Monitoring of asparagine depletion and anti-L-asparaginase antibodies in adult acute lymphoblastic leukemia treated in the pediatric-inspired GRAALL-2005 trial

International audienceno abstrac

Middle Risle critical zone observatory : monitoring karstic processes evolution in the river, their impacts on surface water/groundwater interaction and their consequences on aquatic ecosystems

International audienceThe Risle river, in its middle portion, is frequently affected by episodes of major sinkholes development; indeed, in the last decade or so, two major sinkholes developed in the river bed leading to crisis situation with a complete river loss in the underlying groundwater and a dried up river course over distances of several kilometers downstream during the summer season. This resulted in major modifications in hydrogeological and in surface – groundwater interaction processes, with major consequences on water quality, water uses and water dependent ecosystems. To understand this phenomenon, its impact both on surface-groundwater interaction processes and on aquatic ecosystems and to improve crisis management, a multi-parameter monitoring program called the middle Risle critical zone observatory has been set up, in order to acquire the necessary data and knowledge and develop proper tools to best manage these situations. Several monitoring networks were implemented involving several partners. Exploratory tools and methodologies were also developed. The work carried out in this project notably included setting up monitoring networks for groundwater level, water river level, differential flow in rivers, temperature and conductivity surveys, springs yield, ecosystem surveys (fishes, macroinvertebrates, vegetation) as well as modelling surface, karst and groundwater flow… Results obtained were numerous including river loss impacts on fishes, macroinvertebrates and vegetation and population recovery rates. Some vegetal species seem to be a reliable indicator for surface/groundwater interaction. The dynamics of local hydrogeological processes are assessed and linked to the consequences on the ecosystems habitats and on water use. Inverse modelling using an analytical solution of the diffusive wave equation helped assessing for lateral flows during flood events, quantifying spatio-temporal variability for surface water and groundwater exchanges. It also highlighted the important role of the karstic zones both on storage and on river flood peak attenuation processes, thereby protecting downstream villages against floods. Finally an approach using transfer model based on computing the convolution integral of up to several signals allowed building the first functional scheme of this karst system

DNMT3A mutation is associated with increased age and adverse outcome in adult T-acute lymphoblastic leukemia

International audienceThe prognostic implications of DNMT3A genotype in T-ALL are incompletely understood. We performed comprehensive genetic and clinicobiological analyses of T-ALL patients with DNMT3A mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had DNMT3A alterations. Two patients also had DNMT3A mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-ALL. DNMT3A mutation was associated with older age (median 43.9 years v 29.4 years, p &lt; 0.001), immature T-receptor genotype (53.3% v 24.4%, p = 0.016) and lower remission rates (72.2% mutated v 94.4% non-mutated, p = 0.006). DNMT3A alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (CIR, HR 2.33, 95% CI 1.05-5.16, p = 0.037) and markedly poorer event-free survival (EFS, HR 3.22, 95% CI 1.81-5.72, p &lt; 0.001) and overall survival (OS, HR 2.91, 95% CI 1.56-5.43, p = 0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of DNMT3A-mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, DNMT3A mutation was significantly associated with shorter EFS (HR 2.33, 95% CI 1.06 - 4.04, p = 0.02). Altogether, these results identify DNMT3A genotype as a predictor of aggressive T-ALL biology. The GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.</p

Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study.

Purpose Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL) is an immunophenotypically defined subgroup of T-cell ALL (T-ALL) associated with high rates of intrinsic treatment resistance. Studies in children have shown that the negative prognostic impact of chemotherapy resistance is abrogated by the implementation of early response-based intensification strategies. Comparable data in adults are lacking. Patients and Methods We performed comprehensive clinicobiologic, genetic, and survival analyses of a large cohort of 213 adult patients with T-ALL, including 47 patients with ETP-ALL, treated in the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia) -2003 and -2005 studies. Results Targeted next-generation sequencing revealed that the genotype of immunophenotypically defined adult T-ALL is similar to the pediatric equivalent, with high rates of mutations in factors involved in cytokine receptor and RAS signaling (62.2%), hematopoietic development (29.7%), and chemical modification of histones (48.6%). In contrast to pediatric cases, mutations in DNA methylation factor genes were also common (32.4%). We found that despite expected high levels of early bone marrow chemotherapy resistance (87%), the overall prognosis for adults with ETP-ALL treated using the GRAALL protocols was not inferior to that of the non-ETP-ALL group (5-year overall survival: ETP, 59.6%; 95% CI, 44.2% to 72.0% v non-ETP, 66.5%; 95% CI, 58.7% to 73.2%; P = 0.33) and that allogeneic stem-cell transplantation had a beneficial effect in a large proportion of patients with ETP-ALL. Conclusion Our results suggest that the use of response-based risk stratification and therapy intensification abrogates the poor prognosis of adult ETP-ALL

Thromboembolism prophylaxis in adult patients with acute lymphoblastic leukemia treated in the GRAALL-2005 study.

Patients undergoing treatment of acute lymphoblastic leukemia (ALL) are at risk for thrombosis, caused in part by the use of l-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent venous thromboembolism (VTE) and thus may increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatrics-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia- ALL were included. The incidence rate of VTE was 16%, with 69% of cases occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or who developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE. Administration of fibrinogen concentrates was associated with an increased risk of VTE, whereas transfusion of fresh frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE. Prophylactic measures were not associated with an increased risk of grade 3 to 4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1 of 34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. VTE developed despite extensive AT supplementation, which suggests the need for additional prophylactic measures. Although this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. This trial was registered at www.clinicaltrials.gov as #NCT00327678