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3. Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

Author

Al-Sawaf, Othman, Ligtvoet, Rudy, Robrecht, Sandra, Stumpf, Janina, Fink, Anna-Maria, Tausch, Eugen, Schneider, Christof, Boettcher, Sebastian, Mikusko, Martin, Ritgen, Matthias, Schetelig, Johannes, von Tresckow, Julia, Vehling-Kaiser, Ursula, Gaska, Tobias, Wendtner, Clemens Martin, Chapuy, Bjoern, Fischer, Kirsten, Kreuzer, Karl-Anton, Stilgenbauer, Stephan, Staber, Philipp, Niemann, Carsten, Hallek, Michael, and Eichhorst, Barbara

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

5. Molecular map of chronic lymphocytic leukemia and its impact on outcome

Author

Knisbacher, Binyamin A, Lin, Ziao, Hahn, Cynthia K, Nadeu, Ferran, Duran-Ferrer, Martí, Stevenson, Kristen E, Tausch, Eugen, Delgado, Julio, Barbera-Mourelle, Alex, Taylor-Weiner, Amaro, Bousquets-Muñoz, Pablo, Diaz-Navarro, Ander, Dunford, Andrew, Anand, Shankara, Kretzmer, Helene, Gutierrez-Abril, Jesus, López-Tamargo, Sara, Fernandes, Stacey M, Sun, Clare, Sivina, Mariela, Rassenti, Laura Z, Schneider, Christof, Li, Shuqiang, Parida, Laxmi, Meissner, Alexander, Aguet, François, Burger, Jan A, Wiestner, Adrian, Kipps, Thomas J, Brown, Jennifer R, Hallek, Michael, Stewart, Chip, Neuberg, Donna S, Martín-Subero, José I, Puente, Xose S, Stilgenbauer, Stephan, Wu, Catherine J, Campo, Elias, and Getz, Gad

Subjects
Hematology, Clinical Research, Cancer, Human Genome, Rare Diseases, Biotechnology, Genetics, Lymphoma, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Immunoglobulin Variable Region, Mutation, Prognosis, Genomics, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.

Published
2022

6. Six-year follow-up and subgroup analyses of a phase 2 trial of venetoclax for del(17p) chronic lymphocytic leukemia

Author

Stilgenbauer, Stephan, Tausch, Eugen, Roberts, Andrew W., Davids, Matthew S., Eichhorst, Barbara, Hallek, Michael, Hillmen, Peter, Schneider, Christof, Schetelig, Johannes, Böttcher, Sebastian, Kater, Arnon P., Jiang, Yanwen, Boyer, Michelle, Popovic, Relja, Ghanim, Majd T., Moran, Michael, Sinai, Wendy J., Wang, Xifeng, Mukherjee, Nabanita, Chyla, Brenda, Wierda, William G., and Seymour, John F.

Published
2024
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7. Author Correction: Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia

Author

Al-Sawaf, Othman, Zhang, Can, Jin, Hyun Yong, Robrecht, Sandra, Choi, Yoonha, Balasubramanian, Sandhya, Kotak, Alex, Chang, Yi Meng, Fink, Anna Maria, Tausch, Eugen, Schneider, Christof, Ritgen, Matthias, Kreuzer, Karl-Anton, Chyla, Brenda, Paulson, Joseph N., Pallasch, Christian P., Frenzel, Lukas P., Peifer, Martin, Eichhorst, Barbara, Stilgenbauer, Stephan, Jiang, Yanwen, Hallek, Michael, and Fischer, Kirsten

Published
2023
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8. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia

Author

Al-Sawaf, Othman, Zhang, Can, Jin, Hyun Yong, Robrecht, Sandra, Choi, Yoonha, Balasubramanian, Sandhya, Kotak, Alex, Chang, Yi Meng, Fink, Anna Maria, Tausch, Eugen, Schneider, Christof, Ritgen, Matthias, Kreuzer, Karl-Anton, Chyla, Brenda, Paulson, Joseph N., Pallasch, Christian P., Frenzel, Lukas P., Peifer, Martin, Eichhorst, Barbara, Stilgenbauer, Stephan, Jiang, Yanwen, Hallek, Michael, and Fischer, Kirsten

Published
2023
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9. 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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11. Activation of Notch and Myc signaling via B cell-restricted depletion of Dnmt3a generates a consistent murine model of chronic lymphocytic leukemia

Author

Biran, Anat, Yin, Shanye, Kretzmer, Helene, Ten Hacken, Elisa, Parvin, Salma, Lucas, Fabienne, Uduman, Mohamed, Gutierrez, Catherine, Dangle, Nathan, Billington, Leah, Regis, Fara Faye, Rassenti, Laura Z, Mohammad, Arman, Hoffmann, Gabriela Brunsting, Stevenson, Kristen, Zheng, Mei, Witten, Elizabeth, Fernandes, Stacey M, Tausch, Eugen, Sun, Clare, Stilgenbauer, Stephan, Brown, Jennifer R, Kipps, Thomas J, Aster, John C, Gnirke, Andreas, Neuberg, Donna S, Letai, Anthony, Wang, Lili, Carrasco, Ruben D, Meissner, Alexander, and Wu, Catherine J

Subjects
Genetics, Lymphoma, Cancer, Rare Diseases, Hematology, Aetiology, 2.1 Biological and endogenous factors, Animals, Anti-Bacterial Agents, Apoptosis, Biomarkers, Tumor, Cell Proliferation, DNA Methyltransferase 3A, Daptomycin, Disease Models, Animal, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Prognosis, Proto-Oncogene Proteins c-myc, RNA-Seq, Receptors, Notch, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yields a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haploinsufficient tumor suppressor. B1a cells were confirmed as the cell of origin of disease in this model, and Dnmt3a depletion resulted in focal hypomethylation and activation of Notch and Myc signaling. Amplification of chromosome 15 containing the Myc gene was detected in all CLL mice tested, and infiltration of high-Myc-expressing CLL cells in the spleen was observed. Notably, hyperactivation of Notch and Myc signaling was exclusively observed in the Dnmt3a CLL mice, but not in three other CLL mouse models tested (Sf3b1-Atm, Ikzf3, and MDR), and Dnmt3a-depleted CLL were sensitive to pharmacologic inhibition of Notch signaling in vitro and in vivo. Consistent with these findings, human CLL samples with lower DNMT3A expression were more sensitive to Notch inhibition than those with higher DNMT3A expression. Altogether, these results suggest that Dnmt3a depletion induces CLL that is highly dependent on activation of Notch and Myc signaling. SIGNIFICANCE: Loss of DNMT3A expression is a driving event in CLL and is associated with aggressive disease, activation of Notch and Myc signaling, and enhanced sensitivity to Notch inhibition.

Published
2021

12. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial

Author

Byrd, John C, Hillmen, Peter, Ghia, Paolo, Kater, Arnon P, Chanan-Khan, Asher, Furman, Richard R, O'Brien, Susan, Yenerel, Mustafa Nuri, Illés, Arpad, Kay, Neil, Garcia-Marco, Jose A, Mato, Anthony, Pinilla-Ibarz, Javier, Seymour, John F, Lepretre, Stephane, Stilgenbauer, Stephan, Robak, Tadeusz, Rothbaum, Wayne, Izumi, Raquel, Hamdy, Ahmed, Patel, Priti, Higgins, Kara, Sohoni, Sophia, and Jurczak, Wojciech

Subjects
Clinical Research, Hematology, Lymphoma, Cancer, Rare Diseases, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adenine, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperidines, Prognosis, Prospective Studies, Pyrazines, Survival Rate, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeAmong Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).MethodsPatients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS).ResultsOverall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.ConclusionIn this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

Published
2021

14. Final analysis of the CLL2-GIVe trial: obinutuzumab, ibrutinib, and venetoclax for untreated CLL with del(17p)/TP53mut

Author

Huber, Henriette, Tausch, Eugen, Schneider, Christof, Edenhofer, Simone, von Tresckow, Julia, Robrecht, Sandra, Giza, Adam, Zhang, Can, Fürstenau, Moritz, Dreger, Peter, Ritgen, Matthias, Illmer, Thomas, Illert, Anna Lena, Dürig, Jan, Böttcher, Sebastian, Niemann, Carsten U., Kneba, Michael, Al-Sawaf, Othman, Kreuzer, Karl-Anton, Fink, Anna-Maria, Fischer, Kirsten, Döhner, Hartmut, Hallek, Michael, Eichhorst, Barbara, and Stilgenbauer, Stephan

Published
2023
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15. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial

Author

Seymour, John F., Byrd, John C., Ghia, Paolo, Kater, Arnon P., Chanan-Khan, Asher, Furman, Richard R., O’Brien, Susan, Brown, Jennifer R., Munir, Talha, Mato, Anthony, Stilgenbauer, Stephan, Bajwa, Naghmana, Miranda, Paulo, Higgins, Kara, John, Ellie, de Borja, Marianne, Jurczak, Wojciech, and Woyach, Jennifer A.

Published
2023
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16. High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations

Author

Fürstenau, Moritz, Thus, Yvonne J., Robrecht, Sandra, Mellink, Clemens H. M., van der Kevie-Kersemaekers, Anne-Marie, Dubois, Julie, von Tresckow, Julia, Patz, Michaela, Gregor, Michael, Thornton, Patrick, Staber, Philipp B., Tadmor, Tamar, Levin, Mark-David, da Cunha-Bang, Caspar, Schneider, Christof, Poulsen, Christian Bjoern, Illmer, Thomas, Schöttker, Björn, Janssens, Ann, Christiansen, Ilse, Nösslinger, Thomas, Baumann, Michael, Hebart, Holger, Gaska, Tobias, Regelink, Josien C., Dompeling, Ellen C., Lindström, Vesa, Juliusson, Gunnar, Widmer, Anouk, Goede, Jeroen, Goldschmidt, Neta, Simon, Florian, De Silva, Nisha, Fink, Anna-Maria, Fischer, Kirsten, Wendtner, Clemens-Martin, Ritgen, Matthias, Brüggemann, Monika, Tausch, Eugen, Spaargaren, Marcel, Eldering, Eric, Stilgenbauer, Stephan, Niemann, Carsten U., Hallek, Michael, Eichhorst, Barbara, Kreuzer, Karl-Anton, and Kater, Arnon P.

Published
2023
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17. Oncogenic role and target properties of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia

Author

Jiang, Qu, Stachelscheid, Johanna, Bloehdorn, Johannes, Pacholewska, Alicja, Aszyk, Christoph, Grotenhuijs, Francien, Müller, Tony, Onder, Ozlem, Wagle, Prerana, Herling, Carmen D., Kleppe, Maria, Wang, Zhefang, Coombes, Kevin R., Robrecht, Sandra, Dalvi, Priya S., Plosnita, Bianca, Mayer, Petra, Abruzzo, Lynne V., Altmüller, Janine, Gathof, Birgit, Persigehl, Thorsten, Fischer, Kirsten, Jebaraj, Billy, Rienhoff, Hugh Y., Ecker, Rupert, Zhao, Yue, Bruns, Christiane J., Stilgenbauer, Stephan, Elenitoba-Johnson, Kojo, Hallek, Michael, Schweiger, Michal R., Odenthal, Margarete, Vasyutina, Elena, and Herling, Marco

Published
2023
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18. The impact of complex karyotype on the overall survival of patients with relapsed chronic lymphocytic leukemia treated with idelalisib plus rituximab

Author

Kreuzer, Karl-Anton, Furman, Richard R, Stilgenbauer, Stephan, Dubowy, Ronald L, Kim, Yeonhee, Munugalavadla, Veerendra, Lilienweiss, Esther, Reinhardt, Hans Christian, Cramer, Paula, Eichhorst, Barbara, Hillmen, Peter, O’Brien, Susan M, Pettitt, Andrew R, and Hallek, Michael

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Abnormal Karyotype, Aged, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Neoplasm Recurrence, Local, Progression-Free Survival, Purines, Quinazolinones, Rituximab, Treatment Outcome, Clinical Sciences, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Published
2020

19. The proto-oncogene TCL1A deregulates cell cycle and genomic stability in CLL

Author

Stachelscheid, Johanna, Jiang, Qu, Aszyk, Christoph, Warner, Kathrin, Bley, Nadine, Müller, Tony, Vydzhak, Olga, Symeonidis, Konstantinos, Crispatzu, Giuliano, Mayer, Petra, Blakemore, Stuart James, Goehring, Gudrun, Newrzela, Sebastian, Hippler, Stephanie, Robrecht, Sandra, Kreuzer, Karl-Anton, Pallasch, Christian, Krüger, Marcus, Lechner, Axel, Fischer, Kirsten, Stilgenbauer, Stephan, Beutner, Dirk, Hallek, Michael, Auguin, Daniel, Hüttelmaier, Stefan, Bloehdorn, Johannes, Vasyutina, Elena, and Herling, Marco

Published
2023
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20. Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia.

Author

Sharman, Jeff, Coutre, Steven, Furman, Richard, Cheson, Bruce, Pagel, John, Hillmen, Peter, Barrientos, Jacqueline, Zelenetz, Andrew, Flinn, Ian, Ghia, Paolo, Eradat, Herbert, Ervin, Thomas, Lamanna, Nicole, Coiffier, Bertrand, Pettitt, Andrew, Ma, Shuo, Tausch, Eugen, Cramer, Paula, Huang, Julie, Mitra, Siddhartha, Hallek, Michael, Stilgenbauer, Stephan, OBrien, Susan, and Kipps, Thomas

Subjects
Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Disease Progression, Double-Blind Method, Drug Administration Schedule, Europe, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Progression-Free Survival, Purines, Quinazolinones, Recurrence, Rituximab, Time Factors, United States
Abstract

PURPOSE: A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies. PATIENTS AND METHODS: Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety. RESULTS: The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases. CONCLUSION: IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.

Published
2019

21. Proteogenomics refines the molecular classification of chronic lymphocytic leukemia

Author

Herbst, Sophie A., Vesterlund, Mattias, Helmboldt, Alexander J., Jafari, Rozbeh, Siavelis, Ioannis, Stahl, Matthias, Schitter, Eva C., Liebers, Nora, Brinkmann, Berit J., Czernilofsky, Felix, Roider, Tobias, Bruch, Peter-Martin, Iskar, Murat, Kittai, Adam, Huang, Ying, Lu, Junyan, Richter, Sarah, Mermelekas, Georgios, Umer, Husen Muhammad, Knoll, Mareike, Kolb, Carolin, Lenze, Angela, Cao, Xiaofang, Österholm, Cecilia, Wahnschaffe, Linus, Herling, Carmen, Scheinost, Sebastian, Ganzinger, Matthias, Mansouri, Larry, Kriegsmann, Katharina, Kriegsmann, Mark, Anders, Simon, Zapatka, Marc, Del Poeta, Giovanni, Zucchetto, Antonella, Bomben, Riccardo, Gattei, Valter, Dreger, Peter, Woyach, Jennifer, Herling, Marco, Müller-Tidow, Carsten, Rosenquist, Richard, Stilgenbauer, Stephan, Zenz, Thorsten, Huber, Wolfgang, Tausch, Eugen, Lehtiö, Janne, and Dietrich, Sascha

Published
2022
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22. Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape

Author

Mangolini, Maurizio, Maiques-Diaz, Alba, Charalampopoulou, Stella, Gerhard-Hartmann, Elena, Bloehdorn, Johannes, Moore, Andrew, Giachetti, Giorgia, Lu, Junyan, Roamio Franklin, Valar Nila, Chilamakuri, Chandra Sekkar Reddy, Moutsopoulos, Ilias, Rosenwald, Andreas, Stilgenbauer, Stephan, Zenz, Thorsten, Mohorianu, Irina, D’Santos, Clive, Deaglio, Silvia, Hodson, Daniel J., Martin-Subero, Jose I., and Ringshausen, Ingo

Published
2022
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23. Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia

Author

Huber, Henriette, Edenhofer, Simone, von Tresckow, Julia, Robrecht, Sandra, Zhang, Can, Tausch, Eugen, Schneider, Christof, Bloehdorn, Johannes, Fürstenau, Moritz, Dreger, Peter, Ritgen, Matthias, Illmer, Thomas, Illert, Anna L., Dürig, Jan, Böttcher, Sebastian, Niemann, Carsten U., Kneba, Michael, Fink, Anna-Maria, Fischer, Kirsten, Döhner, Hartmut, Hallek, Michael, Eichhorst, Barbara, and Stilgenbauer, Stephan

Published
2022
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24. Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Author

Jebaraj, Billy Michael Chelliah, Müller, Annika, Dheenadayalan, Rashmi Priyadharshini, Endres, Sascha, Roessner, Philipp M., Seyfried, Felix, Walliser, Claudia, Wist, Martin, Qi, Jialei, Tausch, Eugen, Mertens, Daniel, Fox, Judith A., Debatin, Klaus-Michael, Meyer, Lüder Hinrich, Taverna, Pietro, Seiffert, Martina, Gierschik, Peter, and Stilgenbauer, Stephan

Published
2022
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25. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia

Author

Langerbeins, Petra, Zhang, Can, Robrecht, Sandra, Cramer, Paula, Fürstenau, Moritz, Al-Sawaf, Othman, von Tresckow, Julia, Fink, Anna-Maria, Kreuzer, Karl-Anton, Vehling-Kaiser, Ursula, Tausch, Eugen, Müller, Lothar, Eckart, Michael Josef, Schlag, Rudolf, Freier, Werner, Gaska, Tobias, Balser, Christina, Reiser, Marcel, Stauch, Martina, Wendtner, Clemens-Martin, Fischer, Kirsten, Stilgenbauer, Stephan, Eichhorst, Barbara, and Hallek, Michael

Published
2022
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26. Infections in patients with chronic lymphocytic leukemia treated with time limited targeted drug combinations.

Author

Langerbeins, Petra, Giza, Adam, Robrecht, Sandra, Cramer, Paula, von Tresckow, Julia, Al‐Sawaf, Othman, Fink, Anna Maria, Fürstenau, Moritz, Kater, Arnon P., van der Spek, Ellen, Niemann, Carsten Utoft, da Cunha‐Bang, Caspar, Tausch, Eugen, Schneider, Christof, Stilgenbauer, Stephan, Fischer, Kirsten, Hallek, Michael, and Eichhorst, Barbara

Published
2024
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27. Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Author

Jones, Jeffrey, Mato, Anthony, Coutre, Steven, Byrd, John C, Furman, Richard R, Hillmen, Peter, Osterborg, Anders, Tam, Constantine, Stilgenbauer, Stephan, Wierda, William G, Heerema, Nyla A, Eckert, Karl, Clow, Fong, Zhou, Cathy, Chu, Alvina D, James, Danelle F, and O'Brien, Susan M

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Cancer, Hematology, Lymphoma, Clinical Research, Rare Diseases, Adenine, Adult, Aftercare, Aged, Aged, 80 and over, Chromosome Deletion, Chromosomes, Human, Pair 17, Disease-Free Survival, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperidines, Pyrazoles, Pyrimidines, Recurrence, Smith-Magenis Syndrome, Survival Rate, 17p deletion, BTK inhibitor, chronic lymphocytic leukaemia, ibrutinib, Cardiorespiratory Medicine and Haematology, Immunology, Cardiovascular medicine and haematology
Abstract

Patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1-12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow-up of 28 months, overall response rate was 85% and estimated 30-month progression-free and overall survival rates were 57% [95% confidence interval (CI) 50-64] and 69% (95% CI 61-75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression-free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult-to-treat CLL/SLL populations.

Published
2018

28. Venetoclax Initiation in Chronic Lymphocytic Leukemia: International Insights and Innovative Approaches for Optimal Patient Care

Author

Anderson, Mary Ann, primary, Walewska, Renata, additional, Hackett, Fidelma, additional, Kater, Arnon P., additional, Montegaard, Josie, additional, O’Brien, Susan, additional, Seymour, John F., additional, Smith, Matthew, additional, Stilgenbauer, Stephan, additional, Whitechurch, Ashley, additional, and Brown, Jennifer R., additional

Published
2024
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29. IGLV3-21*01 is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling

Author

Maity, Palash C., Bilal, Mayas, Koning, Marvyn T., Young, Marc, van Bergen, Cornelis A. M., Renna, Valerio, Nicolò, Antonella, Datta, Moumita, Gentner-Göbel, Eva, Barendse, Rob S., Somers, Sebastiaan F., de Groen, Ruben A. L., Vermaat, Joost S. P., Steinbrecher, Daniela, Schneider, Christof, Tausch, Eugen, Bittolo, Tamara, Bomben, Riccardo, Mazzarello, Andrea Nicola, del Poeta, Giovanni, Kroes, Wilma G. M., van Wezel, J. Tom, Imkeller, Katharina, Busse, Christian E., Degano, Massimo, Bakchoul, Tamam, Schulz, Axel Ronald, Mei, Henrik, Ghia, Paolo, Kotta, Konstantia, Stamatopoulos, Kostas, Wardemann, Hedda, Zucchetto, Antonella, Chiorazzi, Nicholas, Gattei, Valter, Stilgenbauer, Stephan, Veelken, Hendrik, and Jumaa, Hassan

Published
2020

30. Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Author

Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee C., Sutton, Lesley-Ann, Baliakas, Panagiotis, Scarfò, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, Langlois de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Brazdilova, Kamila, Ritgen, Matthias, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova Francova, Hana, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon, Panovska, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagiotis, Costeas, Paul, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, Niemann, Carsten, Campo, Elias, Anagnostopoulos, Achilles, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane, Chiorazzi, Nicholas, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W., Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2021
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32. Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy

Author

Jewell, Roxanne C, Kipps, Thomas J, Dürig, Jan, Griskevicius, Laimonas, Stilgenbauer, Stephan, Smolej, Lukáš, Mayer, Jiří, Hess, Georg, Hernandez-Ilizaliturri, Francisco J, Padmanabhan-Iyer, Swaminathan, Fang, Lei, Goldstein, Nancy, Gorczyca, Michele, Gupta, Ira, Lisby, Steen, Wierda, William G, and Investigators, for the Hx-CD20-407 Study

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Hematology, Clinical Trials and Supportive Activities, Rare Diseases, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Chromosome Aberrations, Drug Administration Schedule, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Remission Induction, Treatment Outcome, Chemoimmunotherapy, chronic lymphocytic leukemia, ofatumumab, pharmacokinetics, Hx-CD20-407 Study Investigators, Clinical Sciences, Immunology, Cardiovascular medicine and haematology
Abstract

Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics.Trial registrationwww.clinicaltrials.gov (NCT00410163).

Published
2017

33. Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation

Author

Kharfan-Dabaja, Mohamed A, Kumar, Ambuj, Hamadani, Mehdi, Stilgenbauer, Stephan, Ghia, Paolo, Anasetti, Claudio, Dreger, Peter, Montserrat, Emili, Perales, Miguel-Angel, Alyea, Edwin P, Awan, Farrukh T, Ayala, Ernesto, Barrientos, Jacqueline C, Brown, Jennifer R, Castro, Januario E, Furman, Richard R, Gribben, John, Hill, Brian T, Mohty, Mohamad, Moreno, Carol, O'Brien, Susan, Pavletic, Steven Z, Pinilla-Ibarz, Javier, Reddy, Nishitha M, Sorror, Mohamed, Bredeson, Christopher, Carpenter, Paul, and Savani, Bipin N

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Cancer, Transplantation, Hematology, Rare Diseases, Clinical Research, Clinical Trials and Supportive Activities, Lymphoma, Antineoplastic Agents, Child, Child, Preschool, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Practice Guidelines as Topic, Salvage Therapy, Transplantation Conditioning, Transplantation, Homologous, Chronic lymphocytic leukemia, Allogeneic hematopoietic cell transplantation, BCR inhibitors, BCL-2 inhibitors, Clinical Sciences, Immunology, Cardiovascular medicine and haematology
Abstract

We sought to establish clinical practice recommendations to redefine the role of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with chronic lymphocytic leukemia (CLL) in an era of highly active targeted therapies. We performed a systematic review to identify prospective randomized controlled trials comparing allo-HCT against novel therapies for treatment of CLL at various disease stages. In the absence of such data, we invited physicians with expertise in allo-HCT and/or CLL to participate in developing these recommendations. We followed the Grading of Recommendations Assessment, Development and Evaluation methodology. For standard-risk CLL we recommend allo-HCT in the absence of response or if there is evidence of disease progression after B cell receptor (BCR) inhibitors. For high-risk CLL an allo-HCT is recommended after failing 2 lines of therapy and showing an objective response to BCR inhibitors or to a clinical trial. It is also recommended for patients who fail to show an objective response or progress after BCR inhibitors and receive BCL-2 inhibitors, regardless of whether an objective response is achieved. For Richter transformation, we recommend allo-HCT upon demonstration of an objective response to anthracycline-based chemotherapy. A reduced-intensity conditioning regimen is recommended whenever indicated. These recommendations highlight the rapidly changing treatment landscape of CLL. Newer therapies have disrupted prior paradigms, and allo-HCT is now relegated to later stages of relapsed or refractory CLL.

Published
2016

34. Bendamustine, followed by obinutuzumab and idelalisib in chronic lymphocytic leukemia (CLL2‐BCG): Final analysis of a multicenter, open‐label phase‐II‐trial.

Author

Cramer, Paula, von Tresckow, Julia, Fink, Anna‐Maria, Robrecht, Sandra, Giza, Adam, Tausch, Eugen, Müller, Lothar, Knauf, Wolfgang, Zingerle, Matthias, Al‐Sawaf, Othman, Langerbeins, Petra, Fischer, Kirsten, Kreuzer, Karl‐Anton, Kneba, Michael, Wendtner, Clemens‐Martin, Stilgenbauer, Stephan, Eichhorst, Barbara, and Hallek, Michael

Published
2024
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36. Safety and efficacy of different lenalidomide starting doses in patients with relapsed or refractory chronic lymphocytic leukemia: results of an international multicenter double-blinded randomized phase II trial*

Author

Wendtner, Clemens M, Hallek, Michael, Fraser, Graeme AM, Michallet, Anne-Sophie, Hillmen, Peter, Dürig, Jan, Kalaycio, Matt, Gribben, John G, Stilgenbauer, Stephan, Buhler, Andreas, Kipps, Thomas J, Purse, Brendan, Zhang, Jennie, De Bedout, Sabine, Mei, Jay, and Chanan-Khan, Asher

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Clinical Trials and Supportive Activities, Patient Safety, Hematology, Lymphoma, Rare Diseases, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Drug Resistance, Neoplasm, Female, Humans, Immunologic Factors, Kaplan-Meier Estimate, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Neoplasm Staging, Recurrence, Retreatment, Thalidomide, Treatment Outcome, Clinical trial, CLL, lenalidomide, phase II, Clinical Sciences, Immunology, Cardiovascular medicine and haematology
Abstract

The objective of this study was to evaluate the safety and efficacy of different lenalidomide starting doses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). CLL patients were randomized to receive lenalidomide at initial doses of 5, 10, or 15 mg/d (N = 103). Doses were escalated by 5 mg every 28-d up to a maximum of 25 mg/d; dose reductions in up to 5 mg decrements were permitted. The most common grade ≥3 adverse events (AEs) were neutropenia and thrombocytopenia. Ten patients died during therapy (four deaths considered as related to lenalidomide); 12 patients experienced second primary malignancies. The most common cause for treatment discontinuation was AEs. Overall response rates were similar across arms. Progression-free survival and overall survival rates were longer in patients who escalated treatment (to 15 or 20 mg/d) versus those who did not. Lower starting doses allowed subsequent dose escalation of lenalidomide while maintaining an acceptable tolerability profile in patients with relapsed/refractory CLL.

Published
2016

37. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia

Author

Oakes, Christopher C, Seifert, Marc, Assenov, Yassen, Gu, Lei, Przekopowitz, Martina, Ruppert, Amy S, Wang, Qi, Imbusch, Charles D, Serva, Andrius, Koser, Sandra D, Brocks, David, Lipka, Daniel B, Bogatyrova, Olga, Weichenhan, Dieter, Brors, Benedikt, Rassenti, Laura, Kipps, Thomas J, Mertens, Daniel, Zapatka, Marc, Lichter, Peter, Döhner, Hartmut, Küppers, Ralf, Zenz, Thorsten, Stilgenbauer, Stephan, Byrd, John C, and Plass, Christoph

Subjects
Hematology, Genetics, Human Genome, Rare Diseases, Cancer, Lymphoma, Adult, Aged, Aged, 80 and over, B-Lymphocytes, Binding Sites, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Leukemic, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Neoplasm Proteins, Phenotype, Promoter Regions, Genetic, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.

Published
2016

38. Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

Author

Al-Sawaf, Othman, primary, Ligtvoet, Rudy, additional, Robrecht, Sandra, additional, Stumpf, Janina, additional, Fink, Anna-Maria, additional, Tausch, Eugen, additional, Schneider, Christof, additional, Boettcher, Sebastian, additional, Mikusko, Martin, additional, Ritgen, Matthias, additional, Schetelig, Johannes, additional, von Tresckow, Julia, additional, Vehling-Kaiser, Ursula, additional, Gaska, Tobias, additional, Wendtner, Clemens Martin, additional, Chapuy, Bjoern, additional, Fischer, Kirsten, additional, Kreuzer, Karl-Anton, additional, Stilgenbauer, Stephan, additional, Staber, Philipp, additional, Niemann, Carsten, additional, Hallek, Michael, additional, and Eichhorst, Barbara, additional

Published
2023
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39. Relationship Between Venetoclax Exposure and Undetectable Minimal Residual Disease Rates in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia: A Pooled Analysis of Six Clinical Studies

Author

Gopalakrishnan, Sathej, primary, Menon, Rajeev, additional, Suleiman, Ahmed A., additional, Kater, Arnon P., additional, Stilgenbauer, Stephan, additional, Seymour, John F., additional, Chyla, Brenda, additional, Lu, Tong, additional, Young Kim, Su, additional, Roberts, Andrew W., additional, Woyach, Jennifer A., additional, Mensing, Sven, additional, and Salem, Ahmed Hamed, additional

Published
2023
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40. Acquired BTK mutations associated with resistance to noncovalent BTK inhibitors

Author

Qi, Jialei, primary, Endres, Sascha, additional, Yosifov, Deyan Yordanov, additional, Tausch, Eugen, additional, Dheenadayalan, Rashmi Priyadharshini, additional, Gao, Xiang, additional, Müller, Annika, additional, Schneider, Christof, additional, Mertens, Daniel, additional, Gierschik, Peter, additional, Wist, Martin, additional, Jebaraj, Billy Michael Chelliah, additional, and Stilgenbauer, Stephan, additional

Published
2023
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42. Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia

Author

Bloehdorn, Johannes, Braun, Andrejs, Taylor-Weiner, Amaro, Jebaraj, Billy Michael Chelliah, Robrecht, Sandra, Krzykalla, Julia, Pan, Heng, Giza, Adam, Akylzhanova, Gulnara, Holzmann, Karlheinz, Scheffold, Annika, Johnston, Harvey E., Yeh, Ru-Fang, Klymenko, Tetyana, Tausch, Eugen, Eichhorst, Barbara, Bullinger, Lars, Fischer, Kirsten, Weisser, Martin, Robak, Tadeusz, Schneider, Christof, Gribben, John, Dahal, Lekh N., Carter, Mathew J., Elemento, Olivier, Landau, Dan A., Neuberg, Donna S., Cragg, Mark S., Benner, Axel, Hallek, Michael, Wu, Catherine J., Döhner, Hartmut, Stilgenbauer, Stephan, and Mertens, Daniel

Published
2021
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45. Final results of EFC6663: A multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia

Author

Lanasa, Mark C, Andritsos, Leslie, Brown, Jennifer R, Gabrilove, Janice, Caligaris-Cappio, Federico, Ghia, Paolo, Larson, Richard A, Kipps, Thomas J, Leblond, Veronique, Milligan, Donald W, Janssens, Ann, Johnson, Amy J, Heerema, Nyla A, Bühler, Andreas, Stilgenbauer, Stephan, Devin, Jeanne, Hallek, Michael, Byrd, John C, and Grever, Michael R

Subjects
Rare Diseases, Cancer, Clinical Trials and Supportive Activities, Patient Safety, Lymphoma, Hematology, Clinical Research, Pediatric, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Female, Flavonoids, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperidines, Recurrence, Survival Analysis, Treatment Failure, Vidarabine, Chronic lymphocytic leukemia, Flavopiridol, Therapy, Tumor lysis syndrome, Cyclin dependent kinase inhibitor, Clinical Sciences, Immunology
Abstract

Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results. Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration. One hundred and sixty five patients were enrolled and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months, respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common. Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures.

Published
2015

46. IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia

Author

Scheffold, Annika, Jebaraj, Billy Michael Chelliah, Tausch, Eugen, Bloehdorn, Johannes, Ghia, Paolo, Yahiaoui, Anella, Dolnik, Anna, Blätte, Tamara Jacqueline, Bullinger, Lars, Dheenadayalan, Rashmi Priyadharshini, Li, Li, Schneider, Christof, Chen, Shih-Shih, Chiorazzi, Nicholas, Dietrich, Sascha, Seiffert, Martina, Tannheimer, Stacey, Döhner, Hartmut, Mertens, Daniel, and Stilgenbauer, Stephan

Published
2019
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49. Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma

Author

Thurner, Lorenz, Preuss, Klaus-Dieter, Bewarder, Moritz, Kemele, Maria, Fadle, Natalie, Regitz, Evi, Altmeyer, Sarah, Schormann, Claudia, Poeschel, Viola, Ziepert, Marita, Walter, Silke, Roth, Patrick, Weller, Michael, Szczepanowski, Monika, Klapper, Wolfram, Monoranu, Camelia, Rosenwald, Andreas, Möller, Peter, Hartmann, Sylvia, Hansmann, Martin-Leo, Mackensen, Andreas, Schäfer, Henning, Schorb, Elisabeth, Illerhaus, Gerald, Buslei, Rolf, Bohle, Rainer Maria, Stilgenbauer, Stephan, Kim, Yoo-Jin, and Pfreundschuh, Michael

Published
2018
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50. 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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