93 results on '"Nicolas Boissel"'
Search Results
2. Laboratory tests for investigating anemia: From an expert system to artificial intelligence
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Philippe Halfon, Guillaume Penaranda, Dan Ringwald, Frederique Retornaz, Nicolas Boissel, Sylvain Bodard, Jean Marc Feryn, David Bensoussan, and Patrice Cacoub
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Anemia ,Laboratory tests ,Expert system ,Artificial intelligence ,Medicine (General) ,R5-920 ,Chemistry ,QD1-999 - Abstract
Objective: To compare the laboratory tests conducted in real-life settings for patients with anemia with the expected prescriptions derived from an optimal checkup. Methods: A panel of experts formulated an “optimal laboratory test assessment'' specific to each anemia profile. A retrospective analysis was done of the laboratory tests conducted according to the type of anemia (microcytic, normocytic or macrocytic). Using an algorithmic system, the laboratory tests performed in real-life practice were compared with the recommendations suggested in the “optimal laboratory test assessment” and with seemingly “unnecessary” laboratory tests. Results: In the analysis of the “optimal laboratory test assessment”, of the 1179 patients with microcytic anemia, 269 (22.8%) had had one of the three tests recommended by the expert system, and only 33 (2.8%) had all three tests. For normocytic anemia, 1054 of 2313 patients (45.6%) had one of the eleven recommended tests, and none had all eleven. Of the 384 patients with macrocytic anemia, 196 (51%) had one of the four recommended tests, and none had all four. In the analysis of “unnecessary laboratory tests'', one lab test was unnecessarily done in 727/3876 patients (18.8%), i.e. 339 of 1179 (28.8%) microcytic, 171 of 2313 (7.4%) normocytic, and 217 of 384 (56.5 %) macrocytic anemias. Conclusion: Laboratory investigations of anemia remain imperfect as more than half of the cases did not receive the expected tests. Analyzing other diagnostic domains, the authors are currently developing an artificial intelligence system to assist physicians in enhancing the efficiency of their laboratory test prescriptions.
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- 2024
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3. TREC mediated oncogenesis in human immature T lymphoid malignancies preferentially involves ZFP36L2
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Estelle Balducci, Thomas Steimlé, Charlotte Smith, Patrick Villarese, Mélanie Feroul, Dominique Payet-Bornet, Sophie Kaltenbach, Lucile Couronné, Ludovic Lhermitte, Aurore Touzart, Marie-Emilie Dourthe, Mathieu Simonin, André Baruchel, Hervé Dombret, Norbert Ifrah, Nicolas Boissel, Bertrand Nadel, Elizabeth Macintyre, Agata Cieslak, and Vahid Asnafi
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T-cell receptor excision circles (TREC) ,Oncogenesis ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The reintegration of excised signal joints resulting from human V(D)J recombination was described as a potent source of genomic instability in human lymphoid cancers. However, such molecular events have not been recurrently reported in clinical patient lymphoma/leukemia samples. Using a specifically designed NGS-capture pipeline, we here demonstrated the reintegration of T-cell receptor excision circles (TRECs) in 20/1533 (1.3%) patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Remarkably, the reintegration of TREC recurrently targeted the tumor suppressor gene, ZFP36L2, in 17/20 samples. Thus, our data identified a new and hardly detectable mechanism of gene deregulation in lymphoid cancers providing new insights in human oncogenesis.
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- 2023
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4. Long-term outcome after autologous BCR::ABL1-negative peripheral blood stem cell transplantation in adults with Philadelphia-positive acute lymphoblastic leukemia: a comparative study
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Leo Caillot, Mathieu Leclerc, Emmanuel Jacques Raphael Sleiman, Ivan Sloma, Orianne Wagner-Ballon, Alexis Claudel, Florence Beckerich, Rabah Redjoul, Christine Robin, Vincent Parinet, Cecile Pautas, Dehbia Menouche, Selwa Bouledroua, Ludovic Cabanne, Yakout Nait-Sidenas, Eric Gautier, Helene Rouard, Ingrid Lafon, Yves Chalandon, Nicolas Boissel, Denis Caillot, and Sebastien Maury
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Harnessing the MYB-dependent TAL1 5’super-enhancer for targeted therapy in T-ALL
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Charlotte Smith, Aurore Touzart, Mathieu Simonin, Christine Tran-Quang, Guillaume Hypolite, Mehdi Latiri, Guillaume P. Andrieu, Estelle Balducci, Marie-Émilie Dourthe, Ashish Goyal, Françoise Huguet, Arnaud Petit, Norbert Ifrah, André Baruchel, Hervé Dombret, Elizabeth Macintyre, Christoph Plass, Jacques Ghysdael, Nicolas Boissel, and Vahid Asnafi
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Super-enhancer ,Oncogene ,Targeted therapy ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5’super-enhancer (5’SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5’SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy.
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- 2023
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6. Real-world use of blinatumomab in adult patients with B-cell acute lymphoblastic leukemia in clinical practice: results from the NEUF study
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Nicolas Boissel, Sabina Chiaretti, Cristina Papayannidis, Josep-Maria Ribera, Renato Bassan, Andrey N. Sokolov, Naufil Alam, Alessandra Brescianini, Isabella Pezzani, Georg Kreuzbauer, Gerhard Zugmaier, Robin Foà, and Alessandro Rambaldi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract This retrospective observational study (NEUF) included adult patients with B-cell acute lymphoblastic leukemia (B-cell ALL) who had received blinatumomab for the treatment of minimal residual disease-positive (MRD+) or relapsed/refractory (R/R) B-cell ALL via an expanded access program (EAP). Patients were eligible if blinatumomab was initiated via the EAP between January 2014 and June 2017. Patients were followed from blinatumomab initiation until death, entry into a clinical trial, the end of follow-up, or the end of the study period (December 31, 2017), whichever occurred first. Of the 249 adult patients included, 109 were MRD+ (83 Philadelphia chromosome-negative [Ph−] and 26 Philadelphia chromosome-positive [Ph+]) and 140 had a diagnosis of R/R B-cell ALL (106 Ph− and 34 Ph+). In the MRD+ group, within the first cycle of blinatumomab treatment, 93% (n = 49/53) of Ph− and 64% (n = 7/11) of Ph+ patients with evaluable MRD achieved an MRD response (MRD
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- 2023
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7. Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3
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Daniel J DeAngelo, Yi Lin, Roch Houot, Marion Subklewe, Petra C Schuberth, Michael R Bishop, Nicolas Boissel, Dimitrios Tzachanis, Jae H Park, Monique C Minnema, Thibaut Leguay, Mehrdad Abedi, Bijal D Shah, Ryan D Cassaday, Olalekan O Oluwole, Aaron C Logan, Max S Topp, Kristen M O'Dwyer, Martha L Arellano, Maria R Baer, Gary J Schiller, William G Wierda, Patrick J Stiff, Deepa Jeyakumar, Daqin Mao, Sabina Adhikary, Lang Zhou, Rita Damico Khalid, and Armin Ghobadia
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported.Methods Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided.Results Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7–58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22).Conclusions In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.
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- 2023
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8. S106: METABOLIC PLASTICITY REVEALS A TARGETABLE VULNERABILITY IN LEUKEMIA
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Guillaume Andrieu, Mathieu Simonin, Aurélie Cabannes-Hamy, Etienne Lengliné, Ambroise Marçais, Marie-Emilie Dourthe, Alexandre Theron, Nicolas Boissel, Hervé Dombret, Philippe Rousselot, Olivier Hermine, and Vahid Asnafi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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9. P321: TNF-MEDIATED CELL DEATH: AN ACTIONABLE TARGET FOR IMMUNOTHERAPY IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
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Marie-Emilie Dourthe, Etienne Lengline, Guillaume Charbonnier, Mehdi Latiri, Chaimae Saji, Agata Cieslak, Mathieu Simonin, Norbert Ifrah, Hervé Dombret, Olivier Hermine, Nicolas Boissel, André Baruchel, Jacques Ghysdael, Elizabeth Macintyre, Christine Tran-Quang, Guillaume Andrieu, and Vahid Asnafi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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10. P367: LONG-TERM OUTCOMES OF ADULTS WITH RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH BREXUCABTAGENE AUTOLEUCEL IN ZUMA-3 BY AGE, PRIOR THERAPIES, AND SUBSEQUENT TRANSPLANT
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Bijal Shah, Ryan D. Cassaday, Jae H. Park, Roche Houot, Olalekan O. Oluwole, Aaron C. Logan, Nicolas Boissel, Thibaut Leguay, Michael R. Bishop, Max S. Topp, Kristen M. O’dwyer, Maria R. Baer, Gary J. Schiller, Mehrdad Abedi, Monique C. Minnema, Patrick Stiff, Lang Zhou, Tsveta Hadjivassileva, Rita Damico Khalid, and Armin Ghobadi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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11. P319: IL7-RECEPTOR EXPRESSION IS FREQUENT IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA AND PREDICTS SENSITIVITY TO JAK-INHIBITION
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Lucien Courtois, Aurélie Cabannes-Hamy, Rathana Kim, Marine Delecourt, Antoine Pinton, Guillaume Charbonnier, Melanie Feroul, Charlotte Smith, Giulia Tueur, Cecile Pivert, Estelle Balducci, Mathieu Simonin, Salvatore Spicuglia, Nicolas Boissel, Guillaume Andrieu, Vahid Asnafi, Philippe Rousselot, and Ludovic Lhermitte
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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12. P315: TP53 ALTERATIONS AND MRD REFINE PROGNOSIS OF ADULT KMT2A-REARRANGED B-ALL
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Rathana Kim, Hugo Bergugnat, Florence Pasquier, Emmanuel Raffoux, Lise Larcher, Marie Passet, Cedric Pastoret, Grardel Nathalie, Vahid Asnafi, Eric Delabesse, Aurélie Caye-Eude, Claus Meyer, Rolf Masrschalek, Anne Thiebaut-Bertrand, Marie Balsat, Martine Escoffre, Sabine Blum, Michael Baumann, Anne Banos, Nicole Straetmans, Maria Pilar Gallego Hernanz, Yves Chalandon, Carlos Graux, Thibaut Leguay, Mathilde Hunault, Françoise Huguet, Véronique Lhéritier, Jean Soulier, Nicolas Boissel, and Emmanuelle Clappier
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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13. P494: A FIRST-IN-HUMAN STUDY OF CD123 NK CELL ENGAGER SAR443579 IN RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA, B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA OR HIGH RISK-MYELODYSPLASIA
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Anthony Selwyn Stein, Mojca Jongen-Lavrencic, Sylvain Garciaz, Gerwin A Huls, Abhishek Maiti, Nicolas Boissel, Stephane De Botton, Shaun Fleming, C. Michel Zwaan, David C. de Leeuw, Pinkal Desai, Martha Lucia Arellano, David Avigan, Saskia Langemeijer, Kyle Jensen, Timothy Wagenaar, Gu MI, Giovanni Abbadessa, and Ashish Bajel
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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14. P1408: UPDATED RESULTS OF THE PHASE I BALLI-01 TRIAL OF UCART22, AN ANTI-CD22 ALLOGENEIC CAR-T CELL PRODUCT, IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) CD22+ B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL)
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Nicolas Boissel, Patrice Chevallier, Kevin Curran, Gary Schiller, Hongtau Liu, Richard Larson, Daniel J. Deangelo, Jean-Baptiste Mear, Stephan Grupp, André Baruchel, Marina Konopleva, Alexandra Lacroce, Caroline Roudet, Ana Korngold, Katie Newhall, Eric Laille, Daniel Lee, Mark Frattini, and Nitin Jain
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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15. Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study
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Bijal D. Shah, Armin Ghobadi, Olalekan O. Oluwole, Aaron C. Logan, Nicolas Boissel, Ryan D. Cassaday, Thibaut Leguay, Michael R. Bishop, Max S. Topp, Dimitrios Tzachanis, Kristen M. O’Dwyer, Martha L. Arellano, Yi Lin, Maria R. Baer, Gary J. Schiller, Jae H. Park, Marion Subklewe, Mehrdad Abedi, Monique C. Minnema, William G. Wierda, Daniel J. DeAngelo, Patrick Stiff, Deepa Jeyakumar, Jinghui Dong, Sabina Adhikary, Lang Zhou, Petra C. Schuberth, Imi Faghmous, Behzad Kharabi Masouleh, and Roch Houot
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B-precursor acute lymphoblastic leukemia ,Brexucabtagene autoleucel ,CAR T-cell therapy ,KTE-X19 ,SCHOLAR-3 ,ZUMA-3 ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. Methods Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. Results After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively. Conclusions These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. Trial Registration: NCT02614066.
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- 2022
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16. The use of ICU resources in CAR-T cell recipients: a hospital-wide study
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Sandrine Valade, Michael Darmon, Lara Zafrani, Eric Mariotte, Virginie Lemiale, Swann Bredin, Guillaume Dumas, Nicolas Boissel, Florence Rabian, André Baruchel, Isabelle Madelaine, Jérôme Larghero, Anne Brignier, Etienne Lengliné, Stéphanie Harel, Bertrand Arnulf, Roberta Di Blasi, Catherine Thieblemont, and Elie Azoulay
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Anti-CD19 chimeric antigen receptor ,Intensive care ,Hematological malignancies ,Sepsis ,Performance status ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Abstract Background CAR-T cell (chimeric antigen receptor T) therapy has emerged as an effective treatment of refractory hematological malignancies. Intensive care management is intrinsic to CAR-T cell therapy. We aim to describe and to assess outcomes in critically ill CAR-T cell recipients. Study design and methods Hospital-wide retrospective study. Consecutive CAR-T cell recipients requiring ICU admission from July 2017 and December 2020 were included. Results 71 patients (median age 60 years [37–68]) were admitted to the ICU 6 days [4–7] after CAR-T cell infusion. Underlying malignancies included diffuse large B cell lymphoma (n = 53, 75%), acute lymphoblastic leukemia (17 patients, 24%) and multiple myeloma (n = 1, 1.45%). Performance status (PS) was 1 [1–2]. Shock was the main reason for ICU admission (n = 40, 48%). Isolated cytokine release syndrome (CRS) was the most common complication (n = 33, 46%), while 21 patients (30%) had microbiologically documented bacterial infection (chiefly catheter-related infection). Immune effector cell-associated neurotoxicity syndrome was reported in 26 (37%) patients. At ICU admission, vasopressors were required in 18 patients (25%) and invasive mechanical ventilation in two. Overall, 49 (69%) and 40 patients (56%) received tocilizumab or steroids, respectively. Determinant of mortality were the reason for ICU admission (disease progression vs. sepsis or CRS (HR 4.02 [95%CI 1.10–14.65]), Performance status (HR 1.97/point [95%CI 1.14–3.41]) and SOFA score (HR 1.16/point [95%CI 1.01–1.33]). Conclusions Meaningful survival could be achieved in up to half the CAR-T cell recipients. The severity of organ dysfunction is a major determinant of death, especially in patients with altered performance status or disease progression.
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- 2022
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17. Real-world Experience of Approved Chimeric Antigen Receptor T-cell Therapies Compared to Clinical Trials Data
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Jérôme Lambert, Roberta Di Blasi, Florence Rabian, Marie-Emilie Dourthe, André Baruchel, Catherine Thiéblemont, Nicolas Boissel, Vincent Levy, Marie-Quitterie Picat, and Sylvie Chevret
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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18. Impact of T-cell Receptor Status on Mutational Landscape and Outcome in T-ALL
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Marie Emilie Dourthe, Lucien Courtois, Guillaume P. Andrieu, Mathieu Simonin, Aurore Touzart, Ludovic Lhermitte, Arnaud Petit, Nicolas Boissel, André Baruchel, Vahid Asnafi, and Elizabeth Macintyre
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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19. A multiparametric niche-like drug screening platform in acute myeloid leukemia
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Reinaldo Dal Bello, Justine Pasanisi, Romane Joudinaud, Matthieu Duchmann, Bryann Pardieu, Paolo Ayaka, Giuseppe Di Feo, Gaetano Sodaro, Clémentine Chauvel, Rathana Kim, Loic Vasseur, Laureen Chat, Frank Ling, Kim Pacchiardi, Camille Vaganay, Jeannig Berrou, Chaima Benaksas, Nicolas Boissel, Thorsten Braun, Claude Preudhomme, Hervé Dombret, Emmanuel Raffoux, Nina Fenouille, Emmanuelle Clappier, Lionel Adès, Alexandre Puissant, and Raphael Itzykson
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O2 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs. We refined our niche-like culture by including plasma-like amino-acid and cytokine concentrations identified by targeted metabolomics and proteomics of primary AML bone marrow plasma samples. Systematic interrogation revealed distinct contributions of each niche-like component to leukemic outgrowth and drug response. Short-term niche-like culture preserved clonal architecture and transcriptional states of primary leukemic cells. In a cohort of 45 AML samples enriched for NPM1c AML, the niche-like multiparametric assay could predict morphologically (p = 0.02) and molecular (NPM1c MRD, p = 0.04) response to anthracycline-cytarabine induction chemotherapy. In this cohort, a 23-drug screen nominated ruxolitinib as a sensitizer to anthracycline-cytarabine. This finding was validated in an NPM1c PDX model.
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- 2022
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20. Allogeneic transplantation in acute myelogenous leukemia: a comprehensive single institution's experience
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Gerard Socie, Jacques-Emmanuel Galimard, Emmanuel Raffoux, Raphael Itzykson, Pierre Edouard Debureaux, David Michonneau, Etienne Lengliné, Marie Robin, Flore Sicre de Fontbrune, Marie Sébert, Aliénor Xhaard, Rathana Kim, Anne Couprie, Nathalie Dhedin, Matteo Dragani, Pierre Lemaire, Lise Larcher, Emmanuelle Clappier, Nicolas Boissel, Jean Soulier, Hervé Dombret, Pierre Fenaux, Régis Peffault de Latour, and Lionel Adès
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P
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- 2023
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21. Impact of central nervous system involvement in adult patients with Philadelphia-negative acute lymphoblastic leukemia: a GRAALL-2005 study
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Corentin Orvain, Sylvain Chantepie, Xavier Thomas, Martine Escofrre-Barbe, Francoise Huguet, Yohan Desbrosses, Gaelle Guillerm, Madalina Uzunov, Thibaut Leguay, Sarah Barbieux, Norbert Vey, Patrice Chevallier, Jean-Valere Malfuson, Stephane Lepretre, Michael Baumann, Murat Aykut, Abdelaziz Chaib, Magalie Joris, Hacene Zerazhi, Georg Stussi, Jacques Chapiro, Celine Berthon, Caroline Bonmati, Eric Jourdan, Diana Carp, Amb roise Marcais, Maria-Pilar Gallego-Hernanz, Iona Vaida, Karin Bilger, Alban Villate, Florence Pasquier, Yves Chalandon, Sebastien Maury, Veronique Lheritier, Norbert Ifrah, Herve Dombret, Nicolas Boissel, and Mathilde Hunault-Berger.
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P
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- 2023
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22. The oncogenetic landscape and clinical impact of BCL11B alterations in adult and pediatric T-cell acute lymphoblastic leukemia
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Marie Emilie Dourthe, Guillaume P. Andrieu, Amandine Potier, Estelle Balducci, Julie Guerder, Mathieu Simonin, Lucien Courtois, Arnaud Petit, Elizabeth Macintyre, Nicolas Boissel, André Baruchel, and Vahid Asnafi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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23. Isatuximab monotherapy in patients with refractory T‐acute lymphoblastic leukemia or T‐lymphoblastic lymphoma: Phase 2 study
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Nicolas Boissel, Patrice Chevallier, Vadim Doronin, Laimonas Griskevicius, Alexey Maschan, James McCloskey, Alessandro Rambaldi, Giuseppe Rossi, Andrey Sokolov, Ulla Wartiovaara‐Kautto, Corina Oprea, Giovanni Abbadessa, Alice Gosselin, Sandrine Macé, and Xavier Thomas
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acute lymphoblastic leukemia ,isatuximab ,monoclonal antibodies ,monotherapy ,T lymphoblastic lymphoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The poor prognosis of acute T‐cell lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) in older adults and patients with relapsed/refractory illness is an unmet clinical need, as there is no defined standard of care and there are few treatment options. Abnormally elevated CD38 expression in T‐ALL and T‐LBL is associated with tumor expansion and disease development, making CD38 a potential target for anti‐T‐ALL and T‐LBL treatment. Isatuximab is a monoclonal antibody that binds to a specific epitope on CD38. The purpose of the study was to assess the efficacy and safety of isatuximab monotherapy in a phase 2, multicenter, one‐arm, open‐label study in patients with relapsed or refractory T‐ALL or T‐LBL (Clinical Trials.gov identifier NCT02999633). The primary endpoint was to assess the efficacy of isatuximab by overall response rate (ORR). An interim analysis based on the efficacy and safety of isatuximab in the first 19 patients enrolled was scheduled, however only 14 patients were enrolled in the study. No patient achieved complete response (CR) or CR with incomplete peripheral recovery. Most patients (11 [78.6%]) developed progressive disease and had progressive disease as their best response. A total of 10 (71.4%) patients had treatment emergent adverse events considered treatment‐related, with infusion reactions as the most frequent drug‐related TEAE, occurring in 8 (57.1%) patients. Despite the low efficacy of isatuximab in the current study, it is likely that the use of immunotherapy medication in T‐ALL will be expanded through logically targeted approaches, together with advances in the design of T‐cell therapy and clinical experience and will provide restorative options beyond chemotherapy and targeted treatments.
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- 2022
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24. Clinico-biological features of T-cell acute lymphoblastic leukemia with fusion proteins
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Thomas Steimlé, Marie-Emilie Dourthe, Marion Alcantara, Aurore Touzart, Mathieu Simonin, Johanna Mondesir, Ludovic Lhermitte, Jonathan Bond, Carlos Graux, Nathalie Grardel, Jean-Michel Cayuela, Isabelle Arnoux, Virginie Gandemer, Marie Balsat, Norbert Vey, Elizabeth Macintyre, Norbert Ifrah, Hervé Dombret, Arnaud Petit, André Baruchel, Philippe Ruminy, Nicolas Boissel, and Vahid Asnafi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.
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- 2022
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25. Improved survival with enasidenib versus standard of care in relapsed/refractory acute myeloid leukemia associated with IDH2 mutations using historical data and propensity score matching analysis
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Stéphane deBotton, Joseph M. Brandwein, Andrew H. Wei, Arnaud Pigneux, Bruno Quesnel, Xavier Thomas, Ollivier Legrand, Christian Recher, Sylvain Chantepie, Mathilde Hunault‐Berger, Nicolas Boissel, Salem A. Nehme, Mark G. Frattini, Alessandra Tosolini, Roland Marion‐Gallois, Jixian J. Wang, Chris Cameron, Muhaimen Siddiqui, Brian Hutton, Gary Milkovich, and Eytan M. Stein
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acute myeloid leukemia ,enasidenib ,IDH2 mutations ,overall survival ,standard of care ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). Methods Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221‐C‐001 trial and SoC outcomes obtained from a real‐world chart review of patients in France. Results Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61–1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47–0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72–13.24) and 4.76 months for SoC (95% CI, 3.81–8.21). Results remained robust across all sensitivity analyses conducted. Conclusions PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes.
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- 2021
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26. Case Report: Hyperammonemic Encephalopathy Linked to Ureaplasma spp. and/or Mycoplasma hominis Systemic Infection in Patients Treated for Leukemia, an Emergency Not to Be Missed
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Manon Delafoy, Juliette Goutines, Aude-Marie Fourmont, André Birgy, Maryline Chomton, Michaël Levy, Jérôme Naudin, Lara Zafrani, Lou Le Mouel, Karima Yakouben, Aurélie Cointe, Marion Caseris, Matthieu Lafaurie, Stéphane Bonacorsi, Françoise Mechinaud, Sabine Pereyre, Nicolas Boissel, and André Baruchel
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Ureaplasma spp. ,Mycoplasma spp. ,systemic infection ,hyperammonemic encephalopathy ,immunocompromised patients ,case report ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundHyperammonemic encephalopathy caused by Ureaplasma spp. and Mycoplasma hominis infection has been reported in immunocompromised patients undergoing lung transplant, but data are scarce in patients with hematological malignancies.Case PresentationWe describe the cases of 3 female patients aged 11–16 years old, developing initially mild neurologic symptoms, rapidly evolving to coma and associated with very high ammonia levels, while undergoing intensive treatment for acute leukemia (chemotherapy: 2 and hematopoietic stem cell transplant: 1). Brain imaging displayed cerebral edema and/or microbleeding. Electroencephalograms showed diffuse slowing patterns. One patient had moderate renal failure. Extensive liver and metabolic functions were all normal. Ureaplasma spp. and M. hominis were detected by PCR and specific culture in two patients, resulting in prompt initiation of combined antibiotics therapy by fluoroquinolones and macrolides. For these 2 patients, the improvement of the neurological status and ammonia levels were observed within 96 h, without any long-term sequelae. M. hominis was detected post-mortem in vagina, using 16S rRNA PCR for the third patient who died of cerebral edema.ConclusionHyperammonemic encephalopathy linked to Ureaplasma spp. and M. hominis is a rare complication encountered in immunocompromised patients treated for acute leukemia, which can lead to death if unrecognized. Combining our experience with the few published cases (n=4), we observed a strong trend among female patients and very high levels of ammonia, consistently uncontrolled by classical measures (ammonia-scavenging agents and/or continuous kidney replacement therapy). The reversibility of the encephalopathy without sequelae is possible with prompt diagnosis and adequate combined specific antibiotherapy. Any neurological symptoms in an immunocompromised host should lead to the measurement of ammonia levels. If increased, and in the absence of an obvious cause, it should prompt to perform a search for Ureaplasma spp. and M. hominis by PCR as well as an immediate empirical initiation of combined specific antibiotherapy.
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- 2022
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27. High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL
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Aurelie Cabannes-Hamy, Eolia Brissot, Thibaut Leguay, Francoise Huguet, Patrice Chevallier, Mathilde Hunault, Martine Escoffre-Barbe, Thomas Cluzeau, Marie Balsat, Stephanie Nguyen, Florence Pasquier, Magda Alexis, Veronique Lheritier, Cedric Pastoret, Eric Delabesse, Emmanuelle Clappier, Herve Dombret, and Nicolas Boissel
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and
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- 2022
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28. Post-remission outcomes in AML patients with high hyperleukocytosis and inaugural life-threatening complications.
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Sofiane Fodil, Sylvie Chevret, Camille Rouzaud, Sandrine Valade, Florence Rabian, Eric Mariotte, Emmanuel Raffoux, Raphael Itzykson, Nicolas Boissel, Marie Sébert, Lionel Adès, Lara Zafrani, Elie Azoulay, and Etienne Lengliné
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Medicine ,Science - Abstract
IntroductionPatients with hyperleukocytic (HL) acute myeloid leukemia (AML) are at higher risk of early death. Initial management of these patients is challenging, not fully codified and heterogenous. Retrospective studies showed that several symptomatic measures might decrease early death rate but long-term data are scarce. We aimed to analyze whether the therapeutic measures carried out urgently at diagnosis may influence the outcome among HL AML patients having achieved who survived inaugural complications.MethodsWe retrospectively reviewed all medical charts from patients admitted to Saint-Louis Hospital between January, 1st 1997 and December, 31st 2018 with newly diagnosed AML and white blood cell (WBC) count above 50x109/L. Outcome measures were cumulative incidence of relapse (CIR), treatment-related mortality (TRM) defined as relapse-free death, and overall survival. Univariate and multivariate analyses were performed using Cox proportional hazards models.ResultsA total of 184 patients with HL AML in complete remission (CR) were included in this study. At 2 years after CR. 62.5% of patients were alive, at 5 years, cumulated incidence of relapse was 55.8%. We found that every therapeutic measure, including life-sustaining therapies carried out in the initial phase of the disease, did not increase the relapse risk. The use of hydroxyurea for more than 4 days was associated with a higher risk of relapse. At the end of the study, 94 patients (51.1%) were still alive including 23 patients out of 44 aged less than 60 yo that were able to return to work.ConclusionWe show that the use of emergency measures including life sustaining therapies does not come at the expense of a higher risk of relapse or mortality, except in the case of prolonged use of hydroxyurea. Patients with HL AML should be able to benefit from all available techniques, regardless of their initial severity.
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- 2022
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29. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial
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Theodore W. Laetsch, Shannon L. Maude, Susana Rives, Hidefumi Hiramatsu, Henrique Bittencourt, Peter Bader, André Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A. Pulsipher, Gary Douglas Myers, Heather E. Stefanski, Paul L. Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L. Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A. Grupp, Laetsch, T, Maude, S, Rives, S, Hiramatsu, H, Bittencourt, H, Bader, P, Baruchel, A, Boyer, M, De Moerloose, B, Qayed, M, Buechner, J, Pulsipher, M, Myers, G, Stefanski, H, Martin, P, Nemecek, E, Peters, C, Yanik, G, Khaw, S, Davis, K, Krueger, J, Balduzzi, A, Boissel, N, Tiwari, R, O'Donovan, D, and Grupp, S
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Cancer Research ,Oncology ,Medicine and Health Sciences ,CAR-T, tisagenlecleucel, acute lymphoblastic leukemia - Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849 ), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.
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- 2023
30. Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from PreleukemicTP53-Mutant Clonal Hematopoiesis
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Rathana Kim, Hugo Bergugnat, Lise Larcher, Matthieu Duchmann, Marie Passet, Stéphanie Gachet, Wendy Cuccuini, Marina Lafage-Pochitaloff, Cédric Pastoret, Nathalie Grardel, Vahid Asnafi, Beat W. Schäfer, Eric Delabesse, Raphaël Itzykson, Lionel Adès, Yosr Hicheri, Yves Chalandon, Carlos Graux, Patrice Chevallier, Mathilde Hunault, Thibaut Leguay, Françoise Huguet, Véronique Lhéritier, Hervé Dombret, Jean Soulier, Philippe Rousselot, Nicolas Boissel, Emmanuelle Clappier, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Necker - Enfants Malades [AP-HP], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpitaux Universitaires de Genève (HUG), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, R. Kim was a recipient of a PhD grant with financial support from ITMO Cancer of Aviesan on funds administered by INSERM. The study was supported by a grant from Force Hémato (2020). The authors thank the patients and all the GRAALL investigators, physicians, and biologists who contributed samples and data for this study. The authors thank the Saint-Louis Molecular Hematology lab for technical support, especially Hélène Boyer, Emilie Gaudas, Léna Yousfi, and Océanne Richard. The authors also thank Stéphanie Mathis, Pierre Lemaire, and Clémentine Chauvel for the flow cytometry evaluation of ALL diagnostic samples. This work benefited from the genomic platform facility of Institut de Recherche Saint-Louis (IRSL), supported by Association Saint-Louis. This work was supported by THEMA, the national center for precision medicine in leukemia.The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked 'advertisement' in accordance with 18 USC section 1734., UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service d'hématologie
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Adult ,Aged, 80 and over ,Lymphoma, B-Cell ,Adolescent ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,General Medicine ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Aneuploidy ,Young Adult ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Mutation ,Humans ,Prospective Studies ,Clonal Hematopoiesis ,Tumor Suppressor Protein p53 ,Aged - Abstract
Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18–84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis.Significance:We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL.See related commentary by Saiki and Ogawa, p. 102.This article is highlighted in the In This Issue feature, p. 101
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- 2023
31. Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
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Sandra Dupouy, Ibtissam Marchiq, Thibaud Derippe, Maria Almena-Carrasco, Agnieszka Jozwik, Sylvain Fouliard, Yasmina Adimy, Julia Geronimi, Charlotte Graham, Nitin Jain, Marcela V. Maus, Mohamad Mohty, Nicolas Boissel, Takanori Teshima, Koji Kato, Reuben Benjamin, and Svetlana Balandraud
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Background: UCART191 is an “off-the-shelf” genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells. Methods: UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology. Results: Responder patients (12/25) had higher UCART19 expansion (Cmax) and exposure (AUCTlast) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28. Conclusions: UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection. Significance: First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.
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- 2022
32. YTB323 (Rapcabtagene Autoleucel) Demonstrates Durable Efficacy and a Manageable Safety Profile in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Phase I Study Update
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Pere Barba, Mi Kwon, Javier Briones, Ulrich Jaeger, Emmanuel Bachy, Didier Blaise, Nicolas Boissel, Koji Kato, Nirav N. Shah, Matthew Frigault, Peter A. Riedell, Leyla O. Shune, Takanori Teshima, Fabio Ciceri, David Pearson, Elena J Orlando, Lan Yi, Jaclyn Davis, Aisha Masood, Ian W. Flinn, and Michael Dickinson
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
33. Broad Activity for the Pivekimab Sunirine (PVEK, IMGN632), Azacitidine, and Venetoclax Triplet in High-Risk Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)
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Naval Daver, Pau Montesinos, Ahmed Aribi, Giovanni Marconi, Jessica K. Altman, Eunice S. Wang, Gail J. Roboz, Patrick W. Burke, Gianluca Gaidano, Roland B. Walter, Xavier Thomas, Deepa Jeyakumar, Daniel J. DeAngelo, Harry P. Erba, Elisabetta Todisco, Kebede H. Begna, Anjali Advani, Lauris Gastaud, Adolfo De La Fuente, Antonio Curti, Lourdes M. Mendez, Paresh Vyas, Nicolas Boissel, Norbert Vey, Christian Recher, Thomas Longval, Uwe Platzbecker, Silke Kapp-Schwoerer, Christoph Schliemann, Marina Konopleva, Laura Torres, David A. Sallman, Guido Marcucci, Naveen Pemmaraju, Giovanni Martinelli, Hagop Kantarjian, Callum M Sloss, Kara E Malcolm, Patrick A Zweidler-McKay, and Kendra Sweet
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
34. Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: a study of the SFGM-TC
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Paul Chauvet, Annalisa Paviglianiti, Myriam Labopin, Hélène Labussière, Nicolas Boissel, Marie Robin, Natacha Maillard, Marie Ouachée-Chardin, Edouard Forcade, Xavier Poiré, Sylvain Chantepie, Anne Huynh, Claude Eric Bulabois, Mathieu Leclerc, Sébastien Maury, Patrice Chevallier, Thomas Cluzeau, Jean-Baptiste Mear, Jérôme Cornillon, Karin Bilger, Célestine Simand, Yves Beguin, Marie-Thérèse Rubio, Ibrahim Yakoub-Agha, and Eolia Brissot
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Transplantation ,Hematology - Abstract
Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic stem cell transplantation (allo-HCT) still represents a major concern with poor outcomes. The aim of this study is to compare the efficacy and safety of blinatumomab and donor lymphocyte infusion (DLI) versus blinatumomab alone in this setting. This is a multicenter retrospective study from centers of SFGM-TC. All transplanted patients who received blinatumomab salvage therapy were included. Patients who received DLI from 1 month before to 100 days after the starting of blinatumomab were included in the blina-DLI group. Seventy-two patients were included. Medium follow-up was 38 months. Fifty received blinatumomab alone and 22 the association blinatumomab-DLI. Two-year overall survival (OS) was 31% in the blinatumomab group and 43% in the blinatumomab-DLI group (p=0.31). Studying DLI as a time dependent variable, PFS did not significantly differ between the 2 groups (HR:0.7, 95%CI:0.4-1.5). In multivariate analysis, DLI was not a prognostic factor for OS, progression-free survival and progression/relapse incidence. Adverse events and graft-versus-disease rates were comparable in the 2 groups. In conclusion, adding DLI between 1 month before and 100 days after start of blinatumomab is safe and does not seem to improve outcomes in B-ALL patients who relapsed after allo-HCT.
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- 2022
35. Oncogenetic landscape of T-cell lymphoblastic lymphomas compared to T-cell acute lymphoblastic leukemia
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Christophe Bontoux, Mathieu Simonin, Nathalie Garnier, Ludovic Lhermitte, Aurore Touzart, Guillaume Andrieu, Julie Bruneau, Etienne Lengliné, Adriana Plesa, Nicolas Boissel, André Baruchel, Yves Bertrand, Thierry Jo Molina, Elizabeth Macintyre, and Vahid Asnafi
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Phosphatidylinositol 3-Kinases ,Cell Transformation, Neoplastic ,Adolescent ,Carcinogenesis ,Class I Phosphatidylinositol 3-Kinases ,T-Lymphocytes ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Lymphoma, T-Cell ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Pathology and Forensic Medicine - Abstract
In the latest 2016 World Health Organization classification of hematological malignancies, T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) are grouped together into one entity called T-cell lymphoblastic leukemia/lymphoma (T-LBLL). However, the question of whether these entities represent one or two diseases remains. Multiple studies on driver alterations in T-ALL have led to a better understanding of the disease while, so far, little data on genetic profiles in T-LBL is available. We sought to define recurrent genetic alterations in T-LBL and provide a comprehensive comparison with T-ALL. Targeted whole-exome next-generation sequencing of 105 genes, multiplex ligation-dependent probe amplification, and quantitative PCR allowed comprehensive genotype assessment in 818, consecutive, unselected, newly diagnosed patients (342 T-LBL vs. 476 T-ALL). The median age at diagnosis was similar in T-LBL and T-ALL (17 vs. 15 years old, respectively; p = 0.2). Although we found commonly altered signaling pathways and co-occurring mutations, we identified recurrent dissimilarities in actionable gene alterations in T-LBL as compared to T-ALL. HOX abnormalities (TLX1 and TLX3 overexpression) were more frequent in T-ALL (5% of T-LBL vs 13% of T-ALL had TLX1 overexpression; p = 0.04 and 6% of T-LBL vs 17% of T-ALL had TLX3 overexpression; p = 0.006). The PI3K signaling pathway was significantly more frequently altered in T-LBL as compared to T-ALL (33% vs 19%; p 0.001), especially through PIK3CA alterations (9% vs 2%; p 0.001) with PIK3CA
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- 2022
36. Semen Cryopreservation in Adolescents and Young Adults with Hematologic Diseases: from Bed to Benchside
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Xavier Pollet-Villard, Aurélie Cabannes-Hamy, Annalisa Andreoli, Elise Ricadat, Isabelle Berthaut, Raphael Itzykson, Etienne Lengliné, Nicolas Boissel, David Beauvais, Virginie Barraud-Lange, Catherine Poirot, Nathalie Dhedin, Rachel Levy, Hélène Behal, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), CHU Lille, Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], M-Lab, Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut Humanités, Sciences et Sociétés [Paris] (UPCité IHSS), Sorbonne Université (SU), and Levy, Rachel
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Male ,MESH: Premature Birth ,MESH: Pre-Eclampsia ,[SDV]Life Sciences [q-bio] ,MESH: Pregnancy ,MESH: Obesity ,media_common ,MESH: Aged ,MESH: Semen Preservation ,human immunodeficiency virus ,Obstetrics ,MESH: Sperm Motility ,Assisted reproductive technology ,MESH: Hematologic Diseases ,Semen cryopreservation ,MESH: Postpartum Hemorrhage ,[SDV] Life Sciences [q-bio] ,sperm banking ,Oncology ,MESH: Pregnancy Complications ,MESH: Young Adult ,Sperm Motility ,Adult ,Infertility ,MESH: Pandemics ,endocrine system ,medicine.medical_specialty ,Adolescent ,fertility preservation ,media_common.quotation_subject ,Fertility ,Semen collection ,Young Adult ,Semen quality ,Semen ,MESH: Cryopreservation ,medicine ,Humans ,MESH: SARS-CoV-2 ,MESH: Semen ,Aged ,Retrospective Studies ,Cryopreservation ,MESH: Adolescent ,MESH: Humans ,urogenital system ,business.industry ,hematological diseases ,MESH: Adult ,MESH: Retrospective Studies ,MESH: Pregnancy Outcome ,medicine.disease ,Sperm bank ,Hematologic Diseases ,Sperm ,MESH: Male ,Semen Analysis ,quality of life ,Oligospermia ,MESH: Semen Analysis ,Pediatrics, Perinatology and Child Health ,in vitro fertilization outcomes ,MESH: Pregnant Women ,business ,Semen Preservation - Abstract
International audience; Purpose: Infertility in adolescents and young adult (AYA) survivors of malignant disease remains a major long-term adverse effect, but semen collection for fertility preservation in fertility centers is not always feasible and makes AYAs uncomfortable. We evaluated the feasibility of collecting sperm samples on the ward versus in fertility centers. Methods: Consecutive hospitalized AYA-aged male patients in the Hematology AYA unit (Saint-Louis Hospital, France) between August 2010 and June 2016 with hematological disease and indication of semen collection (n = 95) were included in this retrospective study. Semen quality was analyzed according to World Health Organization guidelines and was compared according to semen collection place: on the ward (n = 46) or in fertility center (n = 49). Results: The median age was median age 19.1 years (range: 13.7-33.3; interquartile range: 17.1-22.8) and 85 patients successfully collected semen. Sperm collection failure was ∼11% and was comparable between the two modalities as were main sperm quality characteristics (semen volume, sperm concentration, total sperm count, progressive motility and vitality, sperm morphology, and multiple anomalies index). Oligospermia was significantly higher in the samples obtained in fertility center (47.7%) than on the ward (26.8%), p = 0.047. Average frozen straws were comparable, 12.2 ± 6.4 on the ward versus 11.9 ± 6.3 in fertility center. Conclusion: Semen collection on the ward is feasible and would be particularly interesting for AYA male patients without altering semen quality characteristics.
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- 2022
37. IL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibition
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Lucien Courtois, Aurelie Cabannes-Hamy, Rathana Kim, Marine Delecourt, Antoine Pinton, Guillaume Charbonnier, Mélanie Féroul, Charlotte Smith, Giulia Tueur, Cecile Pivert, Estelle Balducci, Mathieu Simonin, Laure Hélène Angel, Salvatore Spicuglia, Nicolas Boissel, Guillaume P Andrieu, Vahid Asnafi, Philippe Rousselot, and Ludovic Lhermitte
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.
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- 2023
38. Data from Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
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Svetlana Balandraud, Reuben Benjamin, Koji Kato, Takanori Teshima, Nicolas Boissel, Mohamad Mohty, Marcela V. Maus, Nitin Jain, Charlotte Graham, Julia Geronimi, Yasmina Adimy, Sylvain Fouliard, Agnieszka Jozwik, Maria Almena-Carrasco, Thibaud Derippe, Ibtissam Marchiq, and Sandra Dupouy
- Abstract
Background:UCART191 is an “off-the-shelf” genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells.Methods:UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology.Results:Responder patients (12/25) had higher UCART19 expansion (Cmax) and exposure (AUCTlast) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28.Conclusions:UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection.Significance:First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.
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- 2023
39. Supplementary Figures S1-S10 from Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis
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Emmanuelle Clappier, Nicolas Boissel, Philippe Rousselot, Jean Soulier, Hervé Dombret, Véronique Lhéritier, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Patrice Chevallier, Carlos Graux, Yves Chalandon, Yosr Hicheri, Lionel Adès, Raphaël Itzykson, Eric Delabesse, Beat W. Schäfer, Vahid Asnafi, Nathalie Grardel, Cédric Pastoret, Marina Lafage-Pochitaloff, Wendy Cuccuini, Stéphanie Gachet, Marie Passet, Matthieu Duchmann, Lise Larcher, Hugo Bergugnat, and Rathana Kim
- Abstract
Supplementary figure 1. Sequencing-based analysis of CNA and LOH in adult LH-ALL. Supplementary figure 2. Representation of mutations in the frequent targeted genes in adult LH-ALL. Supplementary figure 3. Longitudinal assessment of TP53-mutant cell fraction as determined by ddPCR along with clonal IG/TR-based MRD quantification in three patients with undetectable TP53 mutation at remission. Supplementary figure 4. Merged single-cell analysis of cell-surface markers by ADT-sequencing of remission samples from three LH-ALL patients. Supplementary figure 5. Individual single-cell analyses of cell-surface markers by ADT-sequencing of remission samples from three LH-ALL patients. Supplementary figure 6. Individual analyses of single-cell immunophenotyping and genotyping of remission samples from three LH-ALL patients. Supplementary figure 7. Evaluation of allelic dropout rate on heterozygous single nucleotide polymorphism (SNPs) in remission samples. Supplementary figure 8. Individual single-cell analysis of cell-surface markers by ADT-sequencing of diagnosis samples from three LH-ALL patients. Supplementary figure 9. Single-cell genotyping of heterozygous SNPs allowing LOH assessment in diagnosis samples from three LH-ALL patients. Supplementary Figure 10. Distribution of single-cell genotypes of two LH-ALL patients with persistent TP53 and JAK2 (EI_046) or DNMT3A (EI_035) mutations in remission samples.
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- 2023
40. Supplementary Tables S1-S4 from Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
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Svetlana Balandraud, Reuben Benjamin, Koji Kato, Takanori Teshima, Nicolas Boissel, Mohamad Mohty, Marcela V. Maus, Nitin Jain, Charlotte Graham, Julia Geronimi, Yasmina Adimy, Sylvain Fouliard, Agnieszka Jozwik, Maria Almena-Carrasco, Thibaud Derippe, Ibtissam Marchiq, and Sandra Dupouy
- Abstract
Table S1: Representativeness of CALM study participants; Table S2: UCART19 dose and cellular kinetics analysis; Table S3: Characteristics of UCART19 PBMC donors; Table S4: Impact of UCART19 and alemtuzumab doses on UCART19 expansion.
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- 2023
41. Supplementary Tables S1-S11 from Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis
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Emmanuelle Clappier, Nicolas Boissel, Philippe Rousselot, Jean Soulier, Hervé Dombret, Véronique Lhéritier, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Patrice Chevallier, Carlos Graux, Yves Chalandon, Yosr Hicheri, Lionel Adès, Raphaël Itzykson, Eric Delabesse, Beat W. Schäfer, Vahid Asnafi, Nathalie Grardel, Cédric Pastoret, Marina Lafage-Pochitaloff, Wendy Cuccuini, Stéphanie Gachet, Marie Passet, Matthieu Duchmann, Lise Larcher, Hugo Bergugnat, and Rathana Kim
- Abstract
Supplementary Table 1. Karyotypes of LH-ALL patients at diagnosis. Supplementary Table 2. Somatic variants detected in LH-ALL patients at diagnosis. Supplementary Table 3. ARCH related variants detected in LH-ALL patients at remission. Supplementary Table 4. Minimal residual disease values of remission samples used for mutation analysis. Supplementary Table 5. Somatic alterations in cell populations from diagnostic samples (BMMC) based on single-cell analyses. Supplementary Table 6. Somatic alterations in FACS-sorted cell populations from diagnostic samples. Supplementary Table 7. Panel of genes for targeted sequencing. Supplementary Table 8. Single cell DNA amplicons for genotyping and LOH analyses. Supplementary Table 9. Single cell DNA amplicons for B-ALL clono-specific IG/TR detection. Supplementary Table 10. ADT-seq panel and spike-in antibodies. Supplementary Table 11. Single cell sequencing metrics.
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- 2023
42. Supplementary Figures S1-S9 from Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
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Svetlana Balandraud, Reuben Benjamin, Koji Kato, Takanori Teshima, Nicolas Boissel, Mohamad Mohty, Marcela V. Maus, Nitin Jain, Charlotte Graham, Julia Geronimi, Yasmina Adimy, Sylvain Fouliard, Agnieszka Jozwik, Maria Almena-Carrasco, Thibaud Derippe, Ibtissam Marchiq, and Sandra Dupouy
- Abstract
Fig.S1: Schematic diagram of CALM study design; Fig.S2: Correlation of UCART19 transgene levels evaluated by qPCR in paired peripheral blood and bone marrow aspirate samples; Fig.S3 & S4: Impact of demographic characteristics, prior therapies and tumor burden on UCART19 in vivo expansion (Cmax) or persistence (AUCTlast), respectively; Fig.S5: Impact of tumor burden at the time of UCART19 infusion on UCART19 kinetics based on response status; Fig.S6: UCART19 product characteristics; Fig.S7: Scatter plots of UCART19 cellular kinetic parameters by qPCR vs transduction efficiency and cell viability; Fig.S8: Impact of lymphodepletion on homeostatic cytokines (IL-7 and IL-15) and UCART19 cellular kinetics; Fig.S9: Impact of number of prior treatment lines on IL-7 exposure (AUC28).
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- 2023
43. Supplementary Materials & Methods SM1 from Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
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Svetlana Balandraud, Reuben Benjamin, Koji Kato, Takanori Teshima, Nicolas Boissel, Mohamad Mohty, Marcela V. Maus, Nitin Jain, Charlotte Graham, Julia Geronimi, Yasmina Adimy, Sylvain Fouliard, Agnieszka Jozwik, Maria Almena-Carrasco, Thibaud Derippe, Ibtissam Marchiq, and Sandra Dupouy
- Abstract
Additional information regarding the CALM study (including study population and summary results) and UCART19 product characterization.
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- 2023
44. Data from Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis
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Emmanuelle Clappier, Nicolas Boissel, Philippe Rousselot, Jean Soulier, Hervé Dombret, Véronique Lhéritier, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Patrice Chevallier, Carlos Graux, Yves Chalandon, Yosr Hicheri, Lionel Adès, Raphaël Itzykson, Eric Delabesse, Beat W. Schäfer, Vahid Asnafi, Nathalie Grardel, Cédric Pastoret, Marina Lafage-Pochitaloff, Wendy Cuccuini, Stéphanie Gachet, Marie Passet, Matthieu Duchmann, Lise Larcher, Hugo Bergugnat, and Rathana Kim
- Abstract
Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18–84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis.Significance:We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL.See related commentary by Saiki and Ogawa, p. 102.This article is highlighted in the In This Issue feature, p. 101
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- 2023
45. Supplementary Material from Novel Intergenically Spliced Chimera, NFATC3-PLA2G15, Is Associated with Aggressive T-ALL Biology and Outcome
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Vahid Asnafi, Salvatore Spicuglia, Nicolas Boissel, Elizabeth Macintyre, Jacques Ghysdael, Gaëlle Cordonnier, Aurélie Bergon, Mohamed Belhocine, Guillaume Hypolite, Christine Tran Quang, and Jonathan Bond
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Supplementary Methods, Tables, figures and references.
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- 2023
46. TAR syndrome
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Maria Helena Lourenço, Nicolas Boissel, and Thomas Funck-Brentano
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Rheumatology - Published
- 2023
47. Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome (Ph)-Negative B-Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL): Results of the EWALL-INO Study
- Author
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Patrice Chevallier, Thibault Leguay, Rathana KIM, Marc Delord, Michael Doubek, Francoise Huguet, Aurelie Cabannes-Hamy, Ulla Wartiovaara-Kautto, Colombe Saillard, Emmanuel Raffoux, Thomas Cluzeau, Stephane Lepretre, Marie Balsat, Anna Berceanu, Nicolas Boissel, Claude Gardin, Emmanuelle Clappier, Herve Dombret, and Philippe Rousselot
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
48. Blinatumomab during Consolidation in High-Risk Philadelphia Chromosome (Ph)-Negative B-Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL) Adult Patients: A Two-Cohort Comparison within the Graall-2014/B Study
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Nicolas Boissel, Francoise Huguet, Thibaut Leguay, Mathilde Hunault, Rathana KIM, Yosr Hicheri, Patrice Chevallier, Marie Balsat, Sébastien Maury, Anne Thiebaut-Bertrand, Florence Van Obbergh, Thomas Cluzeau, Martine Escoffre-Barbe, Nicole Straetmans, Johanna Konopacki, Amine Belhabri, Alban Villate, Florence Pasquier, Ioana Vaida, Laurence Sanhes, Magda Alexis, Cedric Pastoret, Mathlide Lamarque, Laure Farnault, Nathalie Grardel, Celine Berthon, Eric Delabesse, Veronique Lheritier, Norbert Ifrah, Carlos Graux, Yves Chalandon, Emmanuelle Clappier, and Herve Dombret
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
49. Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL
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Marie Passet, Rathana Kim, Stéphanie Gachet, François Sigaux, Julie Chaumeil, Ava Galland, Thomas Sexton, Samuel Quentin, Lucie Hernandez, Lise Larcher, Hugo Bergugnat, Tao Ye, Nezih Karasu, Aurélie Caye, Beate Heizmann, Isabelle Duluc, Patrice Chevallier, Philippe Rousselot, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Françoise Pflumio, Jean-Noël Freund, Camille Lobry, Véronique Lhéritier, Hervé Dombret, Claire Domon-Dell, Jean Soulier, Nicolas Boissel, and Emmanuelle Clappier
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.
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- 2022
50. Data from Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL
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Vahid Asnafi, Nicolas Boissel, Mathilde Hunault, Elizabeth Macintyre, Hervé Dombret, Norbert Ifrah, Stéphane Leprêtre, Françoise Huguet, Yves Chalandon, Carlos Graux, Thibaut Leguay, Françoise Pflumio, Denis Puthier, Salvatore Spicuglia, Xavier Thomas, Charlotte Smith, Mohamed Belhocine, Mehdi Latiri, Etienne Lengliné, and Aurore Touzart
- Abstract
Purpose:Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3+) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1+ and TLX3+ T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes.Experimental Design:We compared TLX1+ and TLX3+ adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase (ASNS) and in vitro l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples.Results:We show that TLX1+ patients expressed low levels of ASNS when compared with TLX3+ and TLX-negative patients, due to epigenetic silencing of ASNS by both DNA methylation and a decrease of active histone marks. Promoter methylation of the ASNS gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally, ASNS promoter methylation was an independent prognostic factor for both event-free survival [HR, 0.42; 95% confidence interval (CI), 0.24–0.71; P = 0.001] and overall survival (HR, 0.40; 95% CI, 0.23–0.70; P = 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas (P = 0.012).Conclusions:We conclude that ASNS methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.
- Published
- 2023
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