ALBERT

Description: RATIONAL Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype, carrying a pejorative prognosis. Constitutive activation of the NF-kB pathway via mutations in B cell receptor (BCR) pathway (CD79B) and mutation of MYD 88 and TBL1XR1 plays an important role in PCNSL. Ibrutinib, an inhibitor of BCR signaling, has been found to have significant therapeutic activity in relapsed or refractory non-CNS non-GC DLBCL. METHODS In this prospective, multicenter, open-label phase II, we enrolled immuno-competent patients over 18 with a refractory or relapse of PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in ibrutinib monotherapy given orally at 560 mg daily until disease progression or unacceptable toxicity. Additional corticosteroids treatment was allowed during the first 4 weeks of treatment in case of a threatening or symptomatic edema. Therapeutic responses were assessed according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The primary objective of the study was the disease control (DC) rate (CR + CRu + PR + SD) after two months of treatment. This study is a two-stage Simon's design. Patients were evaluable for response if they received 〉 90 % of the expected dose during the first month of treatment. An interim analysis for futility was planned when 18 patients were evaluable for response. P0 and P1 hypotheses were 〈 10 % and 〉 30 % respectively. A total of 35 evaluable patients are required for the final analysis. Exploratory ancillary studies are planned and consist in dosage of ibrutinib in the cerebrospinal fluid after one cycle of treatment, and correlation of therapeutic response with mutational status of the disease. This study is registered with ClinicalTrials.gov, number NCT02542514. RESULTS BetweenSeptember 25, 2015 and June 30, 2016, 52 patients were recruited in 10 French centers of the French LOC network for PCNSL. The interim analysis was done on the first 18 patients evaluable for response (median age: 70 y, range 49-80). At initial diagnosis, diagnoses were PCNSL (n = 12) and PVRL (n = 6). Patients were included in the study for a relapse (n = 13) or a progressive disease (n = 5). At time of inclusion in the study, disease status was PCNSL (n = 11) and PVRL or isolated intra-ocular relapse of a PCNSL (n = 7). ECOG performance status was 0, 1 and 2 in 4, 10 and 4 patients respectively. All the patients had previously received high-dose methotrexate-based chemotherapy. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplantation. Patients had received 1, 2 or 3 prior treatments in 12, 5 and 1 cases respectively. Three patients had a concomitant meningeal involvement. Five patients received concomitant corticosteroids during the first month of treatment. At the time of analysis (median follow-up = 6.6 months), nine patients discontinued ibrutinib after a median duration of 3 months (range, 0.9 -6.4) because of a disease progressive(n = 8) or a concurrent illness (n=1). Median number of treatment cycles was 5 (range, 1-9). One patient experienced a pulmonary aspergillosis with a favorable outcome. No hemorrhagic complication was reported. Five patients died due to disease progression (n = 4), and concurrent illness (n = 1). After two months of treatment, a DC was achieved in 15/18 patients (83 %, IC 95 %, [59-96%]) (complete and unconfirmed complete response: n =3; partial response: n = 7; stable disease: n =5). CONCLUSION In this interim analysis, Ibrutinib monotherapy demonstrated a high DC rate of 83%, including 56% objective responses in patients with relapse/refractory PCNSL or PVRL. Regarding safety, Ibrutinib might be a risk factor for aspergillosis in this population of PCNSL patients, otherwise not exposed to fungal infection. A security warning was sent to all the investigators for a close monitoring of infections. The second cohort of patients has been recruited. Thirty-three patients are currently on study treatment. The final analysis of the iLOC study is awaited to confirm these encouraging results and better define the positioning of ibrutinib in the therapeutic strategy of PCNSL and PVR patients. Disclosures Choquet: Janssen: Consultancy; Celgene: Consultancy. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Soussain:Celgene: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding.

Description: Abstract 1980 Background. Chronic GVHD is one of the most serious consequences of allo-SCT associated with high morbidity and mortality. Therefore, identification of potential predictors of cGVHD is crucial. At present, there is no validated prognostic blood test for cGVHD. The aim of this study was to expand the search for cGVHD biomarkers, to validate candidate proteins using high-throughput assays in a series of 152 consecutive patients treated in a single center, and to determine a composite prognostic score for prediction of extensive cGVHD. Patients and Methods. Patients included in the analysis were treated between 2005 and 2008 and had a median follow-up of 2.3 y. Per study definition, patients survived at least 4 months after allo-SCT. Median age at time of allo-SCT was 49 y (range, 17–70) and 55% were males. 87 (57%) recipients were treated for myeloid malignancies. Seventy patients (53%) received allo-SCT from an HLA-matched related donor; while 60 patients (40%) received allo-SCT from an HLA-matched related donor and 22 (14%) received an HLA-mismatched unrelated graft. Prior to allo-SCT, 48 patients (32%) underwent a myeloablative conditioning (MAC) regimen, while 104 cases (68%) received a reduced-intensity conditioning (RIC). G-CSF-mobilized peripheral blood stem cells (PBSCs) were used in 108 cases (72%), bone marrow in 28 cases (18%) and unrelated cord blood cells in 18 cases (12%). In this series, 70 patients were diagnosed with cGVHD (23 with a localized/limited form and 47 with an extensive form) after a median of 7.14 months after allo-SCT. At 2 years, the cumulative incidence of extensive cGVHD was 40% and overall survival of the whole cohort was 69% (95%CI, 62–77 %). For the purpose of this study, serum samples were collected around day 100 (range, 83–119) after allo-SCT. Forty-one cytokines were studied using Luminex xMAP technology (Millipore, Billerica, USA). Results. In multivariate analysis, 2 clinical factors were associated with extensive cGVHD occurrence: history of prior acute GVHD (P=0.0019, HR=2.6, CI95%, 1.429–4.839) and the use of PBSCs as graft source (P=0.0067, HR=3.1, CI95%, 1.365–6.896). Independently from these clinical factors, 10 cytokines were found to be significantly correlated with the incidence of extensive cGVHD. High levels of IP10 (CXCL10) (p=0.0010), IL15 (p=0.0280), IL10 (p=0.0112), IL2RA (p=0.0261) and MIP-1beta (CCL4) (p=0.0108) were associated with higher incidence of extensive cGVHD, while high levels of Fractalkine (CX3CL1) (p=0.0081), MDC (CCL22) (p=0.0005), RANTES (CCL5) (p=0,0083), TARC (CCL17) (p=0.0041), IL12p40 (p=0.0155) were associated with a lower risk of developing extensive cGVHD. Based on these findings, we then sought to establish a practical prognostic score capable of predicting extensive cGVHD. This score was calculated using the traditional multivariate Cox model combined with the statistical approach called “time-dependent receiver-operator characteristic (ROC) curves”, making it possible to assess the predictive capacity marker that is being evaluated, as described bu Heagerty PJ et al., (biometrics 2000). Here, we have focused on the 2 significant clinical variables (prior history of acute GVHD and PBSCs as graft source) and the most significant cytokines found in the multivariate analysis in order to obtain a useful tool in the daily medical practice. Based on 0,632 bootstrap resampling method for repeated cross-validation, the area under the time-dependent ROC curve was 0.80 (95%CI, 0.72–0.87) indicating that such composite score is a powerful predictor of the risk of extensive cGVHD at 2 years. Conclusion. In summary, results from this study allowed to build a new noninvasive score to accurately predict the risk of extensive cGVHD occurrence after allo-SCT. Such score could be used as a decision tool in the clinical management of allo-SCT. We are currently undertaking an additional validation of this score on another independent cohort. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Extranodal NK/T-cell lymphoma (ENKTL) is a rare disease; in Western countries it represents less than 1% of all Non-Hodgkin lymphoma. When localized, ENKTL is associated with a good prognosis. In contrast, patients (pts) with a disseminated disease still have a dismal outcome despite the use of asparaginase (ASPA) containing regimens that have significantly improved the prognosis of this lymphoma. Production of neutralizing anti-ASPA antibodies leading to inactivation of the enzyme can reduce its activity. Inactivation of ASPA activity is correlated with a worse prognosis in acute lymphoblastic leukemia (ALL). Monitoring of ASPA activity is therefore recommended in ALL pts with 100 IU/L as threshold value of serum enzymatic activity considered to be sufficient for complete depletion of l-asparagine in serum. However, ASPA monitoring is not routinely performed in pts with ENKTL, despite the frequent use of ASPA-containing regimens. The main objective of this study was to determine the proportion of pts with an insufficient ASPA activity corresponding to production of neutralizing anti-ASPA antibodies, risk of allergic reaction and inefficacy of the drug. Methods Adult pts with histologically confirmed ENKTL who received an ASPA-containing regimen between 2014 and 2018 and had a monitoring of ASPA activity were included. ASPA activity measurement was usually performed with a quantitive enzyme assay 48 hours after the last ASPA injection of each cycle for native forms of ASPA and 14 days after injection of the pegylated form. Activity below 100 UI/L was considered as insufficient. ASPA activity was correlated with pts outcome. The choice of initial form of ASPA and reasons to switch between two forms of ASPA were also analyzed. Results From 2014 to 2018, a total of 21 pts received an ASPA-containing regimen and were monitored for ASPA activity. Median age was 53 years with 14 men and 7 women. More than half of these pts had a stage IV disease (n=11/21), 6 were in stage I and 4 in stage II. Fifteen pts were in first line and 6 pts were in relapse. Pts have received either native e-coli L-asparaginase (Kidrolase®: KID) (n= 13 in the treatment-naïve group, n=2 in the relapsing group) or a pegylated form of e-coli- L-asparaginase (Oncaspar®: ONC) (n=2 in the treatment-naïve group, n=4 in the relapsing group). Most of the pts received ASPA (8 injections at each cycle for native forms and 1 injection for the pegylated form) associated with gemcitabine, methotrexate and dexamethasone, plus oxaliplatine for disseminated diseases. Six pts had optimal ASPA activity, 3/6 had localized disease: 2 had persistent RC and 1 relapsed, 3/6 had a disseminated disease: 2 progressed during treatment and 1 relapsed. Fifteen pts displayed low ASPA activity, 12/15 pts with a KID containing regimen after 1 cycle (n=10) or 3 cycles (n=2) and 3/6 pts with an ONC containing regimen after the first cycle (n=2) or the second (n=1). Among these 3 pts, 2 have been previously treated with KID that could induce an immunization against ONC. Ten pts received a second form of asparaginase: Erwinia asparaginase (Erwiniase®: ERW) in 9 pts and ONC in 1 pt. In 9/10 cases, this switch was justified by detection of low ASPA activity. Measurement of enzymatic activity in these 9 pts showed satisfactory levels in 2/5 pts treated with ERW and monitored for ASPA activity and in the pt receiving ONC, 4/6 pts with a localized form and 1/3 with a disseminated form are in persistent RC. Six pts with low ASPA activity including one case with a localized form and 5 cases with a disseminated disease, did not receive another form of ASPA, they all progressed or relapsed. Conclusion More than 2/3 of pts had sub-optimal ASPA activity after 1 to 3 cycles of ASPA containing regimens. This finding is probably due to the development of anti-ASPA inhibitory antibodies and may explain the poor outcome of pts with a disseminated disease despite the remarkable efficacy of ASPA in this disease. Although the series reported here is small and heterogeneous, our results still suggest a better outcome in pts with good ASPA activity or in case of switch between ASPA molecules in the context of low activity. ASPA activity monitoring should be recommended in pts with ENKTL, to avoid allergic reaction and ineffective treatment by switching ASPA molecules. Pegylated forms of ASPA, or encapsulated in red cells may, be less immunogenic, should be used in the first line setting instead of native forms. Table. Table. Disclosures Bachy: Celgene: Consultancy; Janssen: Honoraria; Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding.

Description: Abstract 3108 Introduction: RIC regimens are increasingly used for allo-SCT in older patients or patients with co-morbidities. The FB2 regimen (Fludarabine 120–150 mg/m2 + I.V. Busulfan 6.4 mg/Kg + ATG 5 mg/Kg) using PBSC as stem cell source is currently the most widely used RIC regimen in many European centres. On the other hand, in patients without a suitable HLA-matched donor, the use of umbilical cord blood stem cells for allo-SCT (uCBT) is increasingly considered, especially using the RIC regimen developed by the Minneapolis group. Series comparing PBSC vs CB as stem cells source for RIC allo-SCT are still scarce and using various RIC regimens before allo-SCT. Patients and Methods: This retrospective single centre analysis compared two homogeneously treated cohorts of patients who had received between January 2007 and November 2010 in our department either a FB2/PBSC allo-SCT (n=52, males: 61%; median age: 59 years (range: 22–70)) or a FC-TBI/uCBT (Fludarabine 200 mg/m2 + Cyclophosphamide 50 mg/Kg + TBI 2 Grays regimen; n=39, males 49%; median age 56 years (range: 22–70). Except for age (p=0.03), there were no significant differences between the 2 groups regarding patients and diseases characteristics: gender (p=0.22), interval between diagnosis and transplant (PBSC: 9 months vs CB: 10 months, p=0.85), disease type (PBSC: myeloid disease 63% vs CB: 67%, p=0.75), status at transplant (complete remission PBSC: 77% vs CB: 67%, p=0.28), prior auto-SCT (PBSC: 35% vs CB: 33%, p=0.90). Donors in the PBSC group were as follows: sibling donors, n=30; HLA-MUD n=20, mismatched unrelated n=2. All patients from the CB group received 2 CB units (HLA matching 4/6 n=25; 5/6 n=53). As for GVHD prophylaxis, patients received cyclosporine (CsA) alone in case of an HLA-identical sibling donor, and CsA+ mycophenolate mofetyl in all other cases. None of the patients from the PBSC group received G-CSF after transplant, while it was administered to all CB recipients. Results: Median follow-up was respectively 19 and 20 months for the PBSC and the CB groups (p=NS). Engraftment and median time for neutrophils recovery were similar between the 2 groups: PBSC: 96% vs CB: 90%, p=0.22; and 17 days (range: 0–39) vs 16 days (range: 8–60), p=0.88, respectively. The median time for platelets recovery (〉20000/mm3) was significantly higher in the CB group: 38 days (range: 13–150) vs PBSC: 0 days (range: 0–186) (p

Description: Background: R-DHAP regimen (rituximab, cisplatin, dexamethasone, high dose cytarabine) based on the 1988 Velasquez's study is a standard scheme used to treat relapsed Non-Hodgkin lymphomas (NHL). Cisplatin is frequently substituted with oxaliplatin to avoid nephrotoxicity, resulting in R-DHAX that is currently prescribed in first or second line treatment for aggressive NHL. However data are scarce. We compared the nephrotoxicity of cisplatine to oxaliplatine in R-DHA-platinum in this setting. Methods: All consecutive patients with NHL treated by R-DHAP or R-DHAX in Angers hospital between the 1st January 2007 and the 31th December 2014 were included. Either cisplatin 100 mg/m2 during 24 hours (R-DHAP) or oxaliplatin 130 mg/m2 during 2 hours (R-DHAX) were associated at d1 with cytarabine (2000 mg/m2 during 3 hours, two doses, d 2), dexamethasone (40 mg, d 1-4) and rituximab (375mg/m2, d 1) (Details on table 1). Cisplatin dosage were reduced from 25% to 50% according to individual renal tolerance. Up to 6 courses were delivered. Serum creatinine was recorded before each course of chemotherapy and was checked between d3 and d15 after administration, allowing to trace individual profiles of trajectories for their levels. These trajectories were clusterized in order to detect the existence of homogeneous patterns of evolution. This is a classical, semiparametric group-based statistical approach (Ref 1). Concomitant nephrotoxic drugs and events (sepsis…) were recorded to identify potential bias. Results: 21 patients received R-DHAP and 32 received R-DHAX. 6 patients switched from R-DHAP to R-DHAX due to nephrotoxicity. 2 different homogeneous clusters appeared. Cluster A included a majority of R-DHAX: 31 R-DHAX (88.6%), 3 R-DHAP (8.6%), 1 R-DHAP who changed to R-DHAX (2.9%). Cluster B contained a majority of R-DHAP: 11 R-DHAP (64.7%), 1 R-DHAX (5.9%), 5 R-DHAP to R-DHAX (29.4%) (p = 7.5.10-9). Cluster A graphic profile appeared less toxic than cluster B according to average serum creatinine level (mean cluster A: 70.2 µmol/L; mean cluster B: 99.5 µmol/L (p = 2.2.10-16)). Patients treated with R-DHAP experienced more severe renal failure than patients treated with R-DHAX (Chi-square test: p = 2.9.10-8, table 2). Nephrotoxic concomitant treatments have no significant discriminant effect. No differences were observed between either R-DHAP versus R-DHAX or cluster A versus B patients, as regards to age, sex, malnutrition status, histology, stage of the lymphoma, performans status, comorbidities including renal comorbidities and the history of nephrotoxic therapy. No significant difference was shown in OS and EFS (respectively, p = 0.463 and p = 0.290). Conclusions: Although R-DHAX is now widely used in NHL treatment, our study is one of the first to evaluate efficacy and renal tolerance of this treatment. R-DHAX nephrotoxicity is not significant whereas most patients receiving R-DHAP had significant acute renal impairment. We found no difference as regards to survival. A prospective study should compare these schedules in NHL to adapt future practices and improve morbidity. Table 1. Patients characteristics Caractéristics DHAP DHAX Total Sex M 14 (66.7%) 23 (71.9%) 37 (69.8%) F 7 (33.3%) 9 (28.1%) 16 (30.2%) Age (years) Median (min-max) 61 (34-80) 61 (39-77) 61 (34-80) BMI 〈 18 0 0 0 18 to 25 9 (42.9%) 17 (53.1%) 26 (49.1%) 〉 25 12 (57.1%) 15 (46.9%) 27 (50.9%) Performans Status (N=49) PS 〉 = 2 3 (17.6%) 2 (6.3%) 5 (10.2%) PS 〈 2 14 (82.4%) 30 (93.8%) 44 (89.8%) Comorbidities Renal 1 (4.8%) 3 (9.4%) 4 (7.5%) Cardiovascular 8 (38.1%) 13 (40.6%) 21 (39.6%) Other 12 (57.1%) 16 (50%) 28 (52.8%) More than 2 comorbidities 6 (28.6%) 9 (28.1%) 15 (28.3%) Histologie NHL low grade 5 (23.8%) 5 (15.6%) 10 (18.9%) NHL High grade 15 (71.4%) 25 (78.1%) 40 (75.5%) CLL 1 (4.8%) 2 (6.3%) 3 (5.6%) Ann Arbor Stage I 0 0 0 II 2 (9.5%) 2 (6.3%) 4 (7.5%) III 2 (9.5%) 2 (6.3%) 4 (7.5%) IV 16 (76.2%) 26 (81.3%) 42 (79.2%) Previous chemotherapy Nephrotoxic 2 (9.5%) 3 (9.3%) 5 (9.4%) Non nephrotoxic 17 (80.9%) 21 (65.6%) 38 (71.7%) Albumine blood level 〈 = 30 5 (23.8%) 5 (15.6%) 10 (18.9%) LDH 〉 N 11 (52.4%) 12 (37.5%) 23 (43.4%) Total 21 32 53 Table 2. Renal Failures grade R-DHAP R-DHAX No renal failure 13 (27.7%) 100 (74.6%) Renal Failure 34 (72.3%) 34 (25.4%) (Reference 1: Group-based trajectory modeling in clinical research, Nagin et al. Annu Rev Clin Psychol. 2010) Disclosures No relevant conflicts of interest to declare.

Description: Ibrutinib has revolutionized the management of RR CLL in the past 5 years, improving overall survival (OS) over standard chemo-immunotherapies (CIT) in the registration trials HELIOS and RESONATE. Recently, based on these two studies, a score has been validated able to predict 3 groups with different OS (acronym BALL, further validated in cohorts of patients treated with CIT or other targeted agents) (1). The BALL model consists of four factors with 1 point each (serum ß2-microglobulin〉5mg/dL, lactate dehydrogenase 〉upper limit of normal, hemoglobin

Description: Peripheral T-cell lymphoma (PTCL) is an aggressive disease with poor outcome. First line therapies are usually unsatisfactory with frequent need for second-line therapies. Median progression free survival (PFS) and overall survival (OS) for relapse PTCL patients are very short with few available therapeutic options. Bendamustine has been shown to be effective in this setting. In order to assess the efficacy of bendamustine outside clinical trials, we conducted a national retrospective study of patients with the diagnosis of PTCL and who were treated with bendamustine. Between 2011 and 2013, about 200 patients with the diagnosis of PTCL have been treated in 27 centers with bendamustine. We present the results of 142 patients with complete clinical and biological data. The population median age was 64y (range 28-89) with male/female sex ratio of 1,4 (83/59). Histologies were: angio-immunoblastic (AILT=63), PTCL-NOS (n=44), anaplasic-large (ALCL=13), NK/TCL (n=3), mycosis fungoides (MF=7), subcutaneous panniculitis-like-TCL (n=2), hepato-splenic-TCL (n=1) and others (n=9). The majority of patients (96%, n=130) had stage-disseminated disease and 72% (n=102) of them had extranodal localisations. The median number of chemotherapy lines prior to bendamustine was 2 (range 0-8). Seven patients (5%) had received allogeneic stem cells transplantation (SCT) and 16 autologous SCT (11%) prior to bendamustine. The median duration of response (DoR) after the last prior to bendamustine chemotherapy was 4.3 months (range 1-70) and 50% of patients had refractory disease at bendamustine treatment. Seventy-four patients (52%) received less than 3 cycles, mostly because of disease progression. Overall, they received a median of 2 cycles (range 1-8) with a median dose of 90mg/m2 (range 50-150). The best overall response rate (ORR) was 32% (45/141) with complete response of 24% (CR=34). The median DoR was 3.3 months (1-39). For AITL patients, ORR was 52% (33/63) with CR of 41%, whereas it was 18% (8/44) with 11% of CR, in patients with PTCL-nos, respectively (p=0.01). Nine patients (6%) received allogeneic SCT in CR. Median PFS was 3 months (range 0.2-46.3) and median OS was 4.4 months (range 0.2-55.4). On multivariate analysis, chemotherapy refractory (p=0.001) patients' and extranodal disease localization (p=0.028) before bendamustine influenced adversely the ORR. With a median follow up 4.4 months, 72% of patients (102/142) died. The most frequent cause of death were: disease progression (92%) or toxicities (6%). Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22%, 17% and 23% of cases, respectively. Bendamustine as single agent must be considered as a therapeutic option for relapsed or refractory PTCL, particularly in patients with AITL. The safety profile was good. Combination of bendamustine with other drugs should be evaluated prospectively. Disclosures Off Label Use: Bendamustine, single molecule, alkylant agent with antimetabolite properties. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Cartron:Sanofi: Honoraria; GSK: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Roche: Consultancy, Honoraria.

Description: Abstract 4045 Lenalidomide is an effective and widely used therapeutic agent for multiple myeloma. This agent exhibits both anti-tumor and immunomodulatory properties. Recent data suggested a positive impact on outcome of this drug in the setting of maintenance therapy in young multiple myeloma patients receiving autologous stem cell transplantation. On the long term, Lenalidomide is thought to enhance activation of T and NK cells, however its precise immune effects remain to be elucidated, and only a few data is available in this field. This single centre pilot prospective study aimed to assess T-cell polarization and the cytokine secretion profile in ten patients treated with lenalidomide alone in the maintenance setting. In this cohort, patients received at time of analysis between 4 and 12 cycles of lenalidomide alone (one cycle=28 days) at a dose ranging between 5 and 15 mg/day. Five patients received prior high-dose therapy (HDT) and autologous peripheral blood stem cell transplant (PBSCT) and 5 patients received maintenance after induction with the VRD (lenalidomide, bortezomib and dexamethasone) combination. Seven patients were in very good partial response (VGPR) and 3 were in complete response (CR) at the time of analysis. Intracellular cytokine secretion by peripheral blood lymphocytes was analyzed in peripheral blood mononuclear cells (PBMC) by multicolour staining. PBMCs were stimulated for 5 hours with PMA and ionomycin in the presence of 10 μg/mL Brefeldin A. Cells were first stained with CD3 APC-H7, CD4 PE-Cy7 and CD8 APC and permeabilized using Cytofix/cytoperm and were then incubated with FITC-, PE-, PeCy7, V450 Horizon-, AlexaFluor 647- conjugated anti-IFN-gamma, IL-4, IL-10, IL-17A and IL-21. In parallel, we analyzed a total of 39 cytokines in the plasma collected simultaneously from these same patients. Concentrations of IL-21, IL-23, TARC (CCL17), TRAIL (Apo2L), CD40L, Flt3L, Fractalkine (CX3CL1), IFNalpha, IFN-gamma, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IL-1a, IL-1b, IL-1Ralpha, IL-2, IL-2Ralpha, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 (CXCL8), IL-9, IP10 (CXCL10), MCP-1 (CCL2), MCP-3(CCL17), MIP-1alpha (CCL3), MDC (CCL22), MIP-1beta (CCL4), TGFalpha, TNFalpha, TNFbeta, VEGF, Eotaxin and EGF were determined by the bead-based multiplex protein array technology. We observed that T cells derived from myeloma patients receiving lenalidomide maintenance therapy exhibited a significantly higher secretion of TNF-alpha (p=0.03), IL-4 (p=0.003), IL-10 and IL-21 (p=0.004), compared to stimulated T cells obtained from 5 healthy donors (Figure 1 A-B). In the multiplex bead assay, we observed that IP10 (p=0.008), IL-8 (p=0.018), and MIP1beta (p=0.022) levels were also statistically increased in the plasma of patients treated with lenalidomide compared to the control group (Figure 2). Overall, these results suggest that the use of lenalidomide as maintenance therapy in myeloma can induce some potent and critical immunostimulatory activities through induction of a chronic inflammatory reaction. Interestingly, IP10 is a major Th1-related chemokine involved in anti-tumor responses, while IL-8 and MIP1b can positively influence NK cell functions (maturation, migration and augmenting their cytolytic activity). Altogether, these data shed some new light on the immunostimulatory mechanism of action of lenalidomide in the setting of long term maintenance therapy for myeloma, highlighting the need for detailed immunomonitoring studies to be performed as part of the large multicentre randomized trials. Disclosures: No relevant conflicts of interest to declare.

Description: The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation (allo-SCT) is critically determined by cytogenetic abnormalities. In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 patients with MDS transplanted from HLA-identical siblings or HLA allele-matched unrelated donors. According to the C-IPSS-R 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk and 10 (3%) in the very poor risk group. In multivariate analysis, the poor and very poor-risk categories correlated with shorter overall survival (HR = 1.59, P = 0.009 and HR = 3.18, P = 0.002, respectively) and higher relapse rates (HR = 1.82, P = 0.004 and HR = 2.44, P = 0.060, respectively), after a median follow-up of 4 years. Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group with dismal prognosis. These findings urge the investigation of new post-transplant therapeutic approaches for patients with very poor C-IPSS-R karyotypes, including maintenance therapy. Disclosures No relevant conflicts of interest to declare.

Description: Background Philadelphia negative myeloproliferative or myeloproliferative/myelodysplastic neoplasms may evolve towards secondary acute myeloid leukemia (AML). The prognosis of such secondary leukemia is very poor. At present, there are only a few reports assessing the outcome of adult patients with a philadelphia negative myeloproliferative or myeloproliferative/myelodysplastic neoplasm in blast phase (MPN-BP) who received allogeneic stem cell transplantation (allo-SCT). Patients and Methods in this retrospective study, inclusion criteria were: (i) adult patients with a MPN-BP (ii) who received first allo-SCT (iii) between 2000 and 2010 (iv) irrespective of the stem cell source or conditioning regimen. MPN with