Academic literature on the topic 'G 60 UL 2012 B539'

Abstract Background: Low-risk myelodysplastic syndrome (LR-MDS) is a heterogeneous group of diseases characterized by dysplastic ineffective hematopoeisis and risk for acute myelogenous leukemia (AML). Despite improved risk classification, LR-MDS subgroups exhibit outcome heterogeneity. Non-hemopoeitic comorbidities highlight interaction of organ dysfunction and adverse outcomes. Previous studies have identified association between smoking and development of MDS (Du Y. Leuk Res. 2010). Among others, smoking induces DNA double strand breaks (Huang et al, 2012) and gene methylation modification leading to impaired environmental chemicals detoxification. In this study, we analyze the clinical impact of smoking and intensity of exposure on LR-MDS outcome. Methods: With prior IRB approval, 90 LR-MDS patients from the Michael E. DeBakey VA Medical Center cancer registry were analyzed between 2000-2012. Smoked pack-years (PY) was recorded according to accepted definition. PY estimate derived from Framingham heart study (Mannan H et al., Heart International. 2010) was used to evaluate smoking dose-dependent correlation with survival in: (1) non-smoker [NS], (2) <20, (3) >20-39, and (4) >40 PY. Univariate and multi-variable analysis evaluated the impact of potential confounding variables such as degree of cytopenia at disease initiation, blast count, karyotype, and R-IPSS score. Results: 69 (76%) and 22 (24%) pts were smokers and NS. Median age was 71 years (y) (range, 55-84) and 73 y (60-87), for smokers and NS, P=0.38. 22 (24%), 35 (38%) and 34 (37%) of pt were very low, low, and intermediate risk R-IPSS. Median hemoglobin, ANC, and platelet levels among smokers and NS were 9.4 g/dL vs 8.8 g/dL (P=0.18), 2.7 K/uL vs 3.2 K/uL (P=0.13) and 118 K/uL vs 158 K/uL (P=0.11). Median absolute R-IPSS score for smokers and NS were 0.5 (range, 0-1.5) and 0.25 (range, 0-2), P=0.40. OS in smokers vs NS was 728 vs 1877 days (d), P=0.04, 95% CI= 1.015 to 2.923 (Fig. 1). 65/71 (92%) pt contributed to analysis of cumulative effect of smoking on OS. Given the lack of significant survival difference among pt with >20-39 and >40 PY, 3 distinct subgroups were identified showing a median OS of 2117, 1020 and 717 d, for NS, <20 and >20 PY, respectively, P=0.01 (Fig. 2). Univariate and multivariate analysis revealed no impact of blast count, depth of cytopenias, karyotype, and R-IPSS on observed outcomes. Conclusions: Our study suggests a mechanistic link between smoking and adverse outcome in LR-MDS. Higher cumulative smoking exposure is potentially associated with worse OS. Larger studies involving LR-MDS pt with smoking history are necessary to confirm this association. Further research is needed to clarify underpinning mechanisms resulting in unfavorable smoking-induced LR-MDS phenotype. This could facilitate implementation of MDS directed therapy in subgroups with more aggressive outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction Disseminated intravascular coagulation (DIC) occurs about 10% of adult patients with acute lymphoblastic leukemia (ALL) at presentation, and develops in approximately 30-40% of adult patients after starting induction therapy. Although reports of DIC developing with a high frequency in Philadelphia chromosome-positive (Ph+) ALL are scarce, we have experienced many cases of DIC in Ph+ ALL patients. We start chemotherapy and prednisolone (PSL) at the same time after diagnosis of ALL, and give imatinib (IM) at the time it is found to be Ph+. However, we have experienced cases of early death due to severe DIC and tumor lysis syndrome (TLS) when utilizing this approach. Therefore, we have tried mild tumor reduction via initiation of PSL, IM and chemotherapy at different times. We investigated the difference in the incidence of DIC between Ph+ ALL patients and Ph negative (Ph-) ALL patients and discuss the management of DIC and its effect. Patients and methods We examined ALL patients who received their first treatment at our institution between January 2012 and December 2014. We monitored for DIC by twice daily blood testing, and diagnosed DIC according to the diagnostic criteria for DIC of the Japanese Ministry of Health, Labour and Welfare. When DIC developed, the patients were encouraged to rest, and we treated DIC with recombinant human soluble thrombomodulin (rTM) and/or gabexate mesylsate (FOY). To prevent bleeding episodes, platelet (Plt) and fresh frozen plasma transfusion were given to maintain Plt count >50,000/ul and fibrinogen (Fib) level >100 mg/dl. For induction therapy, to avoid rapid development of DIC and TLS, we first administered PSL 60 mg/m2. While confirming a decrease in leukocyte counts and fibrin degradation products (FDP), we started IM followed by chemotherapy (daunorubicin + vincristine + cyclophosphamide + L-asparaginase) in Ph+ ALL patients. We began PSL followed by the same chemotherapy in Ph- ALL patients as well. We used rasburicase to prevent TLS. Results A total of 35 patients with newly diagnosed ALL were examined: 18 patients were Ph+ and 17 were Ph-. The incidence of DIC was 82.3% (14/17) in Ph+ patients and 38.9% (7/18) in Ph- patients. The group with Ph+ showed a significantly higher rate of DIC (p value = 0.015). Duration of the treatment of DIC was 4-14 days (median, 10 days) in Ph+ patients, and 3-10 days (median, 5 days) in Ph- patients. The group with Ph+ also showed significantly longer duration of treatment (p value = 0.02). Twelve Ph+ patients developed DIC (two patients were excluded because of treatment that was different from that described above); five were men and seven were women. Median age was 61 years (range, 34-78 years). Leukocyte counts at the time of diagnosis were 4400-542100 /ul (median 34400 /ul), hemoglobin value was 6.4-15.6 g/dl (median 11.6, g/dl), Plt counts were 6000-262000 /ul (median, 56000 /ul), Fib value was 199-707 mg/dl (median, 299 mg/dl), and FDP value was 3.4-45.7 ug/ml (median, 9.7 ug/ml). DIC occurred at 1-8 days (median, 3 days) from diagnosis. One patient (8%) had DIC at presentation, and the remaining 11 patients (92%) had DIC after the initiation of induction therapy. We started IM at day 3-6 (median, day 5), DIC developed in two patients starting IM, and chemotherapy was started at day 5-10 (median, day 7). Only one patient had slight elevation of FDP, and this value decreased in a progressive fashion in the remaining 11 patients. The maximum FDP value during the treatment of DIC was 32-1162.8 ug/ml (median, 140 ug/ml). We treated DIC with FOY single agent (one patient) or a combination of rTM and FOY (10 patients); all patients showed improvement. The period for improvement of DIC was 4-14 days (median, 8 days), and none of the patients had bleeding or organ damage. Only one patient had TLS, but it immediately improved. In these Ph+ patients, 11/12 patients (92%) achieved complete remission (CR), and one patient had partial remission. Further, 5/5 patients (100%) achieved CR, and none had TLS in the group with Ph-. Conclusion DIC occurred at a high incidence in Ph+ ALL patients. By starting PSL, IM, and chemotherapy at the right time, we can perform induction therapy without generating serious complication due to DIC. Disclosures No relevant conflicts of interest to declare.

Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the International Prognostic Scoring System (IPSS) (Greenberg et al, Blood 1997) and IPSS-R (Greenberg et al, Blood 2012). Recently, next-generation sequencing genetics has been incorporated into management of MDS, however its use is limited in routine clinical practice. Current prognostic models do not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) and poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin <10g/dl, platelet count <50k/uL or 50-200k/uL, bone marrow blasts ≥4% and unfavorable cytogenetics (non-del(5q), non-diploid). This LR-PSS score system enables the stratification of low risk MDS patients into 3 different risk categories; interestingly, the third category identifies a subgroup of patients with a median overall survival (OS) similar to that of patients classified as intermediate-2 and high risk IPSS. Besides, the IPSS-R described by Greenberg et al (Blood 2012) has demonstrated a strong prognostic value for OS and LFS as compared to the IPSS when applied to different independent series of MDS patients. The prognostic impact of the LR-PSS has not been analyzed in MDS patients with very low-, low- and intermediate IPSS-R scores. Aim: To analyze the prognostic value of Low Risk Prognostic Scoring System(LR-PSS) in a population of lower risk MDS patients (very low, low and intermediate IPSS-R) analyzing as endpoints overall survival (OS) and leukemia free survival (LFS). Methods: A total of 890 consecutive patients with MDS (01/1992-7/2018) diagnosed at the Catalan Institute of Oncology in Barcelona were included in the study. 539 (60%) had available cytogenetics and therefore, IPSS-R could be assessed. 474 (88%) patients were classified as very low, low and intermediate IPSS-R and were included in the study. Results: 178 (37.6%) patients were classified as very low, 219 (46.2%) low and 77 (16.2%) intermediated IPSS-R risk MDS. Median age at diagnosis was 73 years (range 32-101). 332 (70%) were male. According to the 2008 WHO classification, 2.5% CRDU, 7.4% RA, 42.2% RCMD, 13.7% RAEB‐1, 3.6% RAEB‐2, 26.4% CMML and 4.2% MDS‐U with isolated 5q deletion. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.6 g/dL (5.5-17.1), 157 x109/L (1-1492) and 2 % (0-17), respectively. 84 (17.7%) patients had unfavorable LR-PSS cytogenetics at diagnosis. Median follow up time for survivors was 5.4 years (range 0.25-23.8). At the time of last follow up, 58.4 % (277) had died and 71 (15%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups, three well-differentiated prognostic categories could be identified: 103 patients (21.7%) category 1 (scores 0-2); 330 (69.6%) patients category 2 (scores 3-4) and 41 (8.7%) patients category 3 (scores 5-7) with significant different OS and LFS. Median OS for categories 1, 2 and were 7.1 years (95% CI 4.9-9.2), 5.7 years (95% CI 4.7-6.7) and 2.8 years (95% CI 2.1-3.6), p<0.001 (Figure 1), respectively. Rate of progression to acute myeloid leukemia was 10% (10/99), 15% (48/323) and 27% (11/411) for categories 1, 2 and 3, respectively. Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early treatment intervention. Disclosures Sureda: Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy; Roche: Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau.

Introduction: The Bruton tyrosine kinase inhibitor ibrutinib is the only FDA approved therapy for the treatment of symptomatic Waldenstrom macroglobulinemia (WM), and has been associated with high response rates and durable progression-free survival (PFS). Factors associated with depth of response and PFS duration are not well established. We performed a retrospective study aimed at identifying predictive and prognostic factors in WM patients treated with ibrutinib. Methods: We included consecutive patients with a diagnosis of WM treated with ibrutinib monotherapy evaluated at the Dana-Farber Cancer Institute since January 2012 through March 2019. Patients with Bing-Neel syndrome (WM involving the central nervous system) were excluded. Baseline clinical and laboratory characteristics were gathered. MYD88 and CXCR4 mutations were assessed using polymerase chain reaction assays and Sanger sequencing. Responses at 6 months were assessed using criteria from IWWM3. PFS was defined as the time from ibrutinib initiation until last follow-up, death or progression. Univariate and multivariate logistic regression models were fitted for partial response (PR) and very good partial response (VGPR) at 6 months, and Cox proportional-hazard regression models were fitted for PFS. Results: A total of 252 patients were included in our analysis. Selected baseline characteristics include: age ≥65 years (60%), hemoglobin <11.5 g/dl (68%), platelet count <100 K/uL (12%), albumin <3.5 g/dl (39%), b2-microglobulin ≥3 mg/l (70%), serum IgM level ≥7,000 mg/dl (6%), bone marrow involvement ≥60% (54%), previously untreated for WM (33%), time to ibrutinib <3 years (46%). MYD88 L265P and CXCR4 mutations were detected in 98% and 38% of patients, respectively. At 6 months, 71% of patients obtained PR, and 17% VGPR. Multivariate logistic regression analyses showed higher odds of PR at 6 months for hemoglobin <11.5 g/dl (78% vs. 56%; OR 2.8, 95% CI 1.1-6.9; p=0.03) and serum albumin <3.5 g/dl (90% vs. 66%; OR 3.2, 95% CI 1.0-10; p=0.045), while CXCR4 mutations associated with lower odds (44% vs. 82%; OR 0.15, 95% CI 0.06-0.37; p<0.001). Multivariate logistic regression analyses showed higher odds of VGPR at 6 months for b2-microglobulin ≥3 mg/l (21% vs. 3%; OR 3.3, 95% CI 1.1-10; p=0.04) and lower odds for serum IgM level ≥4,000 mg/dl (9% vs. 23%; OR 0.3, 95% CI 0.1-0.8; p=0.02). The median follow-up was 30 months, and the median PFS has not yet been reached. The 5-year PFS rate was 60% (95% CI 48-69%). In the multivariate Cox regression analysis, worse outcomes were seen with CXCR4 mutations (5-year PFS: 45% vs. 71%; HR 2.8, 95% CI 1.4-5.8; p=0.004) and serum albumin <3.5 g/dl (5-year PFS: 36% vs. 68%; HR 2.7, 95% CI 1.3-5.5; p=0.007). A novel PFS risk score was designed using CXCR4 mutational status and serum albumin (Figure), which divided patients into 3 distinct groups: low risk (no risk factors: 43%; 5-year PFS 81%), intermediate risk (1 risk factor: 46%; 5-year PFS 51%) and high risk (2 risk factors: 11%; median PFS 25 months). The PFS difference between groups was statistically significant (p<0.001). The PFS risk score showed consistent results when evaluating previously treated and untreated patients, as well as patients on and off clinical trials. Conclusion: Serum albumin and CXCR4 mutations emerge as important factors predictive of PR at 6 months and also prognostic of PFS in WM patients treated with ibrutinib. A novel PFS stratification tool that separates patients into 3 risk groups was established and would need further validation. Figure Disclosures Castillo: Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Hunter:Janssen: Consultancy. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

Abstract Background Treatment related toxicity complicates outcome in elderly patients with AML (Estey et al. Blood. 2006). Conventionally, 7+3 induction (anthracycline plus cytarabine) results in Complete Remission rate of about 30%. Regimens with less toxicity, such as 10-days (d) schedule of DAC, seem promising with CR rate of 47% (Blum et al. PNAS. 2010). In secondary MDS derived AML, response prediction could be derived from mutation status in epigenetic modifiers (IDH1, IDH2, DNMT3 A, TET2), transcriptional regulators (RUNX1, CBL), and genes in spliceosome machinery, such as SF3B1 and SRSF2 (Husseinzadeh et al. American Society of Hem Meeting. Abstract # 1698. 2012). IDH-1 mutation is known to induce hypermethylator phenotype (fig 1) (Figueroa et al. Cancer Cell. 2010) and might be present in conjunction with SRSF2 mutations, an unique unreported molecular subset, feasible for exploring azanucleoside response prediction. Herein, we report a case of trisomy 8 MDS derived IDH1 and SRSF2 mutated AML who underwent rapid morphological blast differentiation in the context of acute differentiation syndrome while treated with 10 days (d) of hypomethylating dose of DAC. Methods A 61-year-old male with performance status (PS) = 3 presented with leukocytosis of 18.9 K/uL (peripheral blast 90%). He had a history of low-grade MDS diagnosed 2 years before AML transformation. After morphological confirmation of M5 AML, fluorescent in situ hybridation (FISH) revealed 81% nuclei with trisomy 8. Extracted DNA was tested with a custom-designed Leukemia Cancer Gene Mutation Panel using AmpliSeq™ technology and showed IDH1 c.394C>T(p.R132C) mutation (Fig. 2B) and c.284C>T(p.P95L) mutation of SRSF2 gene (Fig. 2C). DAC was initiated at 15 mg/m2 for a total of 10 days every 28 d cycle. Results By day 5 of cycle (C)1 of DAC treatment, brisk and significant rebound leukocytosis of 60 K/uL (Fig. 3) was observed, along with shortness of breath, hypoxemia and radiological evidence of floppy bilateral pulmonary infiltrates suggestive of acute-like differentiation syndrome. In addition to broad-spectrum antimicrobial and antifungal, dexamethasone at 4 mg intravenously (IV) every 8-hour (h) and hydroxyurea at 1 g orally every 8 h resulted in progressive normalization of peripheral blood count and hypoxemia after 48 h. Patient (pt) recovered from C1 and proceeded with C2 of treatment. A similar episode of brisk/robust leukocytosis was observed by day 5 of C2 requiring dexamethasone and hydroxyurea. Progressive morphological differentiation was observed to full mature and morphologically normal monocytes and neutrophil (Fig. 4). Pt expired as result of severe clostridium difficile colitis during C3 of DAC. Conclusions In our case, we observed robust acute differentiation syndrome characterized by rapid increase of WBC, shortness of breath and hypoxemia associated with azanucleoside treatment. Beside a novel association of IDH-1 and SRSF2 mutations, acute differentiation might suggest potential feature for azanucleoside response phenotype. Our case adds body of evidence of connection between epigenetic regulator and spliceosome mutations. Further studies on the impact of dual mutations in epigenetic reprogramming, leukemia transformation, and azanucleoside response will allow improved decision algorithm and therapeutic design. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Polycythemia Vera (PV) is a clonal myeloproliferative neoplasm, characterized by the JAK2V617F mutation. The main goal of current therapies for PV is to prevent thrombotic events and delay transformation to Myelofibrosis (MF) or Acute Myeloid Leukemia (AML).Treatment for PV to keep an hematocrit (Hct) level <45 %, has been associated with a reduction in cardiovascular deaths and thrombotic events (Marchioli, R et al. NEJM 2013). Currently, low-risk PV patients (<60 years and no previous thrombotic events) are treated with aspirin and phlebotomy while high-risk patients require additional cytoreductive therapy, usually with Hydroxyurea (HU). Resistance to HU is associated with an increased risk of transformation and reduced survival. This is why for HU-refractory patients, second line treatments with interferon alpha, anagrelide or even ruxolitinib are recommended. In Latin America, because of high cost and drugs availability, this last group reflects difficulties to be treated. Because statins have been reported to modulate the erythroid clonogenic activity of normal BM erythroid colonies we performed a pilot study to investigate in vitro and in vivo the biologic and clinical activity of atorvastatin in PV patients Patients and Methods Ten high risk PV patients with a median age of 64.3 years (range 58-73) entered into this study. The diagnosis of PV was done according to the 2008 World Health Organization diagnostic criteria and patients were stratified according to an algorithm proposal provided by Griesshammer et al. (Ann Hematol, 2015). The definition of HU resistance (Barosi, G et al.: BJH 2009) was applicable to five patients (median age 63.9 years) failing to achieve a satisfactory hematologic response upon treatment with more than 2 g of HU, 100 mg of Aspirin and phlebotomies. The assessment of the JAK2V617F mutation was performed as previously described (Guerini et al.: Leukemia 2009). Colony assay, proliferation and apoptosis tests were performed with or without Simvastatin (3.5 uM), as previously described (Amaru, A, Experimental Hematology 2012), on cell lines (UKE1 and K562) and bone marrow mononuclear cells obtained from PV patients and healthy donors. Patients with HU refractory PV (n=5) and high risk PV with hypercholesterolemia (n=5) were eligible to receive Atorvastatin (20 mg/day) added on the top of the ongoing treatment with phlebotomies, Aspirin (100 mg/day) and cytoreductive HU therapy (500 mg/day). All treated patients were high altitude residents (> 3.600 m.a.s.l.) of La Paz (Bolivia) where the normal Hct level of healthy subjects is 48-57% for men and 44-54% for women. This pilot study was approved by the Review Board of the Hospital and the University of San Andres, La Paz. Results In a preliminary set of in vitro proliferation cell assays, simvastatin (3.5 uM), added for 5 days, induced a 33% inhibition of cell proliferation of UKE-1 (JAK2V617F mutated) as compared to 5 % of K562 (BCR/ABL positive). A comparable result was obtained in a 7-day clonogenic cell assay where the colony inhibition was 50 % for UKE-1 and 10 % for K562. On the basis of these results similar experiments were also performed using BM mononuclear cells derived from PV patients and healthy donors. In these experiments performed with the addition of simvastatin, it induced a 41% of inhibition in BFU-E colonies of PV patients and a 25% of inhibition in healthy donors. Furthermore, BFU-E colonies inhibited by simvastatin presented a decrease in hemoglobinization and the size of colonies. HU refractory PV patients and High-risk PV patients with hypercholesterolemia treated with the addition of Atorvastatin, Aspirin, cytoreductive HU and phlebotomies; after a follow-up of 2.6 years (1-7 years), induced a decrease of WBC from 16.500 to 9.270/ul, Hct 61.1 to 52.3% and PLT 457.900,000 to 324.7000/ul. The number of required phlebotomies is reduced in comparison to the required at starting treatment. None of the patients presented thrombotic or cardiopulmonary event. One patient died within two years of starting treatment, due to complications of diabetes mellitus. Conclusions In vitro and in vivo, statins showed some evidence of inhibitory activity of the hematopoiesis of PV patients. These preliminary results might indicate the opportunity to further investigate the potential clinical value of these molecules in the treatment of PV. Disclosures Off Label Use: Atorvastatin was used for its antiproliferative activity on myeloid progenitor cells shown by in vitro experiments.

Abstract Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the IPSS; however, this score system does not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) but a poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin <10g/dl, platelet count <50k/uL or 50-200k/uL, bone marrow blasts ≥4% and unfavorable cytogenetics (non-del(5q), non-diploid). This LR-PSS score system enables the stratification of low risk MDS patients into 3 different risk categories; interestingly, the third category identifies a subgroup of patients with a median overall survival (OS) similar to that of patients classified as intermediate-2 and high risk IPSS. Besides, the IPSS-R described by Greenberg et al (Blood 2012) has demonstrated a strong prognostic value for OS and LFS as compared to the IPSS when applied to different independent series of MDS patients. The prognostic impact of the LR-PSS has not been analyzed in MDS patients with very low-, low- and intermediate IPSS-R scores. Aim: To analyze the prognostic impact according to OS and leukemia free survival of the LR-PSS when applied to a population MDS patients with very low, low and intermediate IPSS-R. Methods: A total of 789 consecutive patients diagnosed with MDS (01/1992-12/2014) at the Catalan Institute of Oncology of Barcelona were included in the study. 413 (52%) had available cytogenetics and therefore, IPSS-R was calculated. Overall, 371 (89%) patients were classified as very low, low and intermediate IPSS-R and included in the study. Results: 123 (30%) patients were classified as very low, 182 (44%) low and 66 (16%) intermediated IPSS-R risk MDS; median age 72 years (range 32-101) and 258 (69%) male. 1.4 % CRDU, 7.6 % RA, 41.6 % RCMD, 16.2 % RAEB‐1, 4.1 % RAEB‐2, 25.9 % CMML and 3.2 % MDS‐U with isolated 5q deletion according to the 2008 WHO classification. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.8 g/dL (5.5-17.1), 152 x109/L (1-1492) and 3 % (0-17), respectively and fifty-three (14.3 %) patients had unfavorable LR-PSS cytogenetics. For the whole population, median follow up was 6.6 years (range 6-7.7). At the time of last follow up, 48.2 % (179) had died and only 49 (13%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups three well-differentiated prognostic categories could be identified: 58 patients (15.6%) category 1, scores 0-2; 277 (74.6%) patients category 2, scores 3-4 and 36 (9.8%) patients category 3, scores 5-7 with significantly different overall survival and leukemia free survival. Median OS for categories 1 (9.4 years; 95% CI 6.7-12), 2 (6 years; 95% CI 5-7.1) and 3 (2.6 years; 95% CI 2.1-3) were significantly different (p<0.001; Figure 1). Moreover, the rate of progression to acute myeloid leukemia was 5% (3/58), 13% (37/277) and 25% (9/36) for categories 1, 2 and 3, respectively. Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, the LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early intervention. Further studies are warranted. Fig 1. Kaplan-Meier survival for patients with very low-, low- and intermediate IPSS-R risk assigned to categories 1 to 3 by LR-PSS. Fig 1. Kaplan-Meier survival for patients with very low-, low- and intermediate IPSS-R risk assigned to categories 1 to 3 by LR-PSS. Disclosures Sureda: Takeda: Consultancy, Speakers Bureau.

Abstract Background Both primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement carry a poor prognosis. While there has been interest in intensification of treatment with high-dose chemotherapy and autologous stem cell transplant (ASCT), the side effect profile and long-term efficacy of consolidative transplant are not yet clear. Our aim was to investigate the efficacy and safety of a conditioning regimen of thiotepa, busulfan, and cyclophosphamide (TBC) (Soussain C., et al, J. Clin. Oncol., 19:742-749, 2001) followed by ASCT in patients with PCNSL or NHL with CNS involvement. Methods A retrospective analysis was performed among consecutive patients undergoing consolidative ASCT with TBC conditioning for PCNSL or NHL with CNS involvement between July 2006 and December 2017. For patients with PCNSL, a uniform induction therapy was given that consisted of rituximab and high dose methotrexate for 2-4 cycles followed by rituximab / cytarabine / thiotepa for 1-2 cycles based on published data (Illerhaus et al, Blood 120, no. 21 (2012): 302). For patients with secondary CNS lymphoma or relapsed disease, a variety of chemotherapy regimens were used at the discretion of the treating physician. Progression-free survival (PFS) was defined from the date of transplant to the date of relapse or any cause of death. Overall survival (OS) was calculated from the date of transplant to death. Results Forty-eight patients with NHL who underwent ASCT with TBC conditioning were identified: 27 patients with PCNSL, 12 patients with secondary CNSL, and 9 patients with relapsed disease with CNS involvement. Twenty-nine patients (60%) were in their first complete response (CR1) at the time of transplant. The median time from diagnosis to transplant was 7.1 months (range 3.7- 144.4). The median follow-up time after transplant was 23.9 months (range 8.6 - 59.6 months). The median time to neutrophil recovery (absolute neutrophil count > 500/uL) and platelet recovery (>20,000 x 103/μL for > 2 consecutive days) were 9 days (range 7-12 days) and 7 days (range 1-40 days), respectively. Four patients were noted to have anemia (hemoglobin decrease >2 g/dL from baseline). Most patients (89.5%) experienced febrile neutropenia and 68.6% were found to have infection. Other common side effects included mucositis (89.5%, 35.4% with grade 3 or higher), electrolyte abnormalities (89.5%), dermatologic sequelae (31.3%), reversible neurotoxicity (18.8%), renal injury (16.7%), and hemorrhagic cystitis (8.3%). Four patients (8.3%) experienced treatment-related mortality, 3 of which had secondary CNSL. No evidence of pulmonary toxicity or veno-occlusive disease was noted. The 1-year PFS was 78% (95% CI 63.3%-88.0%), and 1-year OS was 80.5% (95% CI 66%-89.8%). When analyzed according to primary diagnosis, 1-year PFS was 82.6% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.69). According to diagnosis, 1-year OS was 87% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.47). Univariate analysis was performed to analyze gender, ethnicity, age > 60, Karnofsky score ≥ 80, diagnosis, cell of origin, and transplant in CR1 versus CR2 or partial response as independent predictors of PFS and OS. Only age (p = 0.001, 95% CI 1.9-42.6 for PFS; p = 0.030, 95% CI 0.99-23.42 for OS) and Karnofsky score ≥ 80 (p = 0.017, 95% CI 0.07-0.81 for PFS; p = 0.047, 95% CI 0.06-1.03 for OS) were found to be significant. Conclusion High dose chemotherapy and autologous stem cell transplant using TBC conditioning for PCNSL and secondary CNSL appears to have encouraging long term efficacy with manageable side effects. Future studies looking at longer follow-up periods and comparison with other conditioning regimens is warranted. Disclosures Schiller: Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding.

Depuis le début des années 2000, la détérioration de la qualité de l’eau de nombreux lacs du sud québécois, résultant souvent en des floraisons de cyanobactéries, inquiète de plus en plus les résidents et les municipalités affectées. Ces préoccupations ont mené à la mise en place d’une étude paléolimnologique du lac Nairne, ayant pour but principal de reconstituer l’évolution trophique du lac. La municipalité de Saint-Aimé-des-lacs et l’Association pour la Protection de l’Environnement du Lac Nairne (APELN), en collaboration avec le partenariat CIMA+/ULaval, ont joint leurs efforts pour fournir aux décideurs les outils nécessaires à une meilleure compréhension de l’évolution de la qualité de l’eau du lac et pour l’élaboration d’un plan de gestion adapté au lac. Cette étude retrace l’évolution trophique du lac Nairne (Charlevoix, Qc) selon une approche paléolimnologique à l’aide des diatomées fossiles, d’analyses géochimiques et de pigments photosynthétiques fossiles. Les résultats obtenus démontrent une eutrophisation progressive du plan d’eau depuis 780 ans BC et une accélération de la détérioration de la qualité de l’eau suite à l’exploitation des terres du bassin versant. Cependant, une amélioration de la qualité de l’eau est également notée suite à la diminution des activités d’exploitation dans le bassin versant et à la recolonisation végétale vers 1950. Ces résultats mettent en évidence les conséquences profondes de l’établissement humain sur l’intégrité des écosystèmes aquatiques et la qualité de l’eau, mais aussi qu’une modification des habitudes de vie peut avoir des incidences positives sur la qualité de l’eau.
Residents and municipalities surrounding many southern Quebec lakes have expressed concerns since the early 2000s following massive cyanobacterial blooms that were followed by rapid deterioration of the lake’s water quality. As a consequence, several research programs have been initiated in order to provide those municipalities with an array of tools for a better management of these water bodies. In this context, the municipality of Saint-Aimé-des-Lacs, the Association pour la Protection de l’Environnement du Lac Nairne (APELN) and a partnership CIMA+/ULaval, have joined forces to conduct a paleolimnological research project at Lake Nairne. This concerted study aims at describing the past and recent evolution of Lake Nairne’s trophic state, and also to provide policy makers with tools for the development of management plans specifically designed for the lake’s watershed. As part of this concerted study, this master’s thesis describes Lake Nairne’s historical trophic state fluctuations. Using a paleolimnological approach, fossil diatoms, geochemical analysis and photosynthetic fossil pigments have shown progressive eutrophication of the lake basin since 780 years BC and rapid deterioration of the lake’s water quality following the beginning of agricultural and industrial activities in the lake’s watershed. However, improvements in water quality were also noted since the recent slowdown of industrial operations and vegetation recolonization since 1950. These results highlight the profound impact that human settlement and activities can have on the ecological stability of Lake Nairne, but also the capacity of such aquatic ecosystems to partly recover following substantial modification of the lake’s watersheds.

La thèse étudie, selon une optique de géographie historique, la ville de Bogotá, capitale de la Colombie juchée sur un haut plateau à 2600 m d’altitude. Fondée dans la foulée de l’expansion coloniale espagnole en Amérique, Bogotá est aujourd’hui une métropole de huit millions qui compte parmi les villes les plus dynamiques de l’Amérique latine. Le but de démontrer comment cette ville, isolée au sein d’un vaste pays montagneux, est devenue au fil des siècles un centre économique de premier ordre à l’échelle continentale. Au plan théorique, l’analyse mobilise trois concepts fondamentaux : la morphologie urbaine, où se combinent la division de la société en classes et l’organisation du territoire; le système urbain, qui place la ville à la fois dans un réseau d’échanges ou d’influences et dans son économie régionale; les discours urbanistiques, qui infléchissent idéologiquement l’organisation de l’espace géographique à l’échelle locale. Croisant constamment ces concepts, la thèse propose une synthèse de l’histoire urbaine de Bogotá. Pour ce qui est des premières périodes, qui se rapportent à la ville coloniale et à la ville républicaine du XIXe siècle, le regard se concentre tout particulièrement sur la dynamique du système urbain dans lequel s’inscrit Bogotá et sur la trajectoire de la ville comme capitale religieuse, administrative et économique de la Nouvelle Grenade et, après l’indépendance, de la Colombie. Concernant le XXe siècle, l’attention se tourne plus spécifiquement vers l’impact de l’industrialisation, de l’exode rural et de l’idéologie moderniste. Enfin, un dernier chapitre explore l’époque contemporaine en étudiant les conséquences à Bogotá de l’urbanisme post-moderne, fréquemment lié à la montée d’une idéologie néolibérale, et l’imposition d’une politique urbaine flexible et éloignée des contrôles gouvernementaux. De même y est scruté l’étalement urbain, en cours depuis deux décennies, et les phénomènes qui y sont associés : ségrégation, embourgeoisement, densification, métropolisation. Il apparaît que ces processus sont tous liés à une planification dérégulée et focalisée presque exclusivement sur l’espace public, la sécurité citoyenne et la narrativité environnementale. Mots clefs : Morphologie urbaine, système urbain, discours urbanistiques, historiographie urbaine, métropolisation, étalement urbain.

La fièvre aphteuse (FA) est l'une des maladies infectieuses les plus importantes qui affectent les animaux biongulés. Le Brésil est libre avec vaccination depuis 2001, mais en 2005, une épidémie est survenue à la frontière entre le Brésil et le Paraguay. Identifier les exploitations agricoles ou des espaces géographiques qui sont le plus à risque de fièvre aphteuse en particulier dans les régions frontalières est l'un des principaux objectifs du service vétérinaire officiel du Brésil et aussi d'autres pays d'Amérique du Sud. Les indicateurs utilisés par le gouvernement brésilien pour indentifier les zones à risque de fièvre aphteuse prennent en considération essentiellement des informations au niveau du troupeau (structure du troupeau, la présence de jeunes animaux, rapport vache / veau, etc.). Dans ce contexte, l'objectif principal de notre recherche est d'élaborer un cadre pour l'évaluation des risques de fièvre aphteuse à la frontière entre le Brésil et le Paraguay prenant en compte les aspects géographiques liés aux systèmes de production. Afin d'atteindre cet objectif, l'étude a été divisée en trois articles. Le premier article dresse un aperçu concernant les pratiques d'hygiène et de contrôle de la FA dans cette zone particulière. Quatre-vingt-sept agriculteurs ont été interrogés sur cinq thèmes principaux: la caractérisation des agriculteurs, les indicateurs sanitaires, la vaccination de la fièvre aphteuse, la circulation des personnes et des animaux ainsi que l'opinion des agriculteurs sur les risques d'introduction de la FA. Les résultats montrent que les agriculteurs sont conscients de leur rôle dans le combat contre la fièvre aphteuse. Il montre également que les agriculteurs, surtout les petits, ont besoin d'être mieux soutenus. Ils n'ont toujours pas de contrôle sanitaire formel. Ils ont besoin de formation et d’un constant soutien. Même si cette région a le même statut sanitaire que le reste du Mato Grosso do Sul, qui est libre de fièvre aphteuse avec vaccination, le contrôle et les différentes mesures sanitaires doivent se poursuivre. Le deuxième article explore la possibilité d'utiliser la télédétection pour cartographier et pour surveiller les zones de pâturage afin d’établir des modèles localisés de prédiction de densité de bétail. Un modèle statistique afin de prédire le nombre de bovins en fonction de la superficie de pâturage déclarée par les agriculteurs, a été réalisé sur la base de données officielle concernant l'élevage de la zone d‘étude. Finalement, ce modèle a été appliqué aux zones de pâturage détectées par classification orientée objet pour prédire la densité bovine. Les résultats indiquent que la méthodologie utilisée pour estimer la densité du bétail peut être utilisée dans des régions où l'information sur l'emplacement et la densité de ferme d'élevage est inexistante. Dans le troisième article, nous avons testé l'approche à majorité floue d’analyse multicritère de décision basée sur un système d’information geographique (SIG - AMC) afin de déterminer les zones à risque d'introduction de la FA. Deux scénarios ont été comparés, le premier basé sur la ferme (où l'information officielle est disponible) et le second basé sur la télédétection (où seulement l'information géographique est disponible). Les cartes obtenues mettent en évidence la forte hétérogénéité spatiale du risque d'introduction de la FA. Une corrélation positive a été observée entre les scénarios basés sur la ferme et les scénarios basés sur la télédétection. Cette étude fournit un cadre alternatif pour détecter les zones à risque de FA et de cette manière pour renforcer les mesures sanitaires brésiliennes. Il a également un grand potentiel pour être extrapolé à d'autres régions ayant des caractéristiques similaires mais où des informations au niveau du troupeau sont rares, ou inexistantes, comme d'autres régions reculées du Brésil ou d'autres pays d'Amérique du Sud Mots-clés : régions frontalières, analyse multicritère à la décision, télédétection, analyse de risques de fièvre aphteuse
Foot and mouth disease (FMD) is one of the most important infectious diseases that can affect cloven hoofed animals. Brazil is free with vaccination since 2001, but in 2005 an outbreak occurred in the border between Brazil and Paraguay. Identifying farms or geographic spaces that are more at risk of FMD, especially in border regions, is one of the main goals of official veterinary service from Brazil and other South American countries. Indicators used by the Brazilian government to indentify FMD risk areas takes into consideration basic information at herd level. For these reasons, the principal objective of this research was to elaborate a framework for FMD risk assessment in the frontier between Brazil and Paraguay that takes in account geographic aspects associated with production systems information. In order to accomplish this objective, the study was divided in three articles. The first article draws an overview regarding sanitary practices and FMD control in this particular zone. Eighty seven farmers were interviewed regarding five main subjects: farmers’ characterization, sanitary indicators, FMD disease vaccination, people and animal movements and farmer’s opinions about FMD risks of introduction. The results show that farmers are conscious of their roles in FMD control. It also shows that among small farmers there is a need to be better assisted. Such farmers lack formal sanitary controls and they need constant training and support. Even if this region has the same sanitary status as the rest of Mato Grosso do Sul State (which is FMD free with vaccination), differentiated sanitary measures and control should continue. The second article explores the potential use of remote sensing to map and monitor pasture areas and to establish models for predicting cattle density and location. A statistical model to predict numbers of cattle in function of declared pasture area by the farmers was produced on the basis of Brazilian official livestock databases for the studied area. Finally, this model was applied to the pasture areas detected by oriented based classification to predict cattle density. The results indicate that the methodology used for estimating cattle density has the potential to be applied in regions where no information about farm location and cattle density exists. In the third article the fuzzy majority approach for GIS based multicriteria decision analysis (GIS – MCDA) was tested to determine risk areas of FMD introduction. Two main scenarios were compared: a farm-based one (where official information is available) and a remote sensing-based one (where only geographic information is available). Resulting maps highlighted a strong spatial heterogeneity in the risk of FMD introduction. A positive correlation was observed between farm-based scenarios and remote sensing-based scenarios. This study provides an alternative framework to detect areas of higher risk of FMD and by this way reinforce Brazilian sanitary measures. It also has great potential to be extrapolated for other regions with similar characteristics but where information at herd level are sparse or inexistent such as remote regions of Brazil and other South American countries. Key-words: border regions, multicriteria decision analysis, remote sensing, FMD risk assessment.

La présente thèse documente le cadre environnemental de la ville de Québec, avant et après l’établissement des premiers Européens en Nouvelle-France. Grâce aux fouilles archéologiques effectuées à l’îlot des Palais, en Basse-Ville, une séquence sédimentaire non perturbée ainsi qu’un segment d’une palissade en bois ont été mis au jour. Cette recherche repose sur des méthodes d’analyses scientifiques et historiques et comprend trois volets. Le premier volet présente une reconstitution paléoenvironnementale dans deux sites (Palais de l’Intendant : PDI et Chateauguay : CHAT) localisés dans le cours inférieur de la rivière Saint-Charles, depuis l’Holocène moyen jusqu’à l’établissement européen. Les données géomorphologiques et macrofossiles, ainsi que le cadre chronologique établi à l’aide de datations au radiocarbone, montrent que l’ancienne plaine d’inondation de la rivière a été influencée par deux transgressions marines (Laurentienne et Mitis). Les assemblages macrofossiles dans les deux sites indiquent que le couvert végétal formait, pendant l’Holocène supérieur, une mosaïque de communautés grandement influencée par la topographie locale et la proximité de la rive. Le deuxième volet documente le contexte écologique et historique dans lequel la palissade mise au jour dans le site PDI a été construite. Cet ouvrage défensif a été construit à l’aide de pieux de thuya occidental (Thuja occidentalis L.) ou cèdre, qui était vraisemblablement abondant dans l’environnement immédiat du site. L’analyse dendrochronologique de ces bois archéologiques a permis de conclure que cette palissade a été érigée en 1690 et 1691, dans un contexte d’empressement, afin de contrer les attaques ennemies. Une longue série dendrochronologique du thuya, d’échelle régionale, la série Saint-Laurent (1489-2001), a été élaborée à cette occasion. Le troisième volet présente une synthèse de données historiques ayant pour but de dégager les perceptions environnementales des premiers européens occupants de la région de Québec, et plus largement de la Nouvelle-France. Aux XVIIème et XVIIIème siècles, les Européens ont cherché à acquérir des connaissances sur leur nouvel environnement, souvent au contact de populations amérindiennes. L’établissement humain passait par l’acclimatation au territoire afin d’en exploiter les ressources. Cette découverte de la Nouvelle-France reflète un engouement pour les sciences naturelles et une certaine sensibilité à la nature.
This dissertation documents the environmental history of Québec City, preceding and after the first European establishments in New France. Archaeological excavations at the Intendant Palace’s site, in Lower Town, has revealed an undisturbed sedimentary sequence and a section of a wooden palisade. This research is based on environmental and historical analyses and includes three sections. The first chapter describes a paleoecological reconstruction at two sites (Intendant’s Palace: PDI and Chateauguay: CHAT) located on the lower course of the Saint-Charles River, and dating as far back as the mid-Holocene up to the beginning of the European settlement of Quebec City. Geomorphological and macrofossil data along with a chronological framework established by using radiocarbon dating, suggest that the former river floodplain was influenced by two marine transgressions (Laurentian and Mitis). Macrofossil assemblages at the two sites indicate that the late-Holocene vegetation consisted of a mosaic of plant communities largely influenced by the local topography and proximity to the river bank. In the second chapter, we document the ecological and historical contexts of palisade construction at PDI. White cedar (Thuja occidentalis L.) posts were used to erect this defensive structure, a species which was probably common in the site’s vicinity. Based on tree-ring data from archeological wood, we conclud that the palisade was quickly assembled in 1690 and 1691, for protection against enemy attacks. A long regional tree-ring chronology for white cedar, called the Saint-Laurent chronology (1489-2001), was constructed from the posts analysed. In the third chapter, we synthesize historical data in order to identify the environmental perceptions of the first european occupants of the Quebec City region and, to a broader scale, of New France. During the 17th and 18th centuries, Europeans experienced their new environment often through contacts with indigenous populations. Human settlement was possible through human adaptation to this new territory with the aim of exploiting its resources. Discovery of New France reflects the learned society’s passion for sciences and a sensitivity to nature.