Xavier Thomas

HCL, Noida, Uttar Pradesh, India

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Publications (308)1742.75 Total impact

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    ABSTRACT: Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells (LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despite the introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.
    08/2015; 7(7):1022-38. DOI:10.4252/wjsc.v7.i7.1022
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    ABSTRACT: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. Sunesis Pharmaceuticals. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 07/2015; 16(9). DOI:10.1016/S1470-2045(15)00201-6 · 24.69 Impact Factor
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    ABSTRACT: Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including L-asparaginase (L-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three L-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36%-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with L-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), p= .0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned L-ASP infusions without recurrence of CNS thrombotic whereas L-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (p= .4). This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 07/2015; DOI:10.1002/ajh.24130 · 3.80 Impact Factor
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    ABSTRACT: Blood transfusions can modify host immunity and clinical outcomes in hematological malignancies. One thousand sixty-seven patients with acute myeloid leukemia (AML) were studied for their transfusion dependency at initial presentation and transfusion frequency during induction chemotherapy. Three hundred five patients (29 %) showed initial dependence to red blood cell (RBC) transfusion and 109 (10 %) to platelet transfusion. Transfusion dependency at presentation was associated with a poorer prognosis. Both initial RBC and platelet transfusion needs were associated with lower response rates (P = 0.04 and P = 0.03). Median overall survival (OS) was 10.8 months for patients with RBC need vs 18.8 months for the other patients (P = 0.02) and 6.8 months for patients with platelet transfusion need vs 13.6 months for the others (P = 0.01). Similarly, transfusion intensity during induction therapy influenced negatively treatment outcome. Median transfusion burden per week was 2.5 (range 0-25.7) RBC units and 1.6 (range 0-15.7) platelet concentrates (PCs). Both high RBC and PC transfusion intensities were associated with lower response rates (P = 0.003 and P < 0.0001). Median OS was 9.08 months for patients with RBC transfusions >3/week vs 18.29 months for those with RBC transfusions ≤3/week (P = 0.0003) and 10.75 months for patients with PC transfusions >2/week vs 19.96 months for those with PC ≤2/week (P = 0.0003). RBC and platelet transfusion intensities during induction therapy remained of prognostic value in multivariate analysis. Transfusion need at presentation and the frequency of transfusions during induction chemotherapy appear as strong prognostic factors.
    Annals of Hematology 07/2015; 94(11). DOI:10.1007/s00277-015-2456-2 · 2.63 Impact Factor
  • G Cannas · J Fattoum · M Boukhit · X Thomas
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    ABSTRACT: Blood transfusion requirement represents one of the most significant cost driver associated with acute myeloid leukemia (AML). Low-intensity treatments (low-dose cytarabine, hypomethylating agents) have the potential to reduce transfusion dependence, and improve health-related quality of life. We assessed the cost-effectiveness of treatment types regarding blood product transfusions in a cohort of 214 AML patients aged ≥70 years. Analyzes did not indicate any significant overall survival (OS) advantage of intensive chemotherapy comparatively to low-intensity treatment. The difference was significant when compared to best supportive care (BSC) (P<0.0001). Blood products transfusion cost per patient was 1.3 times lower with low-intensity therapy and 2.7 times lower with BSC than with intensive chemotherapy. Mean transfusion cost per patient according to OS varied from 2.4 to 1.3 times less with low-intensity treatment comparatively to intensive chemotherapy for patients having OS≤13.3 months. Costs varied from 3.5 to 2.6 times less with BSC comparatively to intensive chemotherapy. In contrast, mean transfusion costs were comparable among treatments for patients with OS>13.3 months. Low-intensity treatments represent a cost-effective alternative to BSC and require a reduced number of transfused blood products comparatively to intensive chemotherapy, while OS was not significantly different. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Transfusion Clinique et Biologique 07/2015; DOI:10.1016/j.tracli.2015.06.249 · 0.71 Impact Factor
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    ABSTRACT: To date, in-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study comprehensively examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germline CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with AML. Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5yrs (1.75-46yrs). In all diagnostic tumors tested (n=18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were found to be unstable throughout the disease course, with different mutations identified at disease recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10yrs (n=11) and 3 patients experienced ≥3 disease episodes over a period of 17-20yrs. Durable responses to secondary therapies were observed, with prolonged median survival post relapse (8yrs) and long term overall survival (10yr OS, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long term outcomes. Copyright © 2015 American Society of Hematology.
    Blood 07/2015; 126(10). DOI:10.1182/blood-2015-05-647172 · 10.45 Impact Factor
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    ABSTRACT: Obesity is associated with an increased risk of mortality from cardiovascular causes and occurrence of malignancies. However, the effect of body mass index (BMI) on survival outcome remains controversial in acute leukemia (AL) patients. A total of 531 adults with AL who entered clinical trials in our institution between 1994 and 2012 were analyzed retrospectively for the effect of BMI at diagnosis on outcome. The median follow-up was 4.7 years (95% confidence interval [CI], 4.0-5.1). BMI had no significant effect on complete response rate, disease-free survival (DFS), or overall survival (OS) in patients from the whole cohort when considering a cutoff value for BMI of 25, and when analyzed according to age, or initial cytogenetics. In T-acute lymphoblastic leukemia (T-ALL) patients with BMI > 25, median DFS was not reached with a 3-year DFS at 76%, and median DFS was 16.1 months with 3-year DFS at 13% for those with BMI ≤ 25 (P = .005). Median OS was not reached in T-ALL patients with BMI > 25 versus 28.3 months in those with BMI ≤ 25 (3-year OS: 78% vs. 41%; P = .04). Multivariate analyses confirmed the prognostic value of BMI (> 25 vs. < 25) in T-ALL, but only in terms of DFS (hazard ratio, 0.25; 95% CI, 0.05-0.87; P = .037). However, in a validation cohort of 211 T-ALL patients, these results were not confirmed. Results from the literature are very heterogeneous and contradictory regarding the effect of BMI on leukemia outcome. Even if nutritional status during chemotherapy courses is critical, these findings provide further evidence that initial body size does not have a major prognostic effect on survival in AL patients. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical lymphoma, myeloma & leukemia 06/2015; 15S:S7-S13. DOI:10.1016/j.clml.2015.02.005 · 2.02 Impact Factor
  • Xavier Thomas
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    ABSTRACT: Despite remarkable improvements in the treatment of pediatric acute leukemia (AL) over the last decades, relapse still carries a poor prognosis with significant morbidity and mortality. Novel targeted therapies are currently being investigated in an attempt to reduce adverse events and improve survival outcomes. This review summarizes recent data from the literature regarding advances in drug discovery based on biological evidence and the novel targeted drug therapies for childhood AL. Significant challenges still remain for novel drug development in childhood AL. However, first results combined with a large number of new agents currently being investigated are very encouraging. Furthermore, therapeutic advances will depend upon combination strategies using the specific action of each agent and their complementary effects on leukemia cells.
    Expert Review of Anti-infective Therapy 05/2015; 15(7):1-18. DOI:10.1586/14737140.2015.1047769 · 2.25 Impact Factor
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    ABSTRACT: In addition to spliceosome gene mutations, oncogene expression and drug resistance in AML might influence exon expression. We performed exon-array analysis and exon-specific PCR (ESPCR) to identify specific landscapes of exon expression that are associated with DEK and WT1 oncogene expression and the resistance of AML cells to AraC, doxorubicin or azacitidine. Data were obtained for these five conditions through exon-array analysis of 17 cell lines and 24 patient samples and were extended through qESPCR of samples from 152 additional AML cases. More than 70% of AEUs identified by exon-array were technically validated through ESPCR. In vitro , 1,130 to 5,868 exon events distinguished the 5 conditions from their respective controls while in vivo 6,560 and 9,378 events distinguished chemosensitive and chemoresistant AML, respectively, from normal bone marrow. Whatever the cause of this effect, 30 to 80% of mis-spliced mRNAs involved genes unmodified at the whole transcriptional level. These AEUs unmasked new functional pathways that are distinct from those generated by transcriptional deregulation. These results also identified new putative pathways that could help increase the understanding of the effects mediated by DEK or WT1, which may allow the targeting of these pathways to prevent resistance of AML cells to chemotherapeutic agents.
    Oncotarget 05/2015; DOI:10.18632/oncotarget.3898 · 6.36 Impact Factor
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    ABSTRACT: In this study, we randomly compared high doses of the tyrosine kinase inhibitor (TKI) imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/HyperCVAD treatment (arm B) in 268 adults (median age, 47 years) with Ph-positive acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor or autologous SCT if in MMolR and no donor. With less induction deaths, the CR rate was higher in arm A (98% versus 91%, P= 0.006), while MMolR rate was similar in both arms (66% versus 64%). With a median follow-up of 4.8 years, 5-year EFS and OS were estimated at 37.1% and 45.6% respectively, without difference between both arms. Allogeneic transplantation was associated with a significant benefit in RFS (HR, 0.69; P= 0.036) and OS (HR, 0.64; P= 0.02), initial WBC being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph-positive ALL adult patients and suggests that SCT in first CR is still a good option in Ph-positive ALL adult patients. The study is registered to www.ClinicalTrials.gov as NCT00327678. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; 125(24). DOI:10.1182/blood-2015-02-627935 · 10.45 Impact Factor
  • American Journal of Hematology 04/2015; 90(7). DOI:10.1002/ajh.24036 · 3.80 Impact Factor
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    ABSTRACT: Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL. The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL. In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P < .001). Treatment of the primary tumor in the APL-2006 trial less frequently included combined radiochemotherapy (28.6% vs 47.2%; P = .044) and no mitoxantrone (0% vs 46.7%; P = .016) but more frequently included anthracyclines (53.3% vs 38.3%; P = .015). In the APL-2006 trial, patients who had secondary APL, compared with those who had de novo APL, were older (mean, 60.2 years vs 48.7 years, respectively; P < .0001) but had a similar complete response rate (97.6% vs 90.3%, respectively), cumulative incidence of relapse (0% vs 1.8%, respectively), and overall survival (92.3% vs 90.9%, respectively) at 18 months. Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL. Cancer 2015. © 2015 American Cancer Society. © 2015 American Cancer Society.
    Cancer 04/2015; 121(14). DOI:10.1002/cncr.29389 · 4.89 Impact Factor
  • Xavier Thomas
    03/2015; DOI:10.2217/ijh.15.4
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    Clinical lymphoma, myeloma & leukemia 03/2015; 15(8):477-83. · 2.02 Impact Factor
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    ABSTRACT: Patients aged ≥ 70 years with acute myeloid leukemia (AML) have a poorer prognosis than those aged 60 to 69 years. We retrospectively analyzed the cases of 183 patients aged ≥ 70 years with a performance status of ≤ 2 treated at our institution from 2000 to 2014. Treatment consisted of anthracycline- and cytarabine-based chemotherapy for 93 patients and lower intensity therapy with low-dose cytarabine or hypomethylating agent cycles for 90 patients. A total of 57 patients (61%) achieved complete remission in the intensive chemotherapy group versus only 11 (12%) in the lower intensity treatment group (P < .0001). The median overall survival (OS) was 14.5 months and 11.7 months with a 3-year OS rate of 34% and 18% (P = .005) for the intensive and lower intensity groups, respectively. The difference remained significant when considering patients aged ≤ 75 years, but not for patients aged > 75 years. Similarly, a significant difference was only observed when considering favorable and intermediate cytogenetic factors (P = .007) but not unfavorable karyotypes. On multivariate analysis, age did not appear as an independent prognostic factor. With intensive chemotherapy, the median OS significantly increased after the introduction of an improved supportive care policy compared with historical controls (14 vs. 5.4 months, with a 3-year OS rate of 33% vs. 8%). After 2006, a more "personalized" therapeutic approach tended to erase the difference in terms of OS, especially in patients aged > 75 years. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical lymphoma, myeloma & leukemia 03/2015; 15(8). DOI:10.1016/j.clml.2015.02.022 · 2.02 Impact Factor
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    ABSTRACT: Hormographiella aspergillata is a rare causative agent of invasive filamentous breakthrough infection, mostly arising after echinocandin exposure. We report a neutropenic patient who developed a severe sino-orbito-cerebral H. aspergillata infection while receiving empirical caspofungin, successfully controlled by an aggressive strategy associating surgical debridement and combined high-dose regimen of antifungal drugs. © 2015 Blackwell Verlag GmbH.
    Mycoses 03/2015; 58(5). DOI:10.1111/myc.12305 · 2.24 Impact Factor
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    EBMT 2015 - 41st Annual Meeting of the European Society for Blood and Marrow Transplantation, Istanbul (Turkey); 03/2015
  • Xavier Thomas
    03/2015; 4(1):1-4. DOI:10.2217/ijh.15.1

Publication Stats

7k Citations
1,742.75 Total Impact Points

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  • 2015
    • HCL
      Noida, Uttar Pradesh, India
  • 2005–2015
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 1990–2015
    • CHU de Lyon - Groupement Hospitalier Edouard Herriot
      Lyons, Rhône-Alpes, France
  • 2013–2014
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
  • 2011–2013
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 2009–2013
    • University of Rome Tor Vergata
      Roma, Latium, Italy
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2005–2013
    • Centre Hospitalier Universitaire de Lyon
      Lyons, Rhône-Alpes, France
  • 2012
    • Université Lumiere Lyon 2
      Брон, Rhône-Alpes, France
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Etablissement Français du Sang (EFS)
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Centre Henri Becquerel
      Rouen, Haute-Normandie, France
  • 2007
    • Centre Hospitalier Universitaire de Nancy
      Nancy, Lorraine, France
  • 2004
    • Centre Hospitalier Universitaire de Caen
      Caen, Lower Normandy, France
  • 2001
    • Cross Cancer Institute
      Edmonton, Alberta, Canada
  • 1995
    • University of Tours
      Tours, Centre, France