1.3 ± 0.8 mg CO 2 -C gdw −1 aerobically, 0.25 ± 0.13 mg CO 2 -C gdw −1 anaerobically) as in 34,000 to 42,000 year old Pleistocene permafrost (1.6 ± 1.2 mg CO 2 -C gdw −1 aerobically, 0.26 ± 0.10 mg CO 2 -C gdw −1 anaerobically). The main predictor for carbon mineralization was the content of organic matter. Anaerobic conditions strongly reduced carbon mineralization since only 25% of aerobically mineralized carbon was released as CO 2 and CH 4 in the absence of oxygen. CH 4 production was low or absent in most of the Pleistocene permafrost and always started after a significant delay. After 1200 days on average 3.1% of initial carbon was mineralized to CO 2 under aerobic conditions while without oxygen 0.55% were released as CO 2 and 0.28% as CH 4 . The calibrated carbon degradation model predicted cumulative CO 2 production over a period of 100 years accounting for 15.1% (aerobic) and 1.8% (anaerobic) of initial organic carbon, which is significantly less than recent estimates. The multi-year time series from the incubation experiments helps to more reliably constrain projections of future trace gas fluxes from thawing permafrost landscapes. © 2012 Blackwell Publishing Ltd

Description: Background and Aims: Patients after allogeneic hematopoietic stem cell transplantation (HSCT) suffer from immunodeficiency, in part due to long-term immunosuppressive medication e.g. by calcineurin inhibitors like cyclosporine A (CsA). Additionally, these patients have an increased risk for opportunistic fungal infections like invasive aspergillosis (IA). The nuclear factor of activated T cells (NFAT) is known as an important transcription factor in signaling-pathways downstream of calcineurin in the adaptive immune systems, e.g. in T cells, but also plays an important role in innate immune response as indicated by recent data in rodent models. These studies showed a relevant impact of NFAT-/calcineurin inhibition on the innate immune response by polymorphonuclear neutrophils (PMN) in a candida sepsis model. To clarify whether this is also relevant in humans, we investigated the role of NFAT signaling pathways in PMN activation and effector functions in healthy volunteer donors and patients under immunosuppressive treatment with CsA after HSCT. Methods: Firstly, we performed in vitro experiments using PMN from healthy donors analyzing their effector functions in absence or presence of CsA in titrated doses according to therapeutic levels. In detail, we examined phagocytosis, activation, generation of reactive oxygen species (ROS) and release of inflammatory mediators like IL-8 and TNF-α. After activation with lipopolysaccharide (LPS) and zymosan, phagocytosis and activation-induced shedding of CD62L were measured by flow cytometry using polychromatic microspheres and matching surface markers (CD11b, CD62L, CD66b). In addition, generation of ROS was analyzed by dichlorofluorescein assay (DCF), whereas activation-induced release of inflammatory mediators was measured by enzyme-linked immunosorbent assay (ELISA) and intracellular flow cytometry. In addition, blood samples of patients after HSCT under continuous CsA medication (n=6) and healthy volunteer donors (n=6) were analyzed ex vivo at two different time points after allogeneic HSCT (day 25-35 and 125-135) concerning their PMN effector functions in the same manner as described above. Results: Analysis of healthy donors PMN in vitro showed that CsA had no significant influence on expression of activation markers and shedding of CD62L. Moreover, no substantial influence of CsA on generation of ROS was detected compared to untreated controls (5245 RFU +/- 354 (CsA) vs. 5763 +/- 520 (control) after stimulation with LPS, mean +/- SEM). Furthermore, activation-induced synthesis of IL-8 was not reduced in presence of CsA (519pg/ml +/- 81 vs. 463 +/- 131 (control) after stimulation with LPS). In contrast, CsA rather enhanced phagocytosis after stimulation with LPS (83.5% +/- 1.7 vs. 71.0 +/- 1.5 (control)). Regarding the ex vivo analysis of HSCT patient and healthy donor blood samples, production of ROS was not affected under CsA therapy (35.1% +/- 9.4 vs. 31.1 +/- 6.6 (control) after stimulation with zymosan). Furthermore, CsA medication showed a stimulating effect on PMN phagocytosis which is in line with our in vitro data (58.4% +/- 7.1 vs. 44.3 +/- 2.3 (control) after stimulation with LPS). Interestingly, in several patients an increased production of IL-8 and TNF-α was detectable after stimulation with zymosan (IL-8: 9.1% +/- 3.6 vs. 1.5 +/- 0.3 (control); TNF-α: 16.6% +/- 6.2 vs. 1.0 +/- 0.4 (control)). Conclusions: In contrast to previous results by others in murine model systems, we found an increased phagocytic activity in vitro and ex vivo in human PMN upon NFAT/calcineurin inhibition, whereas other effector mechanisms were unaffected. In addition, HSCT patients under CsA treatment displayed enhanced inflammatory mediators production in PMN. It is currently unclear whether these findings are clinically relevant for the innate immune response after HSCT, e. g. in terms of anti-fungal immunity. Further studies are needed to address whether these enhanced PMN functions in the presence of CsA contribute to a dysregulated innate immune response in humans. Alternatively, our discrepant results may be due to differences in PMN functionality and CsA responsiveness in mice and man. However, while CsA strongly suppresses adaptive immune responses, i.e. T-cell responses in graft-versus-host disease (GvHD), our results so far suggest that CsA does not affect innate immune effector functions by humans PMN in a comparable way. Disclosures Radsak: Celgene: Research Funding.

Description: Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of tissue mast cells (MC) in various organ systems, including bone marrow (BM). Indolent and advanced forms of SM have been described. Whereas patients with ISM have a normal or near normal life-expectancy, patients with advanced SM, including those suffering from mast cell leukemia (MCL) have a poor prognosis. In these patients, neoplastic MC are usually resistant against conventional drugs and various targeted drugs. In rapidly progressive aggressive SM (ASM) and MCL, polychemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHCT) has been proposed. However, outcome of alloHCT in advanced SM is unknown, and it also remains uncertain whether clinically relevant graft-versus-SM (GVSM) effects may occur in these patients, as only sporadic case reports have been published. We performed a retrospective multi-center analysis to evaluate the outcome of alloHCT in patients with advanced SM. Fifty-four advanced SM patients receiving SCT in 32 transplantation centers in Europe and America were identified between 1990 and 2013. The median patient age was 45 years. Donors were: HLA identical siblings (31), unrelated donors (URD) (15), umbilical cord blood donors (UCB) (2), and haploidentical donors (1). In 5 patients, stem cell source was not defined (5). Thirty-four patients received myeloablative conditioning (MAC) and 18 received reduced intensity conditioning regimens (RIC). In 2 patients, conditioning regimen was not specified. Indications for alloHCT were SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) (n=32), MCL (n=13, including one with MCL-AHNMD), 8 with ASM and 1 with myelomastocytic leukemia (MML). The most prevalent AHNMD was acute myeloid leukemia (AML, n=16). With follow-up of 35-6180 (median 365) days, SM responses (defined as ≥50% decrease in BM mast cells ± decrease in serum tryptase ± regression of other organ manifestations) were observed in 39 patients (72%), including complete responses (CR) documented in 12 patients (22%). Eleven patients had stable disease, whereas 4 patients (7%) progressed immediately after alloHCT (primary resistance). In addition, 10 patients progressed (5 of them within 100 days) after an initial response. Progression was most frequently seen in MCL patients (n=6, 50%). In the AHNMD group, only 8 patients relapsed/progressed (25%). The overall survival (OS) and SM progression-free survival (PFS) at 1 year were 63% and 50% for all patients, 77% and 68% for SM-AHNMD, 63% and 50% for ASM, and 25% and 17% for MCL, respectively. The strongest predictive variable associated with inferior survival was a diagnosis of MCL. Other factors associated with poor outcome were: Karnofsky performance status ≤70%, ≥2 SM regimens given before alloHCT (e.g., steroids, cladribine, chemotherapy, tyrosine kinase inhibitor), donor source (alternative donors-UCB and haploidentical compared to sibling or URD), SM progression within the first 100 days, normal cytogenetics (compared to t(8;21) (q22;q22), and RIC (compared to MAC). The following variables were not associated with poor outcome: patient and donor age, recipient-donor sex match status, graft source (BM vs. peripheral stem cells), BM mast cell percentage at time of alloHCT, and CR status of AML or SM response at time of alloHCT. This largest multi-center analysis of results in advanced SM provides evidence for clinical efficacy of alloHCT, presumably because of a GVSM effect of alloHCT (achieving CR, and response to donor-lymphocyte infusions and RIC alloHCT). However, responses varied among different SM categories: while patients with SM-AHNMD enjoyed excellent outcomes, the OS for MCL patients in general, was poor. Nevertheless it is remarkable that 3 of 13 patients with MCL – an otherwise fatal disease with a median survival of

Description: 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.

Description: Introduction: Relapse of AML after allogeneic HCT has a dismal prognosis. Long-term survival after 2nd allogeneic HCT has been described in selected patients. Here we tested a specific protocol with a fixed drug combination for myeloablative conditioning and GvHD prophylaxis for 2nd allogeneic HCT from a different unrelated donor. (EudraCT no.: 2012-005414-18, German Clinical Trials Registry no.: DRKS00005126) Methods : Aim of the trial was to show efficacy and safety of a 2nd alloHCT from an unrelated donor after a uniform conditioning with Treosulfan 3x12gm/m2, Fludarabin 3x30mg/m2, and Thiotepa 3x 5mg/kg (TFT), and GvHD prophylaxis with cyclosporine A (CyA) /Mycophenolate and ATG-F (Neovii) 3x10mg/kg. Eligible were adult patients with AML, ECOG ≤ 2, with sensitive or refractory hematologic relapse (≥ 20% blasts) 〉 6 months after a prior allogeneic HCT , including secondary (s) and/ or tAML. CR prior 2nd HCT was no prerequisite. The primary endpoint of the study was disease-free survival (DFS) defined as being alive and free of disease at 1 year post 2nd HCT. Secondary endpoints were relapse, relapse mortality (RM), NRM, overall survival (OS), acute GvHD, chronic GvHD, engraftment, and adverse events. According to the Fleming one-stage design, 50 evaluable patients had to be included. If 16 or more patients were alive and free of disease at 1 year post 2nd SCT, the regimen could be considered as successful for evaluation in further trials. With this decision rule, it can be shown at one-sided α=0.1 that the probability of DFS at 1 year post 2nd HCT is higher than 23% with a power of 90%, when it is at least 40%. This is a first analysis of the study covering the first year after 2nd HCT of each patient. The analysis is based on the full analysis set, which includes all patients, for whom the conditioning regimen TFT and the GvHD prophylaxis regimen CyA, MPA/MMF, ATG-F has started, and for whom allogeneic HCT from an unrelated donor has been performed. Results: Fifty-two patients were registered for the study from 25th March 2014 up to 10th March 2017 from 9 German centres. The full analysis set includes 50 patients (median age 53.5 years). ECOG was median 1. Donors for 1st allo HCT had been related (n=11 (22.0%)) or unrelated (n=39 (78.0%)) (n=48 PBSCT, n=2 bone marrow). Conditioning for 1st HCT was myeloablative in 23 (46.0%) patients. After 1st HCT, the rate of acute GvHD I-IV was 34.0%, and of chronic GvHD was 40.0%. Median time from 1st HCT to relapse was 17.2 months and from relapse after 1st HCT to 2nd HCT 2.5 months. Thirty-six (72%) patients had received induction chemotherapy for relapse prior to 2nd HCT, 11 (22.0%) patients had received azacytidine or decitabine, and 11 (22.0%) had received donor lymphocyte infusions (DLI). Remission status prior to 2nd HCT was complete remission in 16 (32.0%) patients, chemo-refractory relapse in 33 (66.0%), one patient was in partial remission. With regard to the primary endpoint, 23 (46%, 95%-CI (31.8-60.7%) of the patients were alive and free of relapse at 1 year after 2nd SCT. With regard to the secondary endpoints at 1 year, the cumulative incidence of relapse (95%-CI) was 26 (17-42)%, 9/50 patients (18 (10-33)%) died after relapse of AML, NRM was 14/50 patients (28 (18-44)%, cause: infection n=6, infection after aGvHD n=6, PTLD n=2), OS was 54 (39-66)%. Four patients are alive after relapse. aGvHD rate was 54 (42-70)%, aGvHD III-IV 26 (16-42)%, cGvHD 26 (16-42)%, extensive cGvHD 20 (12-35)%, engraftment rate with ANC 〉 1.0 x 103/µl was 92 (85-100)%, with platelets 〉 20 x 103/µl was 80 (70-92)%, and with platelets 〉 100 x 103/µl was 66 (54-81)%. After 1 year, 4 patients had received DLI for prophylaxis, and 5 patients for mixed chimerism as per protocol. Conclusion: Second alloHCT with an ablative double alkylator containing conditioning regimen with Thiotepa, Fludarabine, and Treosulfan is feasible and can result in sustained disease control in patients with AML relapse after a first alloHCT, and therefore seems to be a valid option in this otherwise detrimental setting. Disclosures Finke: Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, 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; Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria. Burchert:Novartis: Research Funding; Bayer: Research Funding; AOP Orphan: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Schub:Affimed: Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Description: Background: An ex vivo photodepletion method has been developed to produce ATIR101 (Kiadis Pharma), a donor lymphocyte infusion (2.0 × 106 cells/kg) administered after haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) to aid immune reconstitution. ATIR101 is depleted of alloreactive T-cells and early administration after T-cell-depleted haplo-HSCT has the potential to reduce serious complications resulting from delayed immune reconstitution, such as infections, malignant relapse, and severe graft-versus-host disease (GVHD) in the recipient. The safety and efficacy of a single dose of ATIR101 are presented here in a pooled analysis of two phase II clinical trials: CR-AIR-007 (NCT01794299) & CR-AIR-008 (NCT02500550). Methods: A pooled analysis of 37 adult patients who received haplo-HSCT. All but 3 patients have completed 1 year of follow-up (data cut-off: June 1, 2018). The study designs are aligned, with similar inclusion and exclusion criteria and baseline patient characteristics. Overall, 32 patients received a single dose of ATIR101; n=5 did not receive ATIR101 and discontinued after HSCT due to death (n=2), graft failure (n=1), and rejection of the ATIR101 batch (n=2). In the pooled cohort, n=24 had acute myeloid leukemia (65%), n=10 had acute lymphoblastic leukemia (27%), and n=3 had myelodysplastic syndromes (8%), with 57% of patients having an intermediate disease risk index (DRI) and 43% a high DRI. All patients underwent myeloablative conditioning followed by a CD34+ selected stem cell graft from a haploidentical family donor. ATIR101, prepared from the same donor, was given at a median of 28 days post HSCT as a single dose of 2.0 × 106 cells/kg, without the use of prophylactic immunosuppression. These data were compared with outcomes from a historic control group of 35 patients treated with a T-cell-depleted CD34+ selected haplo-HSCT without ATIR101 at overlapping participating hospitals in a prospectively planned registry study (CR-AIR-006, NCT02188290). Results: Thirty-six patients engrafted, with neutrophil engraftment at a median of 14 days (range 8-34) and platelet engraftment at a median of 12 days (range 7-35) post HSCT. Outcomes are shown in Table 1. In the pooled cohort, non-relapse mortality (NRM) was 33% and relapse-related mortality was 8%, compared with 66% and 15%, respectively, in the historic control group. The overall survival (OS) of patients was 58% in the pooled cohort (Figure 1A) and 20% in the historic control group. In the pooled cohort, total chronic GVHD was 3%, chronic severe GVHD was 0%, and acute GVHD grade III-IV was 5%, with 0% grade IV; in the historic control group, the results for total chronic GVHD, chronic severe GVHD, and acute GVHD grade III-IV were 11%, 9%, and 6%, respectively. The Kaplan-Meier curve for survival without grade III/IV acute GVHD, chronic GVHD requiring systemic treatment, or relapse (GRFS) showed significant separation for the pooled cohort versus the historic control group (P=0.01; Figure 1B); the GRFS rates for the two groups were 53% and 20%, respectively. Conclusion: OS was nearly threefold higher in the pooled cohort than in patients not receiving ATIR101 after haplo-HSCT in the historic control group. These outcomes were achieved without the need for concomitant high-dose immunosuppressive therapy. Disease relapse was limited and NRM in the pooled cohort was half that of the historic control group. Administration of a single dose of ATIR101 after a T-cell-depleted haplo-HSCT was well tolerated. The rate of GVHD is lower in the pooled cohort than the historic control group, suggesting that ATIR101 does not increase GVHD beyond the levels reported with a T-cell-depleted CD34+ selected HSCT alone. GRFS in the pooled cohort was 〉2.5-fold higher than the historic control group and also seems higher than GRFS rates previously reported for other studies using post-transplant cyclophosphamide (PTCy) after T-cell-replete HSCT (Solh 2017, McCurdy 2017). To further investigate the therapeutic potential of ATIR101, a large, phase III, randomized control trial is currently underway to assess the relative safety and efficacy of ATIR101 after T-cell-depleted haplo-HSCT, versus PTCy after T-cell-replete haplo-HSCT (CR-AIR-009 HATCY; NCT02999854). Disclosures Roy: University of Montreal: Patents & Royalties: Author on patent; Kiadis Pharma: Other: Travel support; Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent. Beguin:Kiadis Pharma: Consultancy. Selleslag:Kiadis Pharma: Other: Financial support for study-related issues. Wagner:Medac: Other: Travel grant. Bonig:Kiadis Pharma: Consultancy. Mielke:Kiadis Pharma: Other: Travel grants, Research Funding.

Description: Background The best preparative regimen for the growing number of older acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients undergoing allogeneic hematopoietic cell transplantation (HCT) from matched related (MRD) or unrelated donors (MUD) remains undefined. A large randomized phase III trial (MC-FludT.14/L study: ClinicalTrials.gov Identifier: NCT00822393) recently demonstrated that myeloablative intravenous (IV) treosulfan (10 g/m² IV on days -4 to -2) in combination with fludarabine (TreoFlu) improves outcome in older and/or comorbid patients with AML in complete remission (CR) or MDS compared with the reference reduced intensity busulfan (0.8 mg/kg IV in 6-hour intervals on days -4 and -3) and fludarabine (30 mg/m² IV on days -6 to -2 in each study arm) regimen. The beneficial effect of the TreoFlu regimen resulted from a significantly reduced non-relapse mortality (NRM) and translated to improved event-free survival (EFS) and overall survival (OS) (Beelen DW et al The Lancet Haematology, 2019). These results raised the question, how this new regimen compares to broadly applied myeloablative regimens, namely busulfan (0.8 mg/kg IV in 6-hour intervals over 4 days) plus cyclophosphamide (120 mg/kg IV over 2 days) (BuCy) or melphalan (140 mg/m² IV over 1 day or 2 days) plus fludarabine (MelFlu) in older AML and MDS patients. To address this question, we performed a comparative analysis of MC-FludT.14/L study patients treated with the TreoFlu regimen and similar patients of the European Blood and Marrow Transplantation Society (EBMT) registry, who underwent HCT from MRD or MUD after the BuCy or MelFlu regimen between 2010 and 2016. Patients and Methods Inclusion criteria were essentially the same as for the MC-FludT.14/L-study (patient age 50 to 70 years [yrs], primary or secondary AML in CR or MDS, Karnofsky-index ≥ 60%, MRD or MUD, 1st HCT). The study objectives were to compare OS, relapse incidence (RI), and NRM at 2 yrs after HCT between the TreoFlu regimen and the BuCy or MelFlu regimen. A total of 1493 EBMT registry patients (median age 58 yrs, AML: n=1135 [76%], MDS: n=358 [24%]) were identified for the comparison with the 252 MC-FludT.14/L patients (median age 61 yrs, AML: n=174 [69%], MDS: n=78 [31%]). A 1:1 matching method based on propensity scores (PS) with 14 patient-, donor-, and disease-characteristics was used to reduce confounding due to differences between regimens and was performed separately for AML and MDS patients. With the exception of comparison between the TreoFlu and BuCy regimen in AML patients, a significantly higher proportion of patients in the TreoFlu regimen subsets had a HCT-comorbidity index 〉 2 compared to patient subsets treated with the BuCy or MelFlu regimen. Results For patients with AML, the 2-yrs OS estimate was significantly higher after the TreoFlu compared with the BuCy regimen (76.4%, 95%-confidence interval [95%-CI]: 66.8% - 85.9% vs 49.2%, 95%-CI: 36.4% - 62.1%, p

Description: Introduction: The combination of reduced-intensity conditioning (RIC) with in vivo T-cell depletion by alemtuzumab prior to hematopoietic stem cell transplantation (HSCT) has demonstrated efficient engraftment and reduced graft-versus-host disease (GVHD). However, this regimen is associated with slow lymphocyte recovery leading to a delayed anti-infectious and anti-malignant immunity. DLI can be used to improve immune reconstitution. Here we investigate on the impact of different DLI: prophylactic CD8-depleted DLI vs preemptive non-depleted DLI. Methods: 256 patients with different hematologic malignancies were planned for treatment with DLI after allogeneic HSCT following reduced intensity conditioning (Fludarabin, Melphalan, in vivo Alemtuzumab). All patients received PBSC. Donors were HLA-identical siblings or HLA-matched unrelated donors. The calcineurin-inhibitor used for GVHD-prophylaxis (Cyclospron A) was intended to be tapered until day 50. 134 patients should receive CD8deplDLI prophylactically after day +60 (Group A). 122 patients were planned for non-depleted DLI after day +100 in a preemptive setting. Trigger for preemptive DLI were mixed donor chimerism or MRD positivity. Both groups received DLI in escalating doses with an interval of 60 to 90 days. DLI application was stopped when GVHD occurred (Group A and B), or a full donor chimerism was achieved / MRD became negative (Group B). Both patient-groups did not differ in median age. The majority of patients either suffered from an acute leukemia / MDS (n=42%), lymphoma (n=28%), myeloma (n=17%), or myeloproliferative neoplasms (n=12%) and these diseases were equally distributed among the groups. All patients were treated at the university medical center in Mainz, Germany. Results: Of 134 patients (Group A) 41% received CD8deplDLI prophylactically (GVHD was the main cause for withholding DLI). In group B, 32% of 122 patients received preemptive non-depleted DLI. 2 Year-Overall survival (OS) significantly increased in all patients (both groups) after DLI (74% with DLI, 37% without DLI, p