ALBERT

Description: Data exchange facilitated Nature Geoscience 4, 814 (2011). doi:10.1038/ngeo1335 Authors: Xiaogang Ma, Kristine Asch, John L. Laxton, Stephen M. Richard, Carlos G. Asato, Emmanuel John M. Carranza, Freek D. van der Meer, Chonglong Wu, Guillaume Duclaux & Koji Wakita

Description: Abstract Most of the permanent deformation in the Pampean Flat slab segment of the Central Andes is taken up at the Andean Orogenic Front in Argentina, a narrow zone between the Eastern Precordillera and Sierras Pampeanas that comprises one of the world's most seismically active thrust zones. Active faults and folds in the region have been extensively mapped but still largely lack information on style and rates of deformation, which is essential for understanding the distribution of regional strain and estimating the seismic potential of individual faults. Structural, geomorphic, and 36Cl cosmogenic radionuclide surface exposure ages methods are used to focus on key sites along the 30‐km‐long La Rinconada Fault Zone in this region of west‐central Argentina, which is ~15 km away from the highly‐populated (~500,000) city of San Juan, to define a late Quaternary average shortening rate of 0.41±0.01 mm/yr. This slip rate is the same order of magnitude, but slightly lower than nearby similar east‐dipping Eastern Precordillera faults including the La Laja and Las Tapias faults. Relatively low slip‐rates are interpreted as being a consequence of distributed deformation between the latitude of the La Rinconada Fault Zone (31 and 32°S), as compared to between latitudes 32 to 33°S where deformation appears to be focused on fewer structures, including the Las Peñas and La Cal Thrust faults. The La Rinconada Fault Zone is capable of generating earthquakes of MW 6.6–7.2, but further investigations are required to determine timing and recurrence intervals of discrete events.

Description: Background: Post-remission treatment for AML is very aggressive and many times a SCT is needed. Comparisons between Allo-SCT and Auto-SCT ve always shown more Transplant Related Mortality (TRM) but less Cumulative Incidence of Relapse (CIR) in the first group. Our study describes, not only the long-term survival outcomes, but also the quality of life in long survivors. Methods: Retrospective study of 274 patients diagnosed with non-promyelocytic AML who underwent SCT between 1982 and 2011 in our center. Characteristics in the 162 Allo-SCT and the 112 Auto-SCT groups of patients were respectively: median age of 38 and 45 years old, secondary AML in 20% and 10%, refractory to Induction AML in 16% and 3%, pre-SCT status different from Complete Remission (CR) in 13% and 3% and year of SCT before 2005 in 53% and 86%. No significant differences between both groups were found in other risk factors as hyperleucocytosis at diagnosis or adverse cytogenetics. Results: With a median follow-up of 55 months [2-316], Overall Survival (OS) until 1997 in Allo-SCT and Auto-SCT were respectively, 40% and 61% at 1 year and 28% and 45% at 5 years (figure 1), but from 1997, 66% and 70% at 1 year and 47% and 48% at 5 years (figure 2). Disease Free Survival (DFS) until 1997 in Allo-SCT and Auto-SCT were respectively, 50% and 65% at 1 year and 38% and 46% at 5 years, but from 1997, 67% and 63% at 1 year and 52% and 47% at 5 years. In the last 15 years, no differences were found between both groups in OS nor DFS. CIR in Allo-SCT and Auto-SCT were respectively, 18% and 32% at 1 year and 24% and 50% at 5 years, without dependence on year of SCT. No relapse was observed later in any group. TRM until 1997 in Allo-SCT and Auto-SCT were respectively, 30% and 7% at 1 year and 35% and 9% at 5 years, but from 1997, 16% and 2% at 1 year and 25% and 4% at 5 years. Multivariable analysis showed that the only risk factor with a negative impact on OS was not having achieved CR at the time of SCT. Other variables as older age, hyperleucocytosis at diagnosis, adverse cytogenetics, secondary AML or sooner year of SCT lost their univariable analysis significance. Allo-SCT: From the 162 patients, 72(44%) are alive by this moment, 43(60%) with ECOG 0, 21(29%) with ECOG 1 and the other 8(11%) with ECOG 2, basically because of graft versus host disease (GVHD in 39 patients, 21 steroid-dependent and 3 refractory to any treatment). All of them have been in CR during the last 2 years of follow-up. In contrast, 90(56%) patients have died: 52(58%) because of SCT complications (20 infections, 16 GVHD, 8 toxicity and 8 mixed causes), 33(37%) because of disease and 5(5%) because of other causes. With a median follow-up of 43 months [2-316], there have been 4 secondary neoplasm, all of them solid ones, which appeared with a median of 242 months [179-311] from SCT. None of them had previously received radiotherapy. Auto-SCT: From the 112 patients, 43(38%) are alive by this moment, 32(74%) with ECOG 0 and the other 11(26%) with ECOG 1. All of them have been in CR during the last 2 years of follow-up. In contrast, 69(62%) patients have died: 45(65%) because of disease, 14(20%) because of SCT complications and 10(15%) because of other causes. With a median follow-up of 93 months [5-230], there have been 6 secondary neoplasm, 5 of them hematologic ones, which appeared with a median of 90 months [76-115] from SCT. None of them had received radiotherapy, but previously treated hematopoietic stem cells. Only one is alive at the time of last follow-up. Conclusions: In one hand, despite the high incidence of relapse in Auto-SCT in any period, OS is lower in Allo-SCT during the first years [1982-1996], although it has a tendency towards OS in Auto-SCT from 1997 because of the decrease in TRM, which is more significative in Allo-SCT. In the other hand, DFS is slightly higher in Allo-SCT during the last years [1997-2011], although the quality of life in long survivors is worse, basically because of GVHD. In summary, we have not really found differences between Allo-SCT and Auto-SCT in terms of OS and DFS in our series, so both procedures are efficient to treat AML (near 50% of the patients in both groups are alive at 5 years from SCT in recent years). The decrease in TRM until 4% at 5 years in Auto-SCT makes it a good choice, particularly for older patients without risk factors. However, the development of secondary hematologic neoplasms is a relevant fact, with an incidence of 11% and a high late mortality. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: INTRODUCTION: Graft versus host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). ATG-Fresenius (ATG-F) has demonstrated its efficacy in reducing the risk of acute GvHD (aGvHD) and chronic GvHD (cGvHD) at a dose of 60 mg/kg (Finke J, Lancet Oncology, 2009; Sociè G, Blood, 2011), and at a dose of 30 mg/kg (Ayuk F, Biol Bone Marrow Transplant, 2008; Solano C, abstract EBMT, 2015). AIMS: We analyzed as primary endpoint whether low dose ATG-F (21-32 mg/kg) might be effective in reducing the incidence of acute and chronic GvHD. The secondary endpoints were viral infections, non-relapse mortality (NRM), disease free survival (DSF) and overall survival (OS). METHODS: Between September 2012 and December 2014, 22 patients who underwent HSCT received ATG-F in our hospital. Two patients were excluded because they received a second HSCT. We used ATG-F at a dose of 21 mg/kg (7 mg/Kg days -3,-2,-1) in the case of patients with hematologic malignancies who received a HSCT from an unrelated donor (UnD) with peripheral blood (PB) source and/or from a mismatched donor (MMD). ATG-F at a dose of 28-32 mg/kg (7-8 mg/kg days -4 to -1) was employed in aplasia. Median age was 53 years (9-68) and only 5 patients were

Description: Introduction: Due to its production and mechanism of action, antithymocyte globulin (ATG) is associated with two main side effects: immunological responses and infections. Objective: We evaluate the incidence and differences of ATG infusion reactions and fungal and viral infections in patients who receive SCT across a period of 10 years. Patients and methods: From January 2005 to December 2014, 100 patients who underwent and allogeneic stem cell transplantation (SCT) in our center received ATG (Thymoglobulin [TG] or ATG-Fresenius [ATG-F]) as part of conditioning regimen. Because an out of trend had been noted in stability profiling of TG finished product lots manufactured since December 2009 and since July 2012, TG was switched by ATG-F, patients were divided into three groups (TG-1: 45 patients; TG-2: 31 patients; ATG-F: 24 patients). Total median dose of TG was 7.5 mg/Kg in both groups. Results: Patients transplanted with ATG-F were significantly older than those who received TG (p=0.009). In addition, the use of an unrelated donor and GVHD prophylaxis with calcineurin inhibitor combined with mycophenolate mofetil was more frequent in ATG-F group (p=0.04 and p

Description: Introduction Myelodysplastic syndromes (MDS) are diagnosed at median age of 70 years. Allogeneic stem cell transplantation (HSCT) is the only curative treatment option, but with an increasing age, morbidity escalates. Treatment guidelines suggest HSCT for intermediate-II and high risk constellations up to the age of 65, and reduced intensity conditioning (RIC) regimens are commonly used up to 70 years of age. However, increasing life expectancy, availability of RIC regimens and good Karnofsky performance status (KPS) of MDS patients more than 70 years of age, has led to an increased use of HSCT. We performed a retrospective analysis to investigate results after HSCT for those patients and influence of KPS on outcome. Patients and methods We analyzed data of 345 patients in the EMBT database older than 70 years with MDS/sAML. The disease status at transplantation was available in 233 patients and most of the them were in more advanced stage of the disease: RA/RARS,RCMD (n=25) , RAEB (n=68) and RAEB-T/secondary acute leukemia (sAL, n=140). Donor were: related (n=88) and unrelated (n=257). Cytogenetic data were available only in 73 patients and classified as good (58), intermediate (6), poor (5) and very poor (4). Median follow up was 29.7 months. Median age at transplantation was 72 years (70-79 years) with 249 male and 96 female patients. KPS was defined in 300 cases, being 90-100% in 61% and 80% or less in 39%. Stem cell source was peripheral blood (94%) or bone marrow (6%). The intensity of the conditioning regimen was mainly reduced intensity (78%) rather than myeloablative (22%). Negative or positive CMV sero-status of the patient were seen in 35% and 65%, respectively. Results The number of HSCT for MDS patients of 70 years or more has increased over time. While 2000-2004 only 19 patients received transplantation, the following 3-year periods included 28 (2005-2007), 97 (2008-2010) and 200 (2011-2013) patients, respectively. The estimated 3-year OS was 33% (27-39%). A significant better 3 year OS in the univariate analysis was seen for Karnofsky (90-100%) vs 80% or less (41 vs 23%, p=0.008) and for CMV negative sero-status (46% vs 27%, p〉

Description: Introduction Thymoglobulin (ATG) infusion-related reactions in stem cell transplant (SCT) recipients are frequent. Minor reactions as fever and chills are the most usually observed. Severe and potentially life-threatening reactions are rare (〉1/10.000 and

Description: INTRODUCTION Biosimilars are approved biologics with comparable quality, safety and efficacy to a reference product for which patent protection has expired. Biosimilars of recombinant human granulocyte-colony stimulating factor (G-CSF) have been available for more than 8 years now and are widely used in Europe; however, there are still some concerns regarding their long-term safety and immunogenicity. The objective of this study was to evaluate the efficacy and safety of the biosimilar G-CSF (Zarzio) to mobilize stem cells in the autologous hematopoietic stem cell transplantation (HSCT) setting. METHODS We retrospectively reviewed 209 consecutive patients undergoing peripheral blood stem cells harvest between December 2009 and December 2015 using the biosimilar G-CSF. The target CD34+ stem cell dose at our institution is 2 x 106/kg for autologous HSCT. A survey to evaluate the potential side effects related to the mobilization process was conducted during the follow-up. RESULTS The median age at the time of harvest was 56 years old (range: 16-75) and 113 (54,1%) patients were male. The indication for autologous HSCT was lymphoma in 102 (48,8%) cases, plasma cell neoplasm in 90 (43%), acute leukemia in 12 (5,8%), non-haematological malignancy in 3 (1,4%) and autoimmune disorder in 2 (1%). The patients had received one (n=86; 41,1%), two (n=89; 42,6%) or more than two (14,4%) lines of treatment before mobilization. Only 4 (1,9%) cases had not received prior lines of chemotherapy. Patients were primed with the biosimilar G-CSF alone (n=64) or following a cycle of chemotherapy (n=145). Additional Plerixafor was administered in 31 cases (14,8 %) because peripheral CD34+ count was too low or the patient had poor baseline predictors. Sufficient CD34+ cells were collected with a single priming procedure in 195 (93,3 %) cases and 14 (6,7 %) underwent a second mobilization. Only 4 (1,9 %) patients did not reached the target CD34+ stem cells dose. The median number of harvest days required per patient was 1 (range: 1-5) and the median total CD34+ cells x 106/kg collected was 4,08 (0,36 - 57,42). In 18 (8,6%) patients autologous HSCT was cancelled due to disease progression (14 lymphomas, 3 acute leukemias and 1 Waldenstrom macroglobulinemia). The remaining patients (n = 191) received high dose chemotherapy followed by autologous stem cell infusion. The median CD34+ cells x 106/kg infused was 4,02 (1,79 - 28,71). The median post-HSTC days to neutrophil (〉0,5 x 109/l) and platelet (〉20 x 109/l) engraftment were 12 (range: 7-31) and 12 (8-60) respectively. Three (1,4 %) patients died before engraftment on days 5, 7 and 8 post-HSCT (2: Toxicity related to the conditioning regimen; 1: Bacterial hemorraghic enterocolitis). Sixty-four (30,6 %) patients reported bone or muscle pain during the first weeks following the use of the biosimilar G-CSF but no severe adverse effects were reported after a median follow-up of 31 (1 - 75) months. CONCLUSIONS The target CD34+ stem cells dose was collected in almost all the cases showing that the biosimilar G-CSF was effective for the mobilization process in our patients. The biosimilar G-CSF was also safe with only one third of the patients reporting non-severe side effects being the most common bone or muscle pain. Disclosures No relevant conflicts of interest to declare.

Description: Background: Current guidelines recommend the use of antifungal prophylaxis during, at least, the first three months post allogeneic stem cell transplantation (allo-SCT). However, these drugs are not exempt of adverse effects due to their own toxicity or drug-drug interactions. In addition, breakthrough mold infections seem to be emerging as a new problem in this setting. Objectives: The aim of this study was to analyze the benefit of a strategy in which allo-SCT patients were not routinely prescribed antifungal drugs except for the case of the development of neutropenic fever and/or exposure to high dose of corticosteroids. Main objectives were 1) requirement and time of exposure to antifungal treatment and 2) cumulative incidence (CI) of proven or probable IFI at 1, 3 and 6 months after transplant. Other objectives were IFI description and overall survival (OS). Patients and methods: 319 patients who underwent a first allo-SCT at our center between 2010 and 2017 and were not under antifungal prophylaxis at the moment of transplant were included. 181 patients (57%) were males and median age was 51 years, range (4-74). Acute myeloid leukemia (35%) was the most frequent diagnosis and myeloablative conditioning regimen was mostly used (69%). 99 patients (31%) received the stem cells from a mismatched donor and BM was the preferred stem cell source (72%). Fourteen patients (4%) did not engraft. The median length of neutropenia

Description: Expression of the apoptosis inhibitory protein Bcl-x was studied in CD34+ hematopoietic precursor cells and in the promyelocytic leukemia cell line HL-60. The enriched population of CD34+ cells (more than 95%) was cultured in the presence of stem cell factor, interleukin-3 (IL-3), IL-6, and either granulocyte colony-stimulating factor or macrophage colony-stimulating factor to achieve granulocyte or monocyte/macrophage differentiation, respectively. The expression of Bcl-x increased in the early stages of both differentiation pathways. However, by day 21 of culture mature granulocytes were Bcl-x–negative, whereas monocytes/macrophages either maintained or increased the expression of Bcl-x. The pattern of Bcl-x expression in the differentiated CD34+ cells was similar to that observed in HL-60 cells differentiated along the granulocyte lineage (induced by incubation with retinoic acid), or along the monocyte/macrophage lineage (induced by incubation with phorbol diester). The bcl-x transcript predominant in HL-60 and CD34+ cells differentiated into monocytes/macrophages was bcl-xL . Although little is yet known regarding the functional significance of Bcl-x within the granulomonocytic compartment, marked changes in the pattern of its expression, as observed during granulomonocytic differentiation of HL-60 and CD34+ cells, are likely to alter the life span of mature granulocytes and monocytes/macrophages.