ALBERT

Description: This article describes an application of nonparametric local linear regression to study the spatial structure of the mean trend of earthquake magnitudes. If spatial correlation is suspected in a data set of earthquakes in a particular geographic area, the smoothing parameter needed to obtain the estimator of the mean magnitude will be computed using a corrected version of a generalized cross-validation method. This procedure allows us to take the spatial dependence into account to obtain better smoothing parameters. Additionally, a parametric bootstrap technique is used to quantify the variability of the spatial maps produced with the nonparametric estimation method and to compute the probability of observing a magnitude larger than or equal to a given threshold for an earthquake occurring in a specific epicenter. These techniques are applied to two different earthquake data sets: the historic catalog of the northwest Iberian Peninsula and the earthquakes in California from January 1998 to April 2008.

Description: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults and the second in children. The overall survival is less than 35% and 60% for adults and children respectively. Activating mutations of FLT3 are now recognized as the most common molecular abnormality in this disease, and the poor prognosis of patients harboring these mutations renders FLT3 an obvious target of therapy. Although different tyrosine kinase inhibitors (TKI) have been used for this purpose, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. This strategy could be improved by rationally combining TKIs with other agents. In this work, we have explored by phosphoproteomics the alternative pathways activated after TKI treatment in vitro and ex vivo. The phosphoproteome profile of the bone marrow from a FLT3-AML patient before and after TKI treatment, studied by LC-MSMS after IMAC enrichment, suggested the activation of Ras-Raf-MEK-ERK1/2 pathway as a possible mechanism for TKI resistance, which could be avoided by dual inhibition using the MEK inhibitor trametinib. Therefore, we characterized the effect of trametinib in combination with the TIK pazopanib and sorafenib by the in vitro cell viability assay using WST8in the FLT3-ITD AML cell line MOLM13. As it is presented in figure 1a, trametinib showed an IC50 value in the low-nanomolar range (5.4 nM) and this MEKI produced a strong synergy (0.5

Description: Introdution Optimal treatment of young patients with high-risk diffuse large B-cell lymphoma (DLBCL) remains a matter of debate. With the addition of rituximab, response rates (RR) and overall survival (OS) have improved significantly, but the best treatment option for this subset of patients with high risk DLBCL is not consensual. Historically, these patients are treated with conventional immunochemotherapy protocols (RCHOP - Rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by autologous stem cell transplantation (ASCT) as a consolidation treatment. Several studies tried to clear the exact role of ASCT, and others were design to answer about addition of other drugs to RCHOP, without conclusive results. Recently, our department review the protocol according to the state of the art, and an intensification of treatment was made for high risk DLBCL in young patients (

Description: Introduction: The incidence of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is approximately 5%. Although the introduction of rituximab for the treatment of DLBCL has reduced the risk of CNS relapse, the median overall survival of these patients remains only few months, emphasizing the need to accurately identify at-risk patients, screen for CNS disease, and develop effective therapeutic/prophylactic strategies. Aim: To identify risk factors for CNS relapse in patients with DLBCL. Methods: Retrospective analysis of patients with DLBCL diagnosed from January 2012 to December 2017 at a Cancer Institute. Patients with exclusive extranodal (EN) disease were excluded. Factors associated with CNS relapse were evaluated using Chi-square, Fisher's Exact Test, Mann-Withney U or T-Test, according to variable types and distributions. Survival was evaluated by Kaplan-Meier method and groups were compared by Log-rank test. Independent predictive factors were identified using Logistic Regression. A p value 〈 0.05 was considered statistically significant. Results: Four hundred and seventy-nine patients were identified, 122 were excluded due to exclusive EN disease, and 357 patients were included in the study. With a median follow-up of 33 months, there were 10 (3%) CNS relapses. According to International Prognostic Index (IPI) factors in addition to involvement of kidneys and/or adrenal glands (CNS-IPI), 5 (50%) of these patients were classified as high risk, 4 (40%) intermediate risk and 1 (10%) low risk. Patients who development CNS involvement were significantly younger (57 vs. 65 years, p=0.036), presented higher levels of lactate dehydrogenase (LDH) (median 738 vs. 282 U/L, p600 was the only independent predictive factor (HR 15.3, CI 95% 3.5 - 65.8, p

Description: Abstract 4549 Introduction Patients with high risk AML have poor outcomes. However, the only approach with curative potential remains allogeneic HSCT. With the aim to improve the effect of allogeneic HSCT by sequential use of chemotherapy, RIC regimen and pDLI, we are currently conducting a prospective pilot study for high risk AML. High risk AML was defined by unfavorable cytogenetics, adverse molecular abnormality, secondary AML, and AML requiring 2 induction courses to obtain CR1. After identification of a HLA 10/10 donor, patients are received the sequential regimen consisted of fludarabine (30mg/m2/d), Ara-c (2g/m2/d) and amsacrine (100mg/m2/d) (FLAMSA) chemotherapy for 4 days. After 3 days of rest, RIC regimen consisted of 4 Gy TBI, cyclophosphamide for 2 days (40 mg/kg in case of matched related donors, and 60 mg/kg for unrelated or mismatched donors), and ATG (5mg/kg total dose) (German regimen) or Busulfan 3.2mg/kg/d during 4 days followed by ATG (5mg/kg total dose) (French regimen). The modified regimen has been established after our results in refractory AML patients (ASH 2011, poster 1957). Prophylactic donor lymphocyte transfusion was given from day +120 in patients who were not receiving immunosuppression and were free of GvHD. Our objective is to include 20 patients and to compare with a control cohort of patients with the same high risk AML treated according to the conventional strategy during the same period. Results Between August 2010 and November 2011, we have included 12 consecutive patients in first complete response who underwent an allogeneic HSCT after sequential FLAMSA-RIC regimen with a median follow-up of 12 months (range [7–22]). Nine patients were 〈 55 years old (median age: 54 [28–64]), 7 patients had an unrelated donor and 5 patients had a related donor. The stem cell source was PBSC for 11 patients and two cord blood unit for 1 patient. Before FLAMSA-RIC regimen, 3 patients had received two induction courses to obtain CR1. All patients had adverse cytogenetics or molecular abnormalities and 1 patient had a secondary AML. At the last follow-up, 6 patients (50%) are alive in CR. (Figure 1.) Four patients (33.3%) died in remission. The cause of death was infection for 2 patients, aGvHD for 1 patient and graft failure for 1 patient. Only one patient died from relapse 6 months after transplantation. Five patients (41.6%) experienced aGvHD and 2 patients (16.6%) had an extensive cGvHD including the patient who has been transplanted with 2 cord blood unit. Six patients (75%) in a group of 8 patients aged 〉 45 years experienced complications (infection (n=3) and GvHD (n=3)). One patient (25%) from a group of 4 patients aged 〈 45 years had infectious complication after transplantation. Prophylactic donor lymphocyte transfusion was given in 6 patients, the causes of no administration were GvHD for 2 patients, cord blood unit as stem cell source for 1 patient and 3 patients were dead before 120 days after transplantation. From the 6 patients who had received pDLI, 5 patients are alive in CR and 1 patient died from GvHD. Conclusion The FLAMSA-RIC regimen before allogeneic HSCT is a new approach for high risk AML. Between 2012 January and 2012 July, 8 additionnal patients have been included and the results for the whole study will be communicated later. Our primary results are promising especially for young patients (〈 45 years) who seem to better profit from this sequential FLAMSA-RIC regimen. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction Tacrolimus is a widely used calcineurin inhibitor in allogeneic HCST for prophylaxis and treatment of GvHD. This molecule is now available in both standard-release (Prograf, twice-daily tacrolimus, Astellas Pharma) and extended-release (Advagraf, once-daily tacrolimus, Astellas Pharma) formulations. Compared with the standard-release formulation, the extended-release (ER) tacrolimus has been shown in previous pharmacological studies to provide bioequivalent drug exposure, efficacy and safety. Moreover, this formulation of tacrolimus was followed by a clinically significant improvement in kidney graft function for kidney recipients. Based on these observations, we have conducted a prospective study in wich ciclosporine A (CsA) (Neoral) is switched for tacrolimus ER (Advagraf) in case of renal impairment after alloHSCT. Method We enrolled 16 consecutive patients with renal impairment (serum creatinine 〉110 µMol/L) from May 2012 to May 2013 during the follow-up at outpatient clinic, the conversion dose was established on an mg:mg basis 1:100 from CsA total oral daily dose to a single dose of oral tacrolimus ER formulation. The dose was readjusted to obtain a tacrolimus blood trough level between 5 and 15 µg/L. Tacrolimus ER was given at noon in a single dose one hour before lunch. We evaluated the tacrolimus blood trough level changes after switch, serum creatinine, glycemia, potassium, acute and chronic GvHD. A satisfaction survey for tacrolimus ER treatment was performed 3 months after the switch, the questionnaire included administration compliance questions. Results All patients in this cohort had hematological malignancies, the median age was 52 years (range, 28-66). Eight patients (50%) had a matched related donor, 7 patients (43.75%) had a HLA-10/10 matched unrelated donor and 1 patient underwent alloHSCT with two cord blood units. Seven patients (43.75%) received a myeloablative regimen with 12 Gy TBI and 9 patients (56.25%) a reduced intensity regimen. The stem cell source was bone marrow for 7 patients (43.75%), PBSC for 8 patients (50%) and cord blood for one patient. The status at transplantation was CR1 for 6 patients (37.5%), CR2 or more for 6 patients (37.5%) and partial response for 4 patients (25%). The median follow-up of the cohort was 7 months (range,2-14). Non-parametric tests such as exact Wilcoxon Mann-Whitney test or Kruskal Wallis were performed for the analysis of the physiological parameters. The median of serum creatinine was 112 µmol/L (range, 51-262) with CsA and 87 µmol/L (range, 50-125) with tacrolimus ER (p 4.5 mmol/L after the switch for tacrolimus ER. The median blood trough level was 300 µg/L (range,100-438) for CsA 14 days after starting and 7.2 (range,3-15) for tacrolimus ER 20 days after starting (Figure). The cumulative incidence of aGvHD grade 〉1 at 3 months was 25% (95%CI,14-36). After the switch for tacrolimus ER, no patient developped aGvHD. Eight patients (50%) developed aGvHD grade 〉1 during the prophylaxis with CsA. For 6 patients (37.5%), aGvHD was resolutive after the switch for tacrolimus ER with an association of tacrolimus ER and prednisone or tacrolimus ER alone. For 2 patients (12.5%), aGvHD was resolutive with CsA and prednisone before the switch for tacrolimus ER. Two patients in this study developed severe chronic GvHD after the discontinuation of prophylaxis (5 months and 10 months). One patient received tacrolimus ER with a complete resolution of cGvHD and the second patient is now on therapy with everolimus. All patients in this cohort are alive and all patients except two are still in complete response. Moreover, the satisfaction survey demonstrated that the patients were satisfied with the switch and the one daily formulation of tacrolimus. Conclusion The conversion from oral CsA to oral tacrolimus ER formulation was followed by a clinically significant improvement in kidney function with stable tacrolimus blood trough levels. The patients were satisfied with this formulation of tacrolimus. We have now extended this study to several centers in the aim to confirm these observations. Disclosures: No relevant conflicts of interest to declare.

Description: [Background on medical need in hematology]Even though significant progress has been made in a number of hematological malignancies in recent years, an unmet medical need still remains in indications such as multiple myeloma (MM), chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML) due to refractory disease, severe adverse events or the failure to achieve sustained minimal residual disease. As a consequence, novel therapies are required to prevent relapse, be safer in administration and to target residual disease. We present here for the first time a novel and innovative therapeutic approach with the potential to treat patients suffering from hard-to-treat hematological malignancies based on the tumor´s pathophysiology and reactive oxygen species (ROS) phenotype. [Background on Ag5]TMC are created by combining the atoms of certain transition metals under specific conditions to form novel molecules with entirely distinct properties from "traditional" metal. For example, silver can be used to create clusters of different and defined sizes, based on the number of atoms making up the final drug candidate. More specifically, Ag5 contains five silver atoms arranged in a specific conformation, is the first TMC derived from this novel platform and has entirely different physiological properties than the three silver atom containing Ag3. Ag5 is a water-soluble and heat stable molecule, it is orally bioavailable and a freely diffusible pan-tumor therapeutic. It selectively kills those cells with high ROS concentrations by oxidizing their antioxidant systems and subsequently drives these cells to programmed cell death. In consequence, Ag5 will preferentially kill cancer cells which typically have higher ROS levels, but will spare normal cells which display lower ROS due to their functional REDOX homeostasis. More specifically, Ag5 efficiently catalyzes the oxidation of thiol groups of thioredoxins and peroxiredoxins and thereby drives sensitive cells above a threshold to irreversible protein misfolding, protein degradation and programmed cell death. [Background on Ag5 experiments]We characterized Ag5 efficacy using a wide range ofin vitroassays and found potent Ag5 efficacy against a number of MM, CLL and AML cell lines with an IC50 in the low nM range. Ag5 sensitivity of all cell lines was correlated with ROS levels, more specifically superoxide, as measured by dihydroethidium (DHE) or MitoSOX. Furthermore, we were able to demonstrate that Ag5 treatment resulted in a concentration dependent cell cycle arrest in G1 phase, mitochondrial swelling and induction of apoptosis. Treatment of primary CLL tumor samples resulted in low nM efficacy. Finally, we could demonstrate that Ag5 was not only safely administered without any side effects in mouse and rat studies, but was equally effective as the stand-of-care bortezomib in a multiple myelomain vivomodel. [Conclusion and clinical significance]In summary, Ag5 is a novel and innovative therapeutic candidate that was shown to be safe and effective in preclinical studies, and has the promise to address the unmet medical need in hard-to-treat hematological malignancies. Keywords: Ag5, Therapeutic molecular cluster (TMC), Redox, ROS, catalysis, Ag3, AML, MM, CLL Disclosures Porto González: Arjuna:Research Funding.Carneiro:Arjuna:Research Funding.Lopez-Quintela:Arjuna:Current equity holder in private company.Treder:Arjuna:Current Employment.Dominguez:Arjuna:Current equity holder in private company.