2,369 results on '"Brown, Jennifer R."'
Search Results
2. A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma
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Merryman, Reid W., Redd, Robert A., Freedman, Arnold S., Ahn, Inhye E., Brown, Jennifer R., Crombie, Jennifer L., Davids, Matthew S., Fisher, David C., Jacobsen, Eric D., Kim, Austin I., LaCasce, Ann S., Ng, Samuel, Odejide, Oreofe O., Parry, Erin M., Isufi, Iris, Kline, Justin, Cohen, Jonathon B., Mehta-Shah, Neha, Bartlett, Nancy L., Mei, Matthew, Kuntz, Thomas M., Wolff, Jacquelyn, Rodig, Scott J., Armand, Philippe, and Jacobson, Caron A.
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- 2024
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3. METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL
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Wu, Yiming, Jin, Meiling, Fernandez, Mike, Hart, Kevyn L, Liao, Aijun, Ge, Xinzhou, Fernandes, Stacey M, McDonald, Tinisha, Chen, Zhenhua, Röth, Daniel, Ghoda, Lucy Y, Marcucci, Guido, Kalkum, Markus, Pillai, Raju K, Danilov, Alexey V, Li, Jingyi Jessica, Chen, Jianjun, Brown, Jennifer R, Rosen, Steven T, Siddiqi, Tanya, and Wang, Lili
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Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Cancer ,Genetics ,Hematology ,Rare Diseases ,Lymphoma ,Aetiology ,2.1 Biological and endogenous factors ,Humans ,Alternative Splicing ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Proteomics ,Methyltransferases ,RNA Splicing Factors ,RNA ,Messenger - Abstract
RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL.SignificanceMETTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller, p. 176. This article is highlighted in the In This Issue feature, p. 171.
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- 2023
4. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial
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Hillmen, Peter, Eichhorst, Barbara, Brown, Jennifer R, Lamanna, Nicole, O'Brien, Susan M, Tam, Constantine S, Qiu, Lugui, Kazmierczak, Maciej, Zhou, Keshu, Šimkovič, Martin, Mayer, Jiří, Gillespie-Twardy, Amanda, Shadman, Mazyar, Ferrajoli, Alessandra, Ganly, Peter S, Weinkove, Robert, Grosicki, Sebastian, Mital, Andrzej, Robak, Tadeusz, Österborg, Anders, Yimer, Habte A, Salmi, Tommi, Ji, Meng, Yecies, Jessica, Idoine, Adam, Wu, Kenneth, Huang, Jane, and Jurczak, Wojciech
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cardiovascular ,Hematology ,Clinical Research ,Lymphoma ,Cancer ,Rare Diseases ,Clinical Trials and Supportive Activities ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Atrial Fibrillation ,Adenine ,Lymphoma ,B-Cell ,Protein Kinase Inhibitors ,Clinical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposeZanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities.Patients and methodsALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled.ResultsBetween November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib.ConclusionZanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.
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- 2023
5. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome
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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
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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.
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- 2023
6. Molecular map of chronic lymphocytic leukemia and its impact on outcome
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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
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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.
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- 2022
7. Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial
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Bannerji, Rajat, Arnason, Jon E, Advani, Ranjana H, Brown, Jennifer R, Allan, John N, Ansell, Stephen M, Barnes, Jeffrey A, O'Brien, Susan M, Chávez, Julio C, Duell, Johannes, Rosenwald, Andreas, Crombie, Jennifer L, Ufkin, Melanie, Li, Jingjin, Zhu, Min, Ambati, Srikanth R, Chaudhry, Aafia, Lowy, Israel, and Topp, Max S
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Cancer ,Rare Diseases ,Clinical Trials and Supportive Activities ,Lymphoma ,Lung ,Hematology ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Aged ,Antibodies ,Bispecific ,Antigens ,CD20 ,Antineoplastic Agents ,Cytokine Release Syndrome ,Female ,Humans ,Lymphoma ,Follicular ,Lymphoma ,Large B-Cell ,Diffuse ,Lymphoma ,Non-Hodgkin ,Male ,Middle Aged ,Cardiorespiratory Medicine and Haematology ,Cardiovascular medicine and haematology - Abstract
BackgroundOdronextamab is a hinge-stabilised, fully human IgG4-based CD20 × CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.MethodsThis single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951.FindingsFrom Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5] previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 [82%]) and not Hispanic or Latino (132 [91%]). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 [25%]), lymphopenia (28 [19%]), hypophosphataemia (27 [19%]), neutropenia (27 [19%]), and thrombocytopenia (20 [14%]). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 [28%]), pyrexia (11 [8%]), pneumonia (nine [6%]), and infusion-related reaction (six [4%]). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30).InterpretationOdronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials.FundingRegeneron Pharmaceuticals.
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- 2022
8. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib
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Moslehi, Javid J., Furman, Richard R., Tam, Constantine S., Salem, Joe-Elie, Flowers, Christopher R., Cohen, Aileen, Zhang, Meng, Zhang, Jun, Chen, Lipeng, Ma, Han, and Brown, Jennifer R.
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- 2024
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9. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL
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Woyach, Jennifer A., Perez Burbano, Gabriela, Ruppert, Amy S., Miller, Cecelia, Heerema, Nyla A., Zhao, Weiqiang, Wall, Anna, Ding, Wei, Bartlett, Nancy L., Brander, Danielle M., Barr, Paul M., Rogers, Kerry A., Parikh, Sameer A., Stephens, Deborah M., Brown, Jennifer R., Lozanski, Gerard, Blachly, James, Nattam, Sreenivasa, Larson, Richard A., Erba, Harry, Litzow, Mark, Luger, Selina, Owen, Carolyn, Kuzma, Charles, Abramson, Jeremy S., Little, Richard F., Dinner, Shira, Stone, Richard M., Uy, Geoffrey, Stock, Wendy, Mandrekar, Sumithra J., and Byrd, John C.
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- 2024
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10. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
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Glaviano, Antonino, Foo, Aaron S. C., Lam, Hiu Y., Yap, Kenneth C. H., Jacot, William, Jones, Robert H., Eng, Huiyan, Nair, Madhumathy G., Makvandi, Pooyan, Geoerger, Birgit, Kulke, Matthew H., Baird, Richard D., Prabhu, Jyothi S., Carbone, Daniela, Pecoraro, Camilla, Teh, Daniel B. L., Sethi, Gautam, Cavalieri, Vincenzo, Lin, Kevin H., Javidi-Sharifi, Nathalie R., Toska, Eneda, Davids, Matthew S., Brown, Jennifer R., Diana, Patrizia, Stebbing, Justin, Fruman, David A., and Kumar, Alan P.
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- 2023
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11. Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors
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Gadi, Deepti, Martindale, Stephen P., Chiu, Pui Yan, Khalsa, Jasneet, Chen, Pei-Hsuan, Fernandes, Stacey M., Wang, Zixu, Tyekucheva, Svitlana, Machado, John-Hanson, Fisher, David C., Armand, Philippe, Davids, Matthew S., Rodig, Scott, Sherry, Barbara, and Brown, Jennifer R.
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- 2023
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12. Recognizing Unmet Need in the Era of Targeted Therapy for CLL/SLL: “What's Past Is Prologue” (Shakespeare)CLL/SLL Unmet Need
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Mato, Anthony R, Davids, Matthew S, Sharman, Jeff, Roeker, Lindsey E, Kay, Neil, Kater, Arnon P, Rogers, Kerry, Thompson, Meghan C, Rhodes, Joanna, Goy, Andre, Skarbnik, Alan, Schuster, Stephen J, Tam, Constantine S, Eyre, Toby A, O'Brien, Susan, Nabhan, Chadi, Lamanna, Nicole, Sun, Clare, Shadman, Mazyar, Pagel, John M, Ujjani, Chaitra, Brander, Danielle, Coombs, Catherine C, Jain, Nitin, Cheah, Chan Y, Brown, Jennifer R, Seymour, John F, and Woyach, Jennifer A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Research ,Hematology ,Lymphoma ,Cancer ,Humans ,Immunotherapy ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Phosphatidylinositol 3-Kinases ,Protein Kinase Inhibitors ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.
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- 2022
13. Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
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Kaufman, Matthew, Yan, Xiao-Jie, Li, Wentian, Ghia, Emanuela M, Langerak, Anton W, Rassenti, Laura Z, Belessi, Chrysoula, Kay, Neil E, Davi, Frederic, Byrd, John C, Pospisilova, Sarka, Brown, Jennifer R, Catherwood, Mark, Davis, Zadie, Oscier, David, Montillo, Marco, Trentin, Livio, Rosenquist, Richard, Ghia, Paolo, Barrientos, Jacqueline C, Kolitz, Jonathan E, Allen, Steven L, R., Kanti, Stamatopoulos, Kostas, Kipps, Thomas J, Neuberg, Donna, and Chiorazzi, Nicholas
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Lymphoma ,Cancer ,Hematology ,Lymphatic Research ,Rare Diseases ,CLL ,chronic lymphocytic leukemia ,immunoglobulin variable domain ,prognosis ,somatic mutations ,Oncology and Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, "(S+Rc) to Rnc IGHV mutation ratio". When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
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- 2022
14. A phase 1b study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia
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Ryan, Christine E., Brander, Danielle M., Barr, Paul M., Tyekucheva, Svitlana, Hackett, Liam R., Collins, Mary C., Fernandes, Stacey M., Ren, Yue, Zhou, Yinglu, McDonough, Mikaela M., Walker, Heather A., McEwan, Monica R., Abramson, Jeremy S., Jacobsen, Eric D., LaCasce, Ann S., Fisher, David C., Brown, Jennifer R., and Davids, Matthew S.
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- 2023
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15. Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL
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Ahn, Inhye E., Brander, Danielle M., Ren, Yue, Zhou, Yinglu, Tyekucheva, Svitlana, Walker, Heather A., Black, Robert, Montegaard, Josie, Alencar, Alvaro, Shune, Leyla, Omaira, Mohammad, Jacobson, Caron A., Armand, Philippe, Ng, Samuel Y., Crombie, Jennifer, Fisher, David C., LaCasce, Ann S., Arnason, Jon, Hochberg, Ephraim P., Takvorian, Ronald W., Abramson, Jeremy S., Brown, Jennifer R., and Davids, Matthew S.
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- 2024
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16. Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: the phase 1b BRUIN trial
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Roeker, Lindsey E., Woyach, Jennifer A., Cheah, Chan Y., Coombs, Catherine C., Shah, Nirav N., Wierda, William G., Patel, Manish R., Lamanna, Nicole, Tsai, Donald E., Nair, Binoj, Wang, Chunxiao, Zhao, Xiang, Liu, Dan, Radtke, David, Chapman, Sonya, Marella, Narasimha, McNeely, Samuel C., and Brown, Jennifer R.
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- 2024
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17. Activation of Notch and Myc signaling via B cell-restricted depletion of Dnmt3a generates a consistent murine model of chronic lymphocytic leukemia
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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
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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.
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- 2021
18. Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History
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Penter, Livius, Gohil, Satyen H, Lareau, Caleb, Ludwig, Leif S, Parry, Erin M, Huang, Teddy, Li, Shuqiang, Zhang, Wandi, Livitz, Dimitri, Leshchiner, Ignaty, Parida, Laxmi, Getz, Gad, Rassenti, Laura Z, Kipps, Thomas J, Brown, Jennifer R, Davids, Matthew S, Neuberg, Donna S, Livak, Kenneth J, Sankaran, Vijay G, and Wu, Catherine J
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Clinical Research ,Hematology ,Human Genome ,Cancer ,Lymphoma ,Rare Diseases ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Chromatin ,Clonal Evolution ,Clone Cells ,DNA Copy Number Variations ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Mutation ,Oncology and Carcinogenesis - Abstract
While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure, indicating clonal persistence, but dramatic changes following tight bottlenecks, including disease transformation and relapse posttherapy, paralleled by acquisition of copy-number variants and changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into nongenetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics.SignificanceSingle-cell multi-omic profiling of CLL reveals the utility of somatic mtDNA mutations as in vivo barcodes, which mark subclones that can evolve over time along with changes in accessible chromatin and gene expression profiles to capture dynamics of disease evolution. See related commentary by Hilton and Scott, p. 2965. This article is highlighted in the In This Issue feature, p. 2945.
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- 2021
19. Broadening Dissemination Genres to Share Hidden Insight via Design Cases in Engineering Education Research
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Svihla, Vanessa, primary, Godwin, Lizandra C., additional, Raihanian Mashhadi, Ardeshir, additional, and Brown, Jennifer R., additional
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- 2023
- Full Text
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20. Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy
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Kretzmer, Helene, Biran, Anat, Purroy, Noelia, Lemvigh, Camilla K, Clement, Kendell, Gruber, Michaela, Gu, Hongcang, Rassenti, Laura, Mohammad, Arman W, Lesnick, Connie, Slager, Susan L, Braggio, Esteban, Shanafelt, Tait D, Kay, Neil E, Fernandes, Stacey M, Brown, Jennifer R, Wang, Lili, Li, Shuqiang, Livak, Kenneth J, Neuberg, Donna S, Klages, Sven, Timmermann, Bernd, Kipps, Thomas J, Campo, Elias, Gnirke, Andreas, Wu, Catherine J, and Meissner, Alexander
- Subjects
Hematology ,Genetics ,Lymphoma ,Human Genome ,Rare Diseases ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Generic health relevance ,CpG Islands ,DNA Methylation ,Disease Progression ,Epigenome ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Oncology and Carcinogenesis - Abstract
Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in pre-neoplastic monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significantly differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and post-therapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state, and a distinct expression profile together with MBL cells compared to normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically-driven growth dynamics and together with its persistent presence suggests a central role in the normal-to-cancer transition.
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- 2021
21. Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice
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O’Brien, Susan M, Brown, Jennifer R, Byrd, John C, Furman, Richard R, Ghia, Paolo, Sharman, Jeff P, and Wierda, William G
- Subjects
Cancer ,Clinical Trials and Supportive Activities ,Hematology ,Rare Diseases ,Lymphoma ,Orphan Drug ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,acalabrutinib ,adverse events ,Bruton tyrosine kinase inhibitor ,chronic lymphocytic leukemia ,ibrutinib ,Oncology and Carcinogenesis - Abstract
Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%-26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%-51% of patients, and is mainly grade 1-2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.
- Published
- 2021
22. Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation
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Merryman, Reid W., Redd, Robert A., Taranto, Eleanor, Ahmed, Gulrayz, Jeter, Erin, McHugh, Kristin M., Brown, Jennifer R., Crombie, Jennifer L., Davids, Matthew S., Fisher, David C., Freedman, Arnold S., Jacobsen, Eric, Jacobson, Caron A., Kim, Austin I., LaCasce, Ann S., Ng, Samuel Y., Odejide, Oreofe O., Parry, Erin M., Jacene, Heather, Park, Hyesun, Dahi, Parastoo B., Nieto, Yago, Joyce, Robin M., Chen, Yi-Bin, Shipp, Margaret A., Herrera, Alex F., and Armand, Philippe
- Published
- 2023
- Full Text
- View/download PDF
23. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial
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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
- Full Text
- View/download PDF
24. Genetic events associated with venetoclax resistance in CLL identified by whole-exome sequencing of patient samples
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Khalsa, Jasneet Kaur, Cha, Justin, Utro, Filippo, Naeem, Aishath, Murali, Ishwarya, Kuang, Yanan, Vasquez, Kevin, Li, Liang, Tyekucheva, Svitlana, Fernandes, Stacey M., Veronese, Lauren, Guieze, Romain, Sasi, Binu Kandathilparambil, Wang, Zixu, Machado, John-Hanson, Bai, Harrison, Alasfour, Maryam, Rhrissorrakrai, Kahn, Levovitz, Chaya, Danysh, Brian P., Slowik, Kara, Jacobs, Raquel A., Davids, Matthew S., Paweletz, Cloud P., Leshchiner, Ignaty, Parida, Laxmi, Getz, Gad, and Brown, Jennifer R.
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- 2023
- Full Text
- View/download PDF
25. Treatment Discontinuation Patterns for Patients With Chronic Lymphocytic Leukemia in Real-World Settings: Results From a Multi-Center International Study
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Shadman, Mazyar, Manzoor, Beenish S., Sail, Kavita, Tuncer, Hande H., Allan, John N., Ujjani, Chaitra, Emechebe, Nnadozie, Kamalakar, Rajesh, Coombs, Catherine C., Leslie, Lori, Barr, Paul M., Brown, Jennifer R., Eyre, Toby A., Rampotas, Alexandros, Schuh, Anna, Lamanna, Nicole, Skarbnik, Alan, Roeker, Lindsey E., Bannerji, Rajat, Eichhorst, Barbara, Fleury, Isabelle, Davids, Matthew S., Alhasani, Hasan, Jiang, Dingfeng, Hill, Brian T., Schuster, Stephen J., Brander, Danielle M., Pivneva, Irina, Burne, Rebecca, Guerin, Annie, and Mato, Anthony R.
- Published
- 2023
- Full Text
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26. Risk factors for grade 3/4 transaminase elevation in patients with chronic lymphocytic leukemia treated with idelalisib
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Brown, Jennifer R, Zelenetz, Andrew, Furman, Richard, Lamanna, Nicole, Mato, Anthony, Montillo, Marco, O’Brien, Susan, Dubowy, Ronald, Gu, Lin, Munugalavadla, Veerendra, Robak, Tadeusz, and Hillmen, Peter
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Purines ,Quinazolinones ,Risk Factors ,Transaminases ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology ,Clinical sciences ,Oncology and carcinogenesis - Published
- 2020
27. Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance
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Naeem, Aishath, Utro, Filippo, Wang, Qing, Cha, Justin, Vihinen, Mauno, Martindale, Stephen, Zhou, Yinglu, Ren, Yue, Tyekucheva, Svitlana, Kim, Annette S., Fernandes, Stacey M., Saksena, Gordon, Rhrissorrakrai, Kahn, Levovitz, Chaya, Danysh, Brian P., Slowik, Kara, Jacobs, Raquel A., Davids, Matthew S., Lederer, James A., Zain, Rula, Smith, C. I. Edvard, Leshchiner, Ignaty, Parida, Laxmi, Getz, Gad, and Brown, Jennifer R.
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- 2023
- Full Text
- View/download PDF
28. Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to the graft-versus-leukemia effect
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Bachireddy, Pavan, Ennis, Christina, Nguyen, Vinhkhang N, Gohil, Satyen H, Clement, Kendell, Shukla, Sachet A, Forman, Juliet, Barkas, Nikolaos, Freeman, Samuel, Bavli, Natalie, Elagina, Liudmila, Leshchiner, Ignaty, Mohammad, Arman W, Mathewson, Nathan D, Keskin, Derin B, Rassenti, Laura Z, Kipps, Thomas J, Brown, Jennifer R, Getz, Gad, Ho, Vincent T, Gnirke, Andreas, Neuberg, Donna, Soiffer, Robert J, Ritz, Jerome, Alyea, Edwin P, Kharchenko, Peter V, and Wu, Catherine J
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Stem Cell Research ,Hematology ,Rare Diseases ,Cancer ,Stem Cell Research - Nonembryonic - Human ,Lymphoma ,Transplantation ,Genetics ,Stem Cell Research - Nonembryonic - Non-Human ,Graft vs Host Disease ,Graft vs Leukemia Effect ,HLA Antigens ,Hematopoietic Stem Cell Transplantation ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Transplantation ,Homologous ,Biological Sciences ,Medical and Health Sciences - Abstract
Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.
- Published
- 2020
29. Final analysis from RESONATE: Up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma
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Munir, Talha, Brown, Jennifer R, O'Brien, Susan, Barrientos, Jacqueline C, Barr, Paul M, Reddy, Nishitha M, Coutre, Steven, Tam, Constantine S, Mulligan, Stephen P, Jaeger, Ulrich, Kipps, Thomas J, Moreno, Carol, Montillo, Marco, Burger, Jan A, Byrd, John C, Hillmen, Peter, Dai, Sandra, Szoke, Anita, Dean, James P, and Woyach, Jennifer A
- Subjects
Lymphoma ,Hematology ,Rare Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adenine ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Agents ,Immunological ,Cardiovascular Diseases ,Female ,Follow-Up Studies ,Hematologic Diseases ,Humans ,Infections ,Kaplan-Meier Estimate ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Piperidines ,Progression-Free Survival ,Protein Kinase Inhibitors ,Pyrazoles ,Pyrimidines ,Remission Induction ,Risk ,Salvage Therapy ,Treatment Outcome ,Cardiorespiratory Medicine and Haematology ,Immunology - Abstract
Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).
- Published
- 2019
30. Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kβ to BCR signalosome while reducing PDK1 in post-therapy CLL cells
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Mamidi, Murali K., Mahmud, Hasan, Maiti, Guru P., Mendez, Mariana T., Fernandes, Stacey M., Vesely, Sara K., Holter-Chakrabarty, Jennifer, Brown, Jennifer R., and Ghosh, Asish K.
- Published
- 2022
- Full Text
- View/download PDF
31. Fixed-Duration Pirtobrutinib plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: Phase 1b BRUIN Trial
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Roeker, Lindsey Elizabeth, primary, Woyach, Jennifer A., additional, Cheah, Chan Yoon Y, additional, Coombs, Catherine C., additional, Shah, Nirav N., additional, Wierda, William G., additional, Patel, Manish R., additional, Lamanna, Nicole, additional, Tsai, Donald E, additional, Nair, Binoj Chandrasekharan, additional, Wang, Chunxiao, additional, Zhao, Xiang, additional, Liu, Dan, additional, Radtke, David, additional, Chapman, Sonya, additional, Marella, Narasimha, additional, McNeely, Samuel C, additional, and Brown, Jennifer R., additional
- Published
- 2024
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- View/download PDF
32. A phase II study of induction followed by intermittent duvelisib dosing in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
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Shouse, Geoffrey, primary, Chen, Lu, additional, Siddiqi, Tanya, additional, Muir, Alex, additional, Brown, Jennifer R., additional, Spurgeon, Stephen E., additional, and Danilov, Alexey V., additional
- Published
- 2024
- Full Text
- View/download PDF
33. Comparative efficacy of Bruton tyrosine kinase inhibitors in the treatment of relapsed/refractory chronic lymphocytic leukemia: A network meta-analysis (NMA).
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Shadman, Mazyar, primary, Brown, Jennifer R., additional, Mohseninejad, Leyla, additional, Yang, Keri, additional, Burnett, Heather, additional, Neupane, Binod, additional, Williams, Rhys, additional, Lamanna, Nicole, additional, O'Brien, Susan M., additional, Tedeschi, Alessandra, additional, and Tam, Constantine S., additional
- Published
- 2024
- Full Text
- View/download PDF
34. Evaluating zanubrutinib for the treatment of adults with chronic lymphocytic leukemia or small lymphocytic lymphoma
- Author
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Javidi-Sharifi, Nathalie, primary and Brown, Jennifer R., additional
- Published
- 2024
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35. Clinical Risks for Chronic Lymphocytic Leukemia
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Brown, Jennifer R., primary
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- 2024
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36. Growth dynamics in naturally progressing chronic lymphocytic leukaemia
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Gruber, Michaela, Bozic, Ivana, Leshchiner, Ignaty, Livitz, Dimitri, Stevenson, Kristen, Rassenti, Laura, Rosebrock, Daniel, Taylor-Weiner, Amaro, Olive, Oriol, Goyetche, Reaha, Fernandes, Stacey M, Sun, Jing, Stewart, Chip, Wong, Alicia, Cibulskis, Carrie, Zhang, Wandi, Reiter, Johannes G, Gerold, Jeffrey M, Gribben, John G, Rai, Kanti R, Keating, Michael J, Brown, Jennifer R, Neuberg, Donna, Kipps, Thomas J, Nowak, Martin A, Getz, Gad, and Wu, Catherine J
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Clinical Research ,Rare Diseases ,Hematology ,Cancer ,Genetics ,Lymphoma ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Cell Proliferation ,Clone Cells ,Cohort Studies ,Disease Progression ,Evolution ,Molecular ,Female ,High-Throughput Nucleotide Sequencing ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Neoplasm Recurrence ,Local ,Recurrence ,Reproducibility of Results ,General Science & Technology - Abstract
How the genomic features of a patient's cancer relate to individual disease kinetics remains poorly understood. Here we used the indolent growth dynamics of chronic lymphocytic leukaemia (CLL) to analyse the growth rates and corresponding genomic patterns of leukaemia cells from 107 patients with CLL, spanning decades-long disease courses. We found that CLL commonly demonstrates not only exponential expansion but also logistic growth, which is sigmoidal and reaches a certain steady-state level. Each growth pattern was associated with marked differences in genetic composition, the pace of disease progression and the extent of clonal evolution. In a subset of patients, whose serial samples underwent next-generation sequencing, we found that dynamic changes in the disease course of CLL were shaped by the genetic events that were already present in the early slow-growing stages. Finally, by analysing the growth rates of subclones compared with their parental clones, we quantified the growth advantage conferred by putative CLL drivers in vivo.
- Published
- 2019
37. Outcomes with ibrutinib by line of therapy and post‐ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis
- Author
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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
38. Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia
- Author
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Lampson, Benjamin L, Kim, Haesook T, Davids, Matthew S, Abramson, Jeremy S, Freedman, Arnold S, Jacobson, Caron A, Armand, Philippe A, Joyce, Robin M, Arnason, Jon E, Rassenti, Laura Z, Kipps, Thomas J, Fein, Joshua, Fernandes, Stacey M, Hanna, John R, Fisher, David C, and Brown, Jennifer R
- Subjects
Hematology ,Lymphoma ,Clinical Research ,Rare Diseases ,Clinical Trials and Supportive Activities ,Patient Safety ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Aged ,Aged ,80 and over ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,Female ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Male ,Middle Aged ,Purines ,Quinazolinones ,Safety-Based Drug Withdrawals ,Survival Analysis ,Treatment Outcome - Abstract
PI3 kinase (PI3K) activity is critical for survival of neoplastic B cells in patients with chronic lymphocytic leukemia (CLL). Blockade of PI3K signaling with idelalisib is effective for the treatment of relapsed CLL in combination with the anti-CD20 antibody ofatumumab. In this single-arm, open-label, nonrandomized phase 2 study, we investigated the efficacy and safety of idelalisib with ofatumumab in 27 patients with treatment-naïve CLL in need of therapy. Patients were planned to receive idelalisib for 2 monthly cycles, then idelalisib and ofatumumab for 6 cycles, followed by idelalisib indefinitely. The study was closed early and all patients ceased therapy when an increased rate of death as a result of infection was observed on other first-line idelalisib trials. Median time on therapy was 8.1 months, and median duration of follow-up was 39.7 months. We previously reported high rates of hepatotoxicity in a smaller cohort of patients in this trial; toxicities necessitated therapy discontinuation in 15 patients after a median of 7.7 months. The most frequent grade ≥3 adverse events were transaminitis (52% of patients), neutropenia (33%), and colitis/diarrhea (15%). The best overall response rate (ORR) was 88.9%, including 1 complete response. Median progression-free survival (PFS) was 23 months (95% confidence interval [CI], 18-36 months); 11 patients have not yet required second-line therapy. Idelalisib and ofatumumab demonstrated an unacceptable safety profile in the first-line setting, which resulted in a short PFS despite a high ORR. Future development of PI3K inhibitors for use in treatment-naïve CLL will require novel approaches to mitigate toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02135133.
- Published
- 2019
39. Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis
- Author
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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
40. Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- Author
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Barrientos, Jacqueline C, O’Brien, Susan, Brown, Jennifer R, Kay, Neil E, Reddy, Nishitha M, Coutre, Steven, Tam, Constantine, Mulligan, Stephen, Jaeger, Ulrich, Devereux, Stephen, Pocock, Christopher, Robak, Tadeusz, Schuster, Stephen J, Schuh, Anna, Gill, Devinder, Bloor, Adrian, Dearden, Claire, Moreno, Carol, Cull, Gavin, Hamblin, Mike, Jones, Jeffrey A, Eckert, Karl, Solman, Isabelle G, Suzuki, Samuel, Hsu, Emily, James, Danelle F, Byrd, John C, and Hillmen, Peter
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Lymphoma ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Clinical Research ,Hematology ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers ,Erythrocyte Indices ,Female ,Follow-Up Studies ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Leukocyte Count ,Male ,Patient Acceptance of Health Care ,Patient Reported Outcome Measures ,Quality of Life ,Recurrence ,Symptom Assessment ,Treatment Outcome ,Bruton's tyrosine kinase ,Disease-related symptoms ,Fatigue ,Quality of life ,Relapsed/refractory CLL/SLL ,Clinical Sciences ,Cardiovascular medicine and haematology ,Oncology and carcinogenesis - Abstract
BackgroundIbrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).Patients and methodsMeasures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization.ResultsWith up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at ≤6 months vs. 5% at 12-18 months). With ibrutinib, grade ≥ 3 hypertension occurred in 6%, grade ≥ 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients.ConclusionIbrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.
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- 2018
41. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial
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Tam, Constantine S, Brown, Jennifer R, Kahl, Brad S, Ghia, Paolo, Giannopoulos, Krzysztof, Jurczak, Wojciech, Šimkovič, Martin, Shadman, Mazyar, Österborg, Anders, Laurenti, Luca, Walker, Patricia, Opat, Stephen, Chan, Henry, Ciepluch, Hanna, Greil, Richard, Tani, Monica, Trněný, Marek, Brander, Danielle M, Flinn, Ian W, Grosicki, Sebastian, Verner, Emma, Tedeschi, Alessandra, Li, Jianyong, Tian, Tian, Zhou, Lei, Marimpietri, Carol, Paik, Jason C, Cohen, Aileen, Huang, Jane, Robak, Tadeusz, and Hillmen, Peter
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- 2022
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42. A T cell inflammatory phenotype is associated with autoimmune toxicity of the PI3K inhibitor duvelisib in chronic lymphocytic leukemia
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Gadi, Deepti, Griffith, Alec, Tyekucheva, Svitlana, Wang, Zixu, Rai, Vanessa, Vartanov, Alexander, Thrash, Emily, Fernandes, Stacey M., Lehmberg, Timothy Z., Lee, Brandon, Martindale, Stephen P., Machado, John-Hanson, Odejide, Oreofe, Armand, Philippe, Fisher, David C., Arnason, Jon, Davids, Matthew S., Lederer, James A., and Brown, Jennifer R.
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- 2022
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43. Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in mature B-cell malignancies
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Furman, Richard R., Byrd, John C., Owen, Roger G., O’Brien, Susan M., Brown, Jennifer R., Hillmen, Peter, Stephens, Deborah M., Chernyukhin, Nataliya, Lezhava, Tamara, Hamdy, Ahmed M., Izumi, Raquel, Patel, Priti, Baek, Marshall, Christian, Beth, Dyer, Martin J. S., Streetly, Matthew J., Sun, Clare, Rule, Simon, Wang, Michael, Ghia, Paolo, Jurczak, Wojciech, Pagel, John M., and Sharman, Jeff P.
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- 2021
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44. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations
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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
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- 2021
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45. PI3K inhibitors are finally coming of age
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Vanhaesebroeck, Bart, Perry, Matthew W. D., Brown, Jennifer R., André, Fabrice, and Okkenhaug, Klaus
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- 2021
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46. Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202
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Ruppert, Amy S., Booth, Allison M., Ding, Wei, Bartlett, Nancy L., Brander, Danielle M., Coutre, Steven, Brown, Jennifer R., Nattam, Sreenivasa, Larson, Richard A., Erba, Harry, Litzow, Mark, Owen, Carolyn, Kuzma, Charles S., Abramson, Jeremy S., Little, Richard F., Smith, Scott E., Stone, Richard M., Byrd, John C., Mandrekar, Sumithra J., and Woyach, Jennifer A.
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- 2021
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47. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials
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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
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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).
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- 2017
48. Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1–2 study
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Eyre, Toby A, Schuh, Anna, Wierda, William G, Brown, Jennifer R, Ghia, Paolo, Pagel, John M, Furman, Richard R, Cheung, Jean, Hamdy, Ahmed, Izumi, Raquel, Patel, Priti, Wang, Min Hui, Xu, Yan, Byrd, John C, and Hillmen, Peter
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- 2021
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49. Table S3 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms
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Arribas, Alberto J., primary, Napoli, Sara, primary, Cascione, Luciano, primary, Barnabei, Laura, primary, Sartori, Giulio, primary, Cannas, Eleonora, primary, Gaudio, Eugenio, primary, Tarantelli, Chiara, primary, Mensah, Afua A., primary, Spriano, Filippo, primary, Zucchetto, Antonella, primary, Rossi, Francesca M., primary, Rinaldi, Andrea, primary, Castro de Moura, Manuel, primary, Jovic, Sandra, primary, Bordone Pittau, Roberta, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Gattei, Valter, primary, Brown, Jennifer R., primary, Esteller, Manel, primary, Zucca, Emanuele, primary, Rossi, Davide, primary, and Bertoni, Francesco, primary
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- 2024
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50. Abstract P01: Impact of Germline and Somatic ATM Variants in Chronic Lymphocytic Leukemia (CLL): Clinical Implications and Response to PARP Inhibition
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Mashima, Kiyomi, primary, Moore, Nicholas, additional, Mikhaleva, Mariia, additional, Petráčková, Anna, additional, Shupe, Samantha, additional, Fernandes, Stacey M, additional, Taylor-Weiner, Amaro, additional, Gillani, Riaz, additional, Chu, Hoyin, additional, Han, Seunghun, additional, Camp, Sabrina, additional, Kofman, Eric, additional, Getz, Gad, additional, Wu, Catherine J., additional, Tyekucheva, Svitlana, additional, Davids, Matthew S, additional, Van Allen, Eliezer Mendel, additional, AlDubayan, Saud, additional, and Brown, Jennifer R, additional
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- 2024
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