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3. Correction: Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia

Author

Sharman, Jeff P., Egyed, Miklos, Jurczak, Wojciech, Skarbnik, Alan, Pagel, John M., Flinn, Ian W., Kamdar, Manali, Munir, Talha, Walewska, Renata, Corbett, Gillian, Fogliatto, Laura Maria, Herishanu, Yair, Banerji, Versha, Coutre, Steven, Follows, George, Walker, Patricia, Karlsson, Karin, Ghia, Paolo, Janssens, Ann, Cymbalista, Florence, Woyach, Jennifer A., Ferrant, Emmanuelle, Wierda, William G., Munugalavadla, Veerendra, Yu, Ting, Wang, Min Hui, and Byrd, John C.

Published
2024
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4. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Author

Parry, Erin M, Leshchiner, Ignaty, Guièze, Romain, Johnson, Connor, Tausch, Eugen, Parikh, Sameer A, Lemvigh, Camilla, Broséus, Julien, Hergalant, Sébastien, Messer, Conor, Utro, Filippo, Levovitz, Chaya, Rhrissorrakrai, Kahn, Li, Liang, Rosebrock, Daniel, Yin, Shanye, Deng, Stephanie, Slowik, Kara, Jacobs, Raquel, Huang, Teddy, Li, Shuqiang, Fell, Geoff, Redd, Robert, Lin, Ziao, Knisbacher, Binyamin A, Livitz, Dimitri, Schneider, Christof, Ruthen, Neil, Elagina, Liudmila, Taylor-Weiner, Amaro, Persaud, Bria, Martinez, Aina, Fernandes, Stacey M, Purroy, Noelia, Anandappa, Annabelle J, Ma, Jialin, Hess, Julian, Rassenti, Laura Z, Kipps, Thomas J, Jain, Nitin, Wierda, William, Cymbalista, Florence, Feugier, Pierre, Kay, Neil E, Livak, Kenneth J, Danysh, Brian P, Stewart, Chip, Neuberg, Donna, Davids, Matthew S, Brown, Jennifer R, Parida, Laxmi, Stilgenbauer, Stephan, Getz, Gad, and Wu, Catherine J

Subjects
Cancer, Rare Diseases, Lymphoma, Genetics, Hematology, Human Genome, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Serine-Arginine Splicing Factors, Medical and Health Sciences, Immunology
Abstract

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.

Published
2023

6. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author

Broséus, Julien, Hergalant, Sébastien, Vogt, Julia, Tausch, Eugen, Kreuz, Markus, Mottok, Anja, Schneider, Christof, Dartigeas, Caroline, Roos-Weil, Damien, Quinquenel, Anne, Moulin, Charline, Ott, German, Blanchet, Odile, Tomowiak, Cécile, Lazarian, Grégory, Rouyer, Pierre, Chteinberg, Emil, Bernhart, Stephan H., Tournilhac, Olivier, Gauchotte, Guillaume, Lomazzi, Sandra, Chapiro, Elise, Nguyen-Khac, Florence, Chery, Céline, Davi, Frédéric, Hunault, Mathilde, Houlgatte, Rémi, Rosenwald, Andreas, Delmer, Alain, Meyre, David, Béné, Marie-Christine, Thieblemont, Catherine, Lichter, Peter, Ammerpohl, Ole, Guéant, Jean-Louis, Guièze, Romain, Martin-Subero, José Ignacio, Cymbalista, Florence, Feugier, Pierre, Siebert, Reiner, and Stilgenbauer, Stephan

Published
2023
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7. A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation

Author

Lazarian, Gregory, Yin, Shanye, Ten Hacken, Elisa, Sewastianik, Tomasz, Uduman, Mohamed, Font-Tello, Alba, Gohil, Satyen H, Li, Shuqiang, Kim, Ekaterina, Joyal, Heather, Billington, Leah, Witten, Elizabeth, Zheng, Mei, Huang, Teddy, Severgnini, Mariano, Lefebvre, Valerie, Rassenti, Laura Z, Gutierrez, Catherine, Georgopoulos, Katia, Ott, Christopher J, Wang, Lili, Kipps, Thomas J, Burger, Jan A, Livak, Kenneth J, Neuberg, Donna S, Baran-Marszak, Fanny, Cymbalista, Florence, Carrasco, Ruben D, and Wu, Catherine J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Hematology, Lymphoma, Rare Diseases, Genetics, Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, B-Lymphocytes, Humans, Ikaros Transcription Factor, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mutation, NF-kappa B, Receptors, Antigen, B-Cell, Signal Transduction, Transcription, Genetic, BCR signaling, CLL, IKZF3, NF-κB, murine mode, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.

Published
2021

8. A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial

Author

Michallet, Anne-Sophie, Letestu, Rémi, Le Garff-Tavernier, Magali, Campos, Lydia, Ticchioni, Michel, Dilhuydy, Marie-Sarah, Morisset, Stephane, Rouille, Valérie, Mahé, Béatrice, Laribi, Kamel, Villemagne, Bruno, Ferrant, Emmanuelle, Tournilhac, Olivier, Delmer, Alain, Molina, Lysiane, Leblond, Véronique, Tomowiak, Cécile, de Guibert, Sophie, Orsini-Piocelle, Frederique, Banos, Anne, Carassou, Philippe, Cartron, Guillaume, Fornecker, Luc Mathieu, Ysebaert, Loic, Dartigeas, Caroline, Truchan-Graczyk, Margot, Vilque, Jean-Pierre, Schleinitz, Thérèse Aurran, Cymbalista, Florence, Leprêtre, Stéphane, Lévy, Vincent, Nguyen-Khac, Florence, and Feugier, Pierre

Published
2023
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9. Outcomes with ibrutinib by line of therapy and post‐ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis

Author

O'Brien, Susan M, Byrd, John C, Hillmen, Peter, Coutre, Steven, Brown, Jennifer R, Barr, Paul M, Barrientos, Jacqueline C, Devereux, Stephen, Robak, Tadeusz, Reddy, Nishitha M, Kipps, Thomas J, Tedeschi, Alessandra, Cymbalista, Florence, Ghia, Paolo, Chang, Stephen, Ninomoto, Joi, James, Danelle F, and Burger, Jan A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Rare Diseases, Cancer, Hematology, Lymphoma, Orphan Drug, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adenine, Adult, Aged, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperidines, Pyrazoles, Pyrimidines, Survival Rate, Cardiorespiratory Medicine and Haematology, Immunology, Cardiovascular medicine and haematology
Abstract

The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first-line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher-risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib-treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single-agent ibrutinib: RESONATE (PCYC-1112) in patients with R/R CLL and RESONATE-2 (PCYC-1115) in patients with treatment-naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib-treated non-del(17p) patients with CLL (136 TN and 135 R/R). Median progression-free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow-up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow-up 18 months, n = 51) and was not reached in TN patients (median follow-up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy.

Published
2019

10. Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis

Author

Brown, Jennifer R, Moslehi, Javid, Ewer, Michael S, O'Brien, Susan M, Ghia, Paolo, Cymbalista, Florence, Shanafelt, Tait D, Fraser, Graeme, Rule, Simon, Coutre, Steven E, Dilhuydy, Marie‐Sarah, Cramer, Paula, Jaeger, Ulrich, Dreyling, Martin, Byrd, John C, Treon, Steven, Liu, Emily Y, Chang, Stephen, Bista, Amulya, Vempati, Rama, Boornazian, Lisa, Valentino, Rudolph, Reddy, Vijay, Mahler, Michelle, Yang, Huiying, Graef, Thorsten, and Burger, Jan A

Subjects
Cancer, Clinical Research, Clinical Trials and Supportive Activities, Hematology, Rare Diseases, Good Health and Well Being, Adenine, Aged, Female, Hematologic Neoplasms, Hemorrhage, Humans, Incidence, Male, Middle Aged, Piperidines, Pyrazoles, Pyrimidines, Randomized Controlled Trials as Topic, Risk Factors, Time Factors, B-cell neoplasms, lymphoid leukaemias, signalling therapies, clinical results in lymphomas, Cardiorespiratory Medicine and Haematology, Immunology
Abstract

Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.

Published
2019

12. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia: CHRONIC LYMPHOCYTIC LEUKEMIA

Author

Sharman, Jeff P., Egyed, Miklos, Jurczak, Wojciech, Skarbnik, Alan, Pagel, John M., Flinn, Ian W., Kamdar, Manali, Munir, Talha, Walewska, Renata, Corbett, Gillian, Fogliatto, Laura Maria, Herishanu, Yair, Banerji, Versha, Coutre, Steven, Follows, George, Walker, Patricia, Karlsson, Karin, Ghia, Paolo, Janssens, Ann, Cymbalista, Florence, Woyach, Jennifer A., Ferrant, Emmanuelle, Wierda, William G., Munugalavadla, Veerendra, Yu, Ting, Wang, Min Hui, and Byrd, John C.

Published
2022
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13. Clinical and biological characterization of involvement of nasal‐associated lymphoid tissues in chronic lymphocytic leukemia

Author

Ranaweera Arachchige, Thimali, primary, Mendiburu, Catherine, additional, Martin, Antoine, additional, Fleury, Carole, additional, Dondi, Elisabetta, additional, Letestu, Rémi, additional, Eclache, Virginie, additional, Baran‐Marszak, Fanny, additional, Cymbalista, Florence, additional, and Lazarian, Gregory, additional

Published
2024
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14. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations

Author

Wierda, William G., Rawstron, Andrew, Cymbalista, Florence, Badoux, Xavier, Rossi, Davide, Brown, Jennifer R., Egle, Alexander, Abello, Virginia, Cervera Ceballos, Eduardo, Herishanu, Yair, Mulligan, Stephen P., Niemann, Carsten U., Diong, Colin P., Soysal, Teoman, Suzuki, Ritsuro, Tran, Hoa T. T., Wu, Shang-Ju, Owen, Carolyn, Stilgenbauer, Stephan, Ghia, Paolo, and Hillmen, Peter

Published
2021
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15. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials

Author

Brown, Jennifer R, Moslehi, Javid, O’Brien, Susan, Ghia, Paolo, Hillmen, Peter, Cymbalista, Florence, Shanafelt, Tait D, Fraser, Graeme, Rule, Simon, Kipps, Thomas J, Coutre, Steven, Dilhuydy, Marie-Sarah, Cramer, Paula, Tedeschi, Alessandra, Jaeger, Ulrich, Dreyling, Martin, Byrd, John C, Howes, Angela, Todd, Michael, Vermeulen, Jessica, James, Danelle F, Clow, Fong, Styles, Lori, Valentino, Rudy, Wildgust, Mark, Mahler, Michelle, and Burger, Jan A

Subjects
Orphan Drug, Clinical Trials and Supportive Activities, Aging, Rare Diseases, Hematology, Lymphoma, Heart Disease, Cancer, Cardiovascular, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adenine, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Atrial Fibrillation, Disease Management, Female, Follow-Up Studies, Hemorrhage, Humans, Incidence, Male, Middle Aged, Piperidines, Protein Kinase Inhibitors, Pyrazoles, Pyrimidines, Randomized Controlled Trials as Topic, Risk Factors, Time Factors, Immunology
Abstract

The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6-16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months versus 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation (clinicaltrials.gov identifier: 01578707, 01722487, 01611090, 01646021).

Published
2017

16. Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort

Author

Bouclet, Florian, Calleja, Anne, Dilhuydy, Marie-Sarah, Véronèse, Lauren, Pereira, Bruno, Amorim, Sandy, Cymbalista, Florence, Herbaux, Charles, de Guibert, Sophie, Roos-Weil, Damien, Hivert, Bénédicte, Aurran, Thérèse, Dupuis, Jehan, Blouet, Anaise, Tchernonog, Emmanuelle, Laribi, Kamel, Dmytruck, Nataliya, Morel, Pierre, Michallet, Anne-Sophie, Dartigeas, Caroline, Tournilhac, Olivier, Nguyen-Khac, Florence, Delmer, Alain, Feugier, Pierre, Ysebaert, Loïc, and Guièze, Romain

Published
2021
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18. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial

Author

Herling, Carmen D., Cymbalista, Florence, Groß-Ophoff-Müller, Carolin, Bahlo, Jasmin, Robrecht, Sandra, Langerbeins, Petra, Fink, Anna-Maria, Al-Sawaf, Othman, Busch, Raymonde, Porcher, Raphael, Cazin, Bruno, Dreyfus, Brigitte, Ibach, Stefan, Leprêtre, Stéphane, Fischer, Kirsten, Kaiser, Florian, Eichhorst, Barbara, Wentner, Clemens-Martin, Hoechstetter, Manuela A., Döhner, Hartmut, Leblond, Veronique, Kneba, Michael, Letestu, Remi, Böttcher, Sebastian, Stilgenbauer, Stephan, Hallek, Michael, and Levy, Vincent

Published
2020
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19. Stabilization of β-catenin upon B-cell receptor signaling promotes NF-kB target genes transcription in mantle cell lymphoma

Author

Lazarian, Gregory, Friedrich, Chloe, Quinquenel, Anne, Tran, Julie, Ouriemmi, Souhail, Dondi, Elisabetta, Martin, Antoine, Mihoub, Imane, Chiron, David, Bellanger, Céline, Fleury, Carole, Gélébart, Pascal, McCormack, Emmet, Ledoux, Dominique, Thieblemont, Catherine, Marzec, Jacek, Gribben, John G., Cymbalista, Florence, Varin-Blank, Nadine, Gardano, Laura, and Baran-Marszak, Fanny

Published
2020
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20. Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial

Author

Michallet, Anne-Sophie, Dilhuydy, Marie-Sarah, Subtil, Fabien, Rouille, Valerie, Mahe, Beatrice, Laribi, Kamel, Villemagne, Bruno, Salles, Gilles, Tournilhac, Olivier, Delmer, Alain, Portois, Christelle, Pegourie, Brigitte, Leblond, Veronique, Tomowiak, Cecile, de Guibert, Sophie, Orsini, Frederique, Banos, Anne, Carassou, Philippe, Cartron, Guillaume, Fornecker, Luc Mathieu, Ysebaert, Loic, Dartigeas, Caroline, Truchan Graczyk, Malgorzata, Vilque, Jean P, Aurran, Thérèse, Cymbalista, Florence, Lepretre, Stéphane, Lévy, Vincent, Nguyen-Khac, Florence, Le Garff-Tavernier, Magali, Aanei, Carmen, Ticchioni, Michel, Letestu, Rémi, and Feugier, Pierre

Published
2019
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21. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia

Author

Byrd, John C, Brown, Jennifer R, O'Brien, Susan, Barrientos, Jacqueline C, Kay, Neil E, Reddy, Nishitha M, Coutre, Steven, Tam, Constantine S, Mulligan, Stephen P, Jaeger, Ulrich, Devereux, Steve, Barr, Paul M, Furman, Richard R, Kipps, Thomas J, Cymbalista, Florence, Pocock, Christopher, Thornton, Patrick, Caligaris-Cappio, Federico, Robak, Tadeusz, Delgado, Julio, Schuster, Stephen J, Montillo, Marco, Schuh, Anna, de Vos, Sven, Gill, Devinder, Bloor, Adrian, Dearden, Claire, Moreno, Carol, Jones, Jeffrey J, Chu, Alvina D, Fardis, Maria, McGreivy, Jesse, Clow, Fong, James, Danelle F, and Hillmen, Peter

Subjects
Lymphoma, Rare Diseases, Orphan Drug, Clinical Research, Hematology, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adenine, Adult, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Cough, Diarrhea, Disease-Free Survival, Fatigue, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Recurrence, Survival Rate, RESONATE Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundIn patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.MethodsIn this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.ResultsAt a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P

Published
2014

24. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL

Author

Flinn, Ian W., Hillmen, Peter, Montillo, Marco, Nagy, Zsolt, Illés, Árpád, Etienne, Gabriel, Delgado, Julio, Kuss, Bryone J., Tam, Constantine S., Gasztonyi, Zoltán, Offner, Fritz, Lunin, Scott, Bosch, Francesco, Davids, Matthew S., Lamanna, Nicole, Jaeger, Ulrich, Ghia, Paolo, Cymbalista, Florence, Portell, Craig A., Skarbnik, Alan P., Cashen, Amanda F., Weaver, David T., Kelly, Virginia M., Turnbull, Barry, and Stilgenbauer, Stephan

Published
2018
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25. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study

Author

Dartigeas, Caroline, Van Den Neste, Eric, Léger, Julie, Maisonneuve, Hervé, Berthou, Christian, Dilhuydy, Marie-Sarah, De Guibert, Sophie, Leprêtre, Stéphane, Béné, Marie C, Nguyen-Khac, Florence, Letestu, Rémi, Cymbalista, Florence, Rodon, Philippe, Aurran-Schleinitz, Thérèse, Vilque, Jean-Pierre, Tournilhac, Olivier, Mahé, Béatrice, Laribi, Kamel, Michallet, Anne-Sophie, Delmer, Alain, Feugier, Pierre, Lévy, Vincent, Delépine, Roselyne, Colombat, Philippe, and Leblond, Véronique

Published
2018
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28. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL

Author

Barr, Paul M., Brown, Jennifer R., Hillmen, Peter, O'Brien, Susan, Barrientos, Jacqueline C., Reddy, Nishitha M., Coutre, Steven, Mulligan, Stephen P., Jaeger, Ulrich, Furman, Richard R., Cymbalista, Florence, Montillo, Marco, Dearden, Claire, Robak, Tadeusz, Moreno, Carol, Pagel, John M., Burger, Jan A., Suzuki, Samuel, Sukbuntherng, Juthamas, Cole, George, James, Danelle F., and Byrd, John C.

Published
2017
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29. The Broad Spectrum of TP53 Mutations in CLL : Evidence of Multiclonality and Novel Mutation Hotspots

Author

Lazarian, Gregory, Leroy, Bernard, Theves, Floriane, Hormi, Myriam, Letestu, Remi, Eclache, Virginie, Tueur, Giulia, Ameur, Adam, Bidet, Audrey, Cornillet-Lefebvre, Pascale, Davi, Frederic, Delabesse, Eric, Estienne, Marie-Helene, Etancelin, Pascaline, Kosmider, Olivier, Laibe, Sophy, Muller, Marc, Nadal, Nathalie, Naguib, Dina, Pastoret, Cedric, Poulain, Stephanie, Sujobert, Pierre, Veronese, Lauren, Imache, Samia, Lefebvre, Valerie, Cymbalista, Florence, Baran-Marszak, Fanny, Soussi, Thierry, Lazarian, Gregory, Leroy, Bernard, Theves, Floriane, Hormi, Myriam, Letestu, Remi, Eclache, Virginie, Tueur, Giulia, Ameur, Adam, Bidet, Audrey, Cornillet-Lefebvre, Pascale, Davi, Frederic, Delabesse, Eric, Estienne, Marie-Helene, Etancelin, Pascaline, Kosmider, Olivier, Laibe, Sophy, Muller, Marc, Nadal, Nathalie, Naguib, Dina, Pastoret, Cedric, Poulain, Stephanie, Sujobert, Pierre, Veronese, Lauren, Imache, Samia, Lefebvre, Valerie, Cymbalista, Florence, Baran-Marszak, Fanny, and Soussi, Thierry

Abstract

TP53 aberrations are a major predictive factor of resistance to chemoimmunotherapy in chronic lymphocytic leukemia (CLL), and an assessment of them before each line of treatment is required for theranostic stratification. Acquisition of subclonal TP53 abnormalities underlies the evolution of CLL. To better characterize the distribution, combination, and impact of TP53 variants in CLL, 1,056 TP53 variants collected from 683 patients included in a multicenter collaborative study in France were analyzed and compared to UMD_CLL, a dataset built from published articles collectively providing 5,173 TP53 variants detected in 3,808 patients. Our analysis confirmed the presence of several CLL-specific hotspot mutations, including a two-base pair deletion in codon 209 and a missense variant at codon 234, the latter being associated with alkylating treatment. Our analysis also identified a novel CLL-specific variant in the splice acceptor signal of intron 6 leading to the use of a cryptic splice site, similarly utilized by TP53 to generate p53psi, a naturally truncated p53 isoform localized in the mitochondria. Examination of both UMD_CLL and several recently released large-scale genomic analyses of CLL patients confirmed that this splice variant is highly enriched in this disease when compared to other cancer types. Using a TP53-specific single-nucleotide polymorphism, we also confirmed that copy-neutral loss of heterozygosity is frequent in CLL. This event can lead to misinterpretation of TP53 status. Unlike other cancers, CLL displayed a high proportion of patients harboring multiple TP53 variants. Using both in silico analysis and single molecule smart sequencing, we demonstrated the coexistence of distinct subclones harboring mutations on distinct alleles. In summary, our study provides a detailed TP53 mutational architecture in CLL and gives insights into how treatments may shape the genetic landscape of CLL patients.

Published
2023
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30. A Fixed-Duration Immunochemotherapy Approach Combined with Ibrutinib in CLL Produces Deep and Sustained MRD Responses: 5.5-Year Results from the Icll-07 Filo Trial

Author

Anne-Sophie Michallet, Rémi Letestu, Magali Le Garff-Tavernier, Carmen Aanaei, Michel Ticchioni, Marie-Sarah Dilhuydy, Stephane Morisset, Valérie Rouille, Béatrice Mahé, Kamel Laribi, Bruno Villemagne, Emmanuelle Ferrant, Olivier Tournilhac, Alain Delmer, Christelle Portois, Lysiane Molina, Véronique Leblond, Cécile Tomowiak, Sophie de Guibert, Frederique Orsini, Anne Banos, Philippe Carassou, Guillaume Cartron, Luc Mathieu Fornecker, Loic Ysebaert, Caroline Dartigeas, Margot Truchan, Jean-Pierre Vilque, Therese Aurran Schleinitz, Cymbalista Florence, Stéphane Leprêtre, Vincent Lévy, Florence Nguyen Khac, and Pierre Feugier

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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31. Identification of the Axis β-Catenin–BTK in the Dynamic Adhesion of Chronic Lymphocytic Leukemia Cells to Their Microenvironment.

Author

Mihoub, Imane, Rharass, Tareck, Ouriemmi, Souhaïl, Oudar, Antonin, Aubard, Laure, Gratio, Valérie, Lazarian, Gregory, Ferreira, Jordan, Dondi, Elisabetta, Cymbalista, Florence, Levy, Vincent, Baran-Marszak, Fanny, Varin-Blank, Nadine, Ledoux, Dominique, Le Roy, Christine, and Gardano, Laura

Subjects
CHRONIC lymphocytic leukemia, CELL adhesion, STROMAL cells, CELLULAR control mechanisms, CELL communication, CELL survival
Abstract

In the microenvironment, cell interactions are established between different cell types to regulate their migration, survival and activation. β-Catenin is a multifunctional protein that stabilizes cell–cell interactions and regulates cell survival through its transcriptional activity. We used chronic lymphocytic leukemia (CLL) cells as a cellular model to study the role of β-catenin in regulating the adhesion of tumor cells to their microenvironment, which is necessary for tumor cell survival and accumulation. When co-cultured with a stromal cell line (HS-5), a fraction of the CLL cells adhere to stromal cells in a dynamic fashion regulated by the different levels of β-catenin expression. In non-adherent cells, β-catenin is stabilized in the cytosol and translocates into the nucleus, increasing the expression of cyclin D1. In adherent cells, the level of cytosolic β-catenin is low but membrane β-catenin helps to stabilize the adhesion of CLL to stromal cells. Indeed, the overexpression of β-catenin enhances the interaction of CLL with HS-5 cells, suggesting that this protein behaves as a regulator of cell adhesion to the stromal component and of the transcriptional regulation of cell survival. Inhibitors that block the stabilization of β-catenin alter this equilibrium and effectively disrupt the support that CLL cells receive from the cross-talk with the stroma. [ABSTRACT FROM AUTHOR]

Published
2023
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32. Supplementary Figure 2 from Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Author

Vlad, Amalia, primary, Deglesne, Pierre-Antoine, primary, Letestu, Rémi, primary, Saint-Georges, Stéphane, primary, Chevallier, Nathalie, primary, Baran-Marszak, Fanny, primary, Varin-Blank, Nadine, primary, Ajchenbaum-Cymbalista, Florence, primary, and Ledoux, Dominique, primary

Published
2023
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33. Supplementary Figure 5 from Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Author

Vlad, Amalia, primary, Deglesne, Pierre-Antoine, primary, Letestu, Rémi, primary, Saint-Georges, Stéphane, primary, Chevallier, Nathalie, primary, Baran-Marszak, Fanny, primary, Varin-Blank, Nadine, primary, Ajchenbaum-Cymbalista, Florence, primary, and Ledoux, Dominique, primary

Published
2023
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34. Supplementary Table 1 from Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Author

Vlad, Amalia, primary, Deglesne, Pierre-Antoine, primary, Letestu, Rémi, primary, Saint-Georges, Stéphane, primary, Chevallier, Nathalie, primary, Baran-Marszak, Fanny, primary, Varin-Blank, Nadine, primary, Ajchenbaum-Cymbalista, Florence, primary, and Ledoux, Dominique, primary

Published
2023
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35. Supplementary Figure 3 from Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Author

Vlad, Amalia, primary, Deglesne, Pierre-Antoine, primary, Letestu, Rémi, primary, Saint-Georges, Stéphane, primary, Chevallier, Nathalie, primary, Baran-Marszak, Fanny, primary, Varin-Blank, Nadine, primary, Ajchenbaum-Cymbalista, Florence, primary, and Ledoux, Dominique, primary

Published
2023
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36. Data from Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Author

Vlad, Amalia, primary, Deglesne, Pierre-Antoine, primary, Letestu, Rémi, primary, Saint-Georges, Stéphane, primary, Chevallier, Nathalie, primary, Baran-Marszak, Fanny, primary, Varin-Blank, Nadine, primary, Ajchenbaum-Cymbalista, Florence, primary, and Ledoux, Dominique, primary

Published
2023
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37. Supplementary Figure 4 from Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Author

Vlad, Amalia, primary, Deglesne, Pierre-Antoine, primary, Letestu, Rémi, primary, Saint-Georges, Stéphane, primary, Chevallier, Nathalie, primary, Baran-Marszak, Fanny, primary, Varin-Blank, Nadine, primary, Ajchenbaum-Cymbalista, Florence, primary, and Ledoux, Dominique, primary

Published
2023
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38. Supplementary Figure 1 from Down-regulation of CXCR4 and CD62L in Chronic Lymphocytic Leukemia Cells Is Triggered by B-Cell Receptor Ligation and Associated with Progressive Disease

Author

Vlad, Amalia, primary, Deglesne, Pierre-Antoine, primary, Letestu, Rémi, primary, Saint-Georges, Stéphane, primary, Chevallier, Nathalie, primary, Baran-Marszak, Fanny, primary, Varin-Blank, Nadine, primary, Ajchenbaum-Cymbalista, Florence, primary, and Ledoux, Dominique, primary

Published
2023
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40. Evolutionary History of Transformation from Chronic Lymphocytic Leukemia to Richter Syndrome

Author

Parry, Erin Michelle, primary, Guieze, Romain, additional, Leshchiner, Ignaty, additional, Johnson, Connor, additional, Tausch, Eugen, additional, Parikh, Sameer A., additional, Lemvigh, Camilla K, additional, Broséus, Julien, additional, Hergalant, Sébastien, additional, Messer, Connor, additional, Utro, Filippo, additional, Levovitz, Chaya, additional, Rhrissorrakrai, Kahn, additional, Li, Liang, additional, Li, Shuqiang, additional, Fell, Geoffrey G, additional, Redd, Robert A., additional, Lin, Ziao, additional, Knisbacher, Binyamin A., additional, Schneider, Christof, additional, Fernandes, Stacey M., additional, Hess, Julian M., additional, Rassenti, Laura Z., additional, Kipps, Thomas J., additional, Jain, Nitin, additional, Wierda, William G., additional, Cymbalista, Florence, additional, Feugier, Pierre, additional, Kay, Neil E., additional, Livak, Kenneth J, additional, Danysh, Brian P, additional, Stewart, Chip, additional, Neuberg, Donna S., additional, Davids, Matthew S., additional, Brown, Jennifer R., additional, Parida, Laxmi, additional, Stilgenbauer, Stephan, additional, Getz, Gad, additional, and Wu, Catherine J., additional

Published
2022
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41. Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR: Results of the Month 15 MRD Evaluation

Author

Quinquenel, Anne, primary, Letestu, Rémi, additional, Le Garff-Tavernier, Magali, additional, Subtil, Fabien, additional, Aurran-Schleinitz, Therese, additional, Laribi, Kamel, additional, Cymbalista, Florence, additional, Levy, Vincent, additional, Simon, Laurence, additional, Roos-Weil, Damien, additional, Leblond, Véronique, additional, Dilhuydy, Marie-Sarah, additional, Dartigeas, Caroline, additional, Tomowiak, Cecile, additional, Guieze, Romain, additional, Tournilhac, Olivier, additional, Ferrant, Emmanuelle, additional, de Guibert, Sophie, additional, Feugier, Pierre, additional, Merabet, Fatiha, additional, Lepretre, Stephane, additional, Carassou, Philippe, additional, Gay, Julie, additional, Hivert, Bénédicte, additional, Fornecker, Luc Mathieu, additional, Dupuis, Jehan, additional, Molina, Lysiane, additional, Villemagne, Bruno, additional, Cartron, Guillaume, additional, Drenou, Bernard, additional, Mahé, Béatrice, additional, Benbrahim, Omar, additional, Cahu, Xavier, additional, Portois, Christelle, additional, Ysebaert, Loic, additional, Nguyen Khac, Florence, additional, Rouille, Valérie, additional, Delmer, Alain, additional, and Michallet, Anne-Sophie, additional

Published
2022
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44. Characteristics of chronic lymphocytic leukemia patients achieving 5+ years of remission after FC‐based first‐line treatment: Retrospective observations from the FILO group

Author

Guillermin, Yann, Herbaux, Charles, Subtil, Fabien, Aurran‐Schleinitz, Thérèse, Cymbalista, Florence, Letestu, Remi, Leprêtre, Stéphane, Vaudaux, Sandrine, Laribi, Kamel, Leblond, Véronique, Defoi, Yasmina, Benchikh, Raouf, Salles, Gilles, Godmer, Pascal, Jardel, Henry, Vallais, Fréderic, Feugier, Pierre, Orsini, Frédérique, Pegourié, Brigitte, Lévy, Vincent, and Michallet, Anne‐Sophie

Published
2018
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45. Abstract A13: Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Author

Parry, Erin M, primary, Leshchiner, Ignaty, additional, Guieze, Romain, additional, Johnson, Connor, additional, Tausch, Eugen, additional, Parikh, Sameer A, additional, Lemvigh, Camilla K, additional, Messer, Conor, additional, Utro, Filippo, additional, Levovitz, Chaya, additional, Rhrissorrakrai, Kahn, additional, Davids, Matthew S, additional, Broseus, Julien, additional, Li, Shuqiang, additional, Lin, Ziao, additional, Knisbacher, Binyamin A, additional, Schneider, Christof, additional, Rassenti, Laura Z, additional, Kipps, Thomas J, additional, Jain, Nitin, additional, Wierda, William, additional, Cymbalista, Florence, additional, Kay, Neil E, additional, Livak, Kenneth J, additional, Danysh, Brian P, additional, Stewart, Chip, additional, Neuberg, Donna, additional, Brown, Jennifer R, additional, Paridi, Laxmi, additional, Stilgenbauer, Stephan, additional, Getz, Gaddy, additional, and Wu, Catherine, additional

Published
2022
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46. TP53 mutations at codon 234 are associated with chlorambucil treatment in chronic lymphocytic leukemia

Author

Lazarian, Gregory, Theves, Floriane, Hormi, Myriam, Letestu, Remi, Eclache, Virginie, Bidet, Audrey, Cornillet-Lefebvre, Pascale, Davi, Frederic, Delabesse, Eric, Estienne, Marie-Helene, Etancelin, Pascaline, Kosmider, Olivier, Laibe, Sophy, Lode, Laurence, Muller, Marc, Nadal, Nathalie, Naguib, Dina, Pastoret, Cedric, Poulain, Stephanie, Sujobert, Pierre, Veronese, Lauren, Imache, Samia, Lefebvre, Valerie, Cymbalista, Florence, Baran-Marszak, Fanny, Soussi, Thierry, Lazarian, Gregory, Theves, Floriane, Hormi, Myriam, Letestu, Remi, Eclache, Virginie, Bidet, Audrey, Cornillet-Lefebvre, Pascale, Davi, Frederic, Delabesse, Eric, Estienne, Marie-Helene, Etancelin, Pascaline, Kosmider, Olivier, Laibe, Sophy, Lode, Laurence, Muller, Marc, Nadal, Nathalie, Naguib, Dina, Pastoret, Cedric, Poulain, Stephanie, Sujobert, Pierre, Veronese, Lauren, Imache, Samia, Lefebvre, Valerie, Cymbalista, Florence, Baran-Marszak, Fanny, and Soussi, Thierry

Published
2022
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47. Management of central nervous system involvement in chronic lymphocytic leukaemia: a retrospective cohort of 30 patients

Author

Wanquet, Anne, Birsen, Rudy, Bonnet, Charlotte, Boubaya, Marouane, Choquet, Sylvain, Dupuis, Jehan, Lepretre, Stephane, Re, Daniel, Fahri, Jonathan, Michallet, AnneSophie, Ysebaert, Loïc, Lemal, Richard, Lamy, Thierry, Delarue, Richard, Troussard, Xavier, Cymbalista, Florence, Levy, Vincent, Dietrich, PierreYves, Leblond, Veronique, and AurranSchleinitz, Therese

Published
2017
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49. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial

Author

Lepretre, Stephane, Aurran, Therese, Mahé, Beatrice, Cazin, Bruno, Tournilhac, Olivier, Maisonneuve, Herve, Casasnovas, Olivier, Delmer, Alain, Leblond, Veronique, Royer, Bruno, Corront, Bernadette, Chevret, Sylvie, Delépine, Roselyne, Vaudaux, Sandrine, Van Den Neste, Eric, Béné, Marie Christine, Letestu, Remi, Cymbalista, Florence, and Feugier, Pierre

Published
2012
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50. Abstract 4007: Evolutionary history of transformation from chronic lymphocytic leukemia to Richter’s syndrome

Author

Parry, Erin M., primary, Leshchiner, Ignaty, additional, Guièze, Romain, additional, Johnson, Connor, additional, Tausch, Eugen, additional, Parikh, Sameer, additional, Lemvigh, Camilla, additional, Messer, Conor, additional, Rosebrock, Daniel, additional, Utro, Filippo, additional, Levovitz, Chaya, additional, Rhrissorrakrai, Kahn, additional, Davids, Matthew, additional, Jacobs, Raquel A., additional, Slowik, Kara, additional, Broseus, Julien, additional, Yin, Shanye, additional, Li, Shuqiang, additional, Fell, Geoff, additional, Lin, Ziao, additional, Knisbacher, Binyamin A., additional, Ruthen, Neil, additional, Livitz, Dimitri, additional, Schneider, Christof, additional, Ma, Jialin, additional, Hess, Julian, additional, Rassenti, Laura Z., additional, Kipps, Thomas J., additional, Jain, Nitin, additional, Wierda, William, additional, Cymbalista, Florence, additional, Kay, Neil E., additional, Livak, Kenneth J., additional, Danysh, Brian P., additional, Stewart, Chip, additional, Neuberg, Donna, additional, Brown, Jennifer R., additional, Parida, Laxmi, additional, Stilgenbauer, Stephan, additional, Getz, Gad, additional, and Wu, Catherine J., additional

Published
2022
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