1,595 results on '"John C, Byrd"'
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2. LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia
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Janani Ravikrishnan, Daisy Y. Diaz-Rohena, Elizabeth Muhowski, Xiaokui Mo, Tzung-Huei Lai, Shrilekha Misra, Charmelle D. Williams, John Sanchez, Andrew Mitchell, Suresh Satpati, Elizabeth Perry, Tierney Kaufman, Chaomei Liu, Arletta Lozanski, Gerard Lozanski, KerryA Rogers, Adam S. Kittai, Seema A. Bhat, Mary C. Collins, Matthew S. Davids, Nitin Jain, William G. Wierda, Rosa Lapalombella, John C. Byrd, Fenlai Tan, Yi Chen, Yu Chen, Yue Shen, Stephen P. Anthony, Jennifer A. Woyach, and Deepa Sampath
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.
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- 2024
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3. NOD2 activation enhances macrophage Fcγ receptor function and may increase the efficacy of antibody therapy
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Giovanna Merchand-Reyes, Mikayla F. Bull, Ramasamy Santhanam, Maria L. Valencia-Pena, Rakesh A. Murugesan, Aadesh Chordia, Xiaokui-Molly Mo, Frank H. Robledo-Avila, Juan De Dios Ruiz-Rosado, William Edgar Carson, John C. Byrd, Jennifer A. Woyach, Susheela Tridandapani, and Jonathan P. Butchar
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NOD2 agonists ,monocytes ,chronic lymphocytic leukemia ,antibody-mediated responses ,pre-clinical model ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionTherapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses. To overcome this suppression, agonists of pattern recognition receptors have been studied which promote direct cytotoxicity or elicit anti-tumoral immune responses. NOD2 is an intracellular pattern recognition receptor that participates in the detection of peptidoglycan, a key component of bacterial cell walls. This detection then mediates the activation of multiple signaling pathways in myeloid cells. Although several NOD2 agonists are being used worldwide, the potential benefit of these agents in the context of antibody therapy has not been explored.MethodsPrimary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody.ResultsTreatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages.ConclusionsTaken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.
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- 2024
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4. Real‐world genomic testing and treatment patterns of newly diagnosed adult acute myeloid leukemia patients within a comprehensive health system
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John C. Byrd, Jennifer L. Gatz, Cynthia Lim Louis, Alice S. Mims, Uma Borate, Ashley O. Yocum, Theophilus J. Gana, and Amy Burd
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academic hospital ,acute myeloid leukemia ,age ,chemotherapy treatment ,community hospitals ,genomic testing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background We evaluated the frequency of genomic testing and treatment patterns by age category in patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated in both academic‐ and community‐based health systems within a single Midwestern State. Methods Retrospective analysis of data from the Indiana University Health System Enterprise Data Warehouse and two local cancer registries, of 629 patients aged ≥18 years with ND AML during 2011–2018. Primary outcome variables were, proportion of patients with genomic analysis and frequency of mutations. Chemotherapy was categorized as “standard induction” or “other chemotherapy”/targeted therapy, and hypomethylating agents. Results Overall, 13% of ND AML patients between 2011 and 2018 had evidence of a genomic sequencing report with a demonstrated increase to 37% since 2016. Genomic testing was more likely performed in patients: aged ≤60 years than >60 years (45% vs. 30%; p = 0.03), treated in academic versus community hospitals (44% vs. 26%; p = 0.01), and in chemotherapy recipients than non‐therapy recipients (46% vs. 19%; p
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- 2023
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5. Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation
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Zachary A. Hing, Janek S. Walker, Ethan C. Whipp, Lindsey Brinton, Matthew Cannon, Pu Zhang, Steven Sher, Casey B. Cempre, Fiona Brown, Porsha L. Smith, Claudio Agostinelli, Stefano A. Pileri, Jordan N. Skinner, Katie Williams, Hannah Phillips, Jami Shaffer, Larry P. Beaver, Alexander Pan, Kyle Shin, Charles T. Gregory, Gulcin H. Ozer, Selen A. Yilmaz, Bonnie K. Harrington, Amy M. Lehman, Lianbo Yu, Vincenzo Coppola, Pearlly Yan, Peggy Scherle, Min Wang, Philip Pitis, Chaoyi Xu, Kris Vaddi, Selina Chen-Kiang, Jennifer Woyach, James S. Blachly, Lapo Alinari, Yiping Yang, John C. Byrd, Robert A. Baiocchi, Bradley W. Blaser, and Rosa Lapalombella
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Science - Abstract
Richter’s Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development.
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- 2023
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6. Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia
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Sydney Fobare, Ola A. Elgamal, Mark Wunderlich, Emily Stahl, Abeera Mehmood, Casie Furby, James R. Lerma, Thomas M. Sesterhenn, Jianmin Pan, Jayesh Rai, Megan E. Johnstone, Amina Abdul-Aziz, Mariah L. Johnson, Shesh N. Rai, John C. Byrd, and Erin Hertlein
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EZH2 ,acute myeloid leukemia ,differentiation therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Acute myeloid leukemia (AML) is the malignant proliferation of immature myeloid cells characterized by a block in differentiation. As such, novel therapeutic strategies to promote the differentiation of immature myeloid cells have been successful in AML, although these agents are targeted to a specific mutation that is only present in a subset of AML patients. In the current study, we show that targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) can induce the differentiation of immature blast cells into a more mature myeloid phenotype and promote survival in AML murine models. Methods: The EZH2 inhibitor EPZ011989 (EPZ) was studied in AML cell lines, primary in AML cells and normal CD34+ stem cells. A pharmacodynamic assessment of H3K27me3; studies of differentiation, cell growth, and colony formation; and in vivo therapeutic studies including the influence on primary AML cell engraftment were also conducted. Results: EPZ inhibited H3K27me3 in AML cell lines and primary AML samples in vitro. EZH2 inhibition reduced colony formation in multiple AML cell lines and primary AML samples, while exhibiting no effect on colony formation in normal CD34+ stem cells. In AML cells, EPZ promoted phenotypic evidence of differentiation. Finally, the pretreatment of primary AML cells with EPZ significantly delayed engraftment and prolonged the overall survival when engrafted into immunodeficient mice. Conclusions: Despite evidence that EZH2 silencing in MDS/MPN can promote AML pathogenesis, our data demonstrate that the therapeutic inhibition of EZH2 in established AML has the potential to improve survival.
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- 2024
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7. P512: A PHASE 1B/2 STUDY OF TP-0903 AND DECITABINE TARGETING MUTANT TP53 AND/OR COMPLEX KARYOTYPE IN PATIENTS WITH UNTREATED ACUTE MYELOID LEUKEMIA (AML) ≥ AGE 60 YEARS: FINAL RESULTS
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Alice Mims, Ying Huang, Eric Eisenmann, Shelley Orwick, Daelynn Buelow, Ronan Swords, Joshua Zeidner, Matthew Foster, Tara L. Lin, Maria Baer, Yazan Madanat, Tibor Kovacsovics, Robert Redner, Zeina Al-Mansour, Mona Stefanos, Molly Martycz, Franchesca Druggan, Timothy Chen, Ashley Yocum, Uma Borate, Brian Druker, Amy Burd, Ross Levine, Sharyn Baker, and John C. Byrd
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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8. P628: UPDATED ANALYSIS OF BELLWAVE-001: A PHASE 1/2 OPEN-LABEL DOSE-EXPANSION STUDY OF THE EFFICACY AND SAFETY OF NEMTABRUTINIB FOR THE TREATMENT OF B-CELL MALIGNANCIES
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Jennifer Woyach, Ian W. Flinn, Farrukh Awan, Herbert Eradat, Danielle M. Brander, Michael Tees, Sameer Parikh, Tycel Phillips, Razi Ghori, Ima Paydar, Mohammed Z. H. Farooqui, John C. Byrd, and Deborah Stephens
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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9. P625: A PHASE 1B/2 STUDY OF NAVTEMADLIN COMBINED WITH ACALABRUTINIB IN BTK INHIBITOR NAÏVE PATIENTS WITH RELAPSED/REFRACTORY (R/R) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) OR SMALL LYMPHOCYTIC LYMPHOMA (SLL)
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John C. Byrd, Seema Ali Bhat, Farrukh Awan, Pratyush Giri, Sumita Ratnasingam, Roman Hájek, Dagmar Hess, Daniela Alves, Jan Maciej Zaucha, Annalise Shen, Elizabeth Bilotti, Jesse Mcgreivy, Wayne P. Rothbaum, and Hanna Ciepluch
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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10. Preclinical evaluation of combination nemtabrutinib and venetoclax in chronic lymphocytic leukemia
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Elizabeth M. Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A. Rogers, John C. Byrd, and Jennifer A. Woyach
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CLL ,Nemtabrutinib ,Ibrutinib ,Venetoclax ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Inhibitors of B cell receptor (BCR) signaling such as the Bruton’s tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.
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- 2022
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11. Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation
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Sunnia T. Chen, Leylah Azali, Lindsay Rosen, Qiuhong Zhao, Tracy Wiczer, Marilly Palettas, John Gambril, Onaopepo Kola-Kehinde, Patrick Ruz, Sujay Kalathoor, Kerry Rogers, Adam Kittai, Michael Grever, Farrukh Awan, John C. Byrd, Jennifer Woyach, Seema A. Bhat, and Daniel Addison
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Hypertension ,Cardiovascular events ,Acalabrutinib ,Cancer-targeted therapy ,Cardio-oncology ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Post-market analyses revealed unanticipated links between first-generation Bruton’s tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. Methods Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. Results Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P
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- 2022
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12. Mass Cytometry as a Tool for Investigating Senescence in Multiple Model Systems
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Amina Abdul-Aziz, Raymond D. Devine, Justin M. Lyberger, Hsiaochi Chang, Amy Kovacs, James R. Lerma, Andrew M. Rogers, John C. Byrd, Erin Hertlein, and Gregory K. Behbehani
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immunology ,mass cytometry ,aging ,senescence ,cell cycle ,Cytology ,QH573-671 - Abstract
Cellular senescence is a durable cell cycle arrest as a result of the finite proliferative capacity of cells. Senescence responds to both intrinsic and extrinsic cellular stresses, such as aging, mitochondrial dysfunction, irradiation, and chemotherapy. Here, we report on the use of mass cytometry (MC) to analyze multiple model systems and demonstrate MC as a platform for senescence analysis at the single-cell level. We demonstrate changes to p16 expression, cell cycling fraction, and histone tail modifications in several established senescent model systems and using isolated human T cells. In bone marrow mesenchymal stromal cells (BMSCs), we show increased p16 expression with subsequent passage as well as a reduction in cycling cells and open chromatin marks. In WI-38 cells, we demonstrate increased p16 expression with both culture-induced senescence and oxidative stress-induced senescence (OSIS). We also use Wanderlust, a trajectory analysis tool, to demonstrate how p16 expression changes with histone tail modifications and cell cycle proteins. Finally, we demonstrate that repetitive stimulation of human T cells with CD3/CD28 beads induces an exhausted phenotype with increased p16 expression. This p16-expressing population exhibited higher expression of exhaustion markers such as EOMES and TOX. This work demonstrates that MC is a useful platform for studying senescence at a single-cell protein level, and is capable of measuring multiple markers of senescence at once with high confidence, thereby improving our understanding of senescent pathways.
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- 2023
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13. Rare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia
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Janek S. Walker, Zachary A. Hing, Steven Sher, James Cronin, Katie Williams, Bonnie Harrington, Jordan N. Skinner, Casey B. Cempre, Charles T. Gregory, Alexander Pan, Max Yano, Larry P. Beaver, Brandi R. Walker, Jadwiga M. Labanowska, Nyla A. Heerema, Krzysztof Mrózek, Jennifer A. Woyach, Amy S. Ruppert, Amy Lehman, Hatice Gulcin Ozer, Vincenzo Coppola, Pearlly Yan, John C. Byrd, James S. Blachly, and Rosa Lapalombella
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Science - Abstract
Some genes that are part of balanced translocations are reported as drivers for tumourigenesis. Here, the authors report a translocation involving MTCP1 in chronic lymphocytic leukemia and show that MTCP1 overexpression leads to the disease in a murine model.
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- 2021
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14. Precision oncology in AML: validation of the prognostic value of the knowledge bank approach and suggestions for improvement
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Marius Bill, Krzysztof Mrózek, Brian Giacopelli, Jessica Kohlschmidt, Deedra Nicolet, Dimitrios Papaioannou, Ann-Kathrin Eisfeld, Jonathan E. Kolitz, Bayard L. Powell, Andrew J. Carroll, Richard M. Stone, Ramiro Garzon, John C. Byrd, Clara D. Bloomfield, and Christopher C. Oakes
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Acute myeloid leukemia ,Knowledge bank ,Next-generation sequencing ,Gene mutations ,Clinical outcome ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Recently, a novel knowledge bank (KB) approach to predict outcomes of individual patients with acute myeloid leukemia (AML) was developed using unbiased machine learning. To validate its prognostic value, we analyzed 1612 adults with de novo AML treated on Cancer and Leukemia Group B front-line trials who had pretreatment clinical, cytogenetics, and mutation data on 81 leukemia/cancer-associated genes available. We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate the predictive values of the KB algorithm and other risk classifications. The KB algorithm predicted 3-year overall survival (OS) probability in the entire patient cohort (AUCKB = 0.799), and both younger (
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- 2021
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15. Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
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Matthew Kaufman, Xiao-Jie Yan, Wentian Li, Emanuela M. Ghia, Anton W. Langerak, Laura Z. Rassenti, Chrysoula Belessi, Neil E. Kay, Frederic Davi, John C. Byrd, Sarka Pospisilova, Jennifer R. Brown, Mark Catherwood, Zadie Davis, David Oscier, Marco Montillo, Livio Trentin, Richard Rosenquist, Paolo Ghia, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, Kostas Stamatopoulos, Thomas J. Kipps, Donna Neuberg, and Nicholas Chiorazzi
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chronic lymphocytic leukemia ,CLL ,somatic mutations ,immunoglobulin variable domain ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - 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
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16. A precision medicine classification for treatment of acute myeloid leukemia in older patients
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Alice S. Mims, Jessica Kohlschmidt, Uma Borate, James S. Blachly, Shelley Orwick, Ann-Kathrin Eisfeld, Dimitrios Papaioannou, Deedra Nicolet, Krzysztof Mrόzek, Eytan Stein, Bhavana Bhatnagar, Richard M. Stone, Jonathan E. Kolitz, Eunice S. Wang, Bayard L. Powell, Amy Burd, Ross L. Levine, Brian J. Druker, Clara D. Bloomfield, and John C. Byrd
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Acute myeloid leukemia ,Mutation ,Cytogenetics ,Precision medicine ,Outcome ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study. Methods We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes. Results Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%. Conclusions By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
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- 2021
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17. Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation
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Shaneice Mitchell, Pu Zhang, Matthew Cannon, Larry Beaver, Amy Lehman, Bonnie Harrington, Deepa Sampath, John C. Byrd, and Rosa Lapalombella
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NAMPT ,Leukemia ,Erythropoietin ,Niacin ,SOD ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.
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- 2021
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18. High-dimensional genomic feature selection with the ordered stereotype logit model.
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Anna Eames Seffernick, Krzysztof Mrózek, Deedra Nicolet, Richard M. Stone, Ann-Katherin Eisfeld, John C. Byrd, and Kellie J. Archer
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- 2022
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19. Preclinical evaluation of the Hsp90 inhibitor SNX-5422 in ibrutinib resistant CLL
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Timothy L. Chen, Bonnie Harrington, Jean Truxall, Ronni Wasmuth, Alexander Prouty, Shelby Sloan, Amy M. Lehman, Deepa Sampath, Eric Orlemans, Robert A. Baiocchi, Lapo Alinari, John C. Byrd, Jennifer A. Woyach, and Erin Hertlein
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Chronic lymphocytic leukemia ,Hsp90 ,BTK ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract B-cell receptor (BCR) antagonists such as the BTK inhibitor ibrutinib have proven to effectively target chronic lymphocytic leukemia (CLL) tumor cells, leading to impressive response rates in these patients. However patients do still relapse on ibrutinib, and the progressive disease is often quite aggressive requiring immediate treatment. Several strategies are being pursued to treat patients who relapse on ibrutinib therapy. As the most common form of relapse is the development of a mutant form of BTK which limits ibrutinib binding, agents which lead to degradation of the BTK protein are a promising strategy. Our study explores the efficacy of the Hsp90 inhibitor, SNX-5422, in CLL. The SNX Hsp90 inhibitor was effective in primary CLL cells, as well as B-cell lines expressing either BTK wild type or C481 mutant BTK, which has been identified as the primary resistance mechanism to ibrutinib in CLL patients. Furthermore the combination of SNX-5422 and ibrutinib provided a remarkable in vivo survival benefit in the Eμ-TCL1 mouse model of CLL compared to the vehicle or single agent groups (51 day median survival in the vehicle and ibrutinib groups versus 100 day median survival in the combination). We report here preclinical data suggesting that the Hsp90 inhibitor SNX-5422, which has been pursued in clinical trials in both solid tumor and hematological malignancies, is a potential therapy for ibrutinib resistant CLL.
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- 2021
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20. Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia
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Janek S. Walker, Zachary A. Hing, Bonnie Harrington, Jordan Baumhardt, Hatice Gulcin Ozer, Amy Lehman, Brian Giacopelli, Larry Beaver, Katie Williams, Jordan N. Skinner, Casey B. Cempre, Qingxiang Sun, Sharon Shacham, Benjamin R. Stromberg, Matthew K. Summers, Lynne V. Abruzzo, Laura Rassenti, Thomas J. Kipps, Sameer Parikh, Neil E. Kay, Kerry A. Rogers, Jennifer A. Woyach, Vincenzo Coppola, Yuh Min Chook, Christopher Oakes, John C. Byrd, and Rosa Lapalombella
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XPO1 ,Chronic lymphocytic leukemia ,Mouse model ,Selinexor ,Sines ,Expression profiling ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Methods We performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor). Results We report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL. Conclusions These findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.
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- 2021
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21. Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia
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Lindsey T. Brinton, Pu Zhang, Katie Williams, Daniel Canfield, Shelley Orwick, Steven Sher, Ronni Wasmuth, Larry Beaver, Casey Cempre, Jordan Skinner, Matthew Cannon, Mukul Govande, Bonnie Harrington, Amy Lehman, John C. Byrd, Rosa Lapalombella, and James S. Blachly
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Gilteritinib ,Midostaurin ,Synergy ,Combination therapy ,FLT3 ,BCL2 ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.
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- 2020
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22. CLEAR: coverage-based limiting-cell experiment analysis for RNA-seq
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Logan A. Walker, Michael G. Sovic, Chi-Ling Chiang, Eileen Hu, Jiyeon K. Denninger, Xi Chen, Elizabeth D. Kirby, John C. Byrd, Natarajan Muthusamy, Ralf Bundschuh, and Pearlly Yan
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Rare cells ,Ultralow input ,Pre-filtering ,RNA-seq ,Differential gene expression analysis ,Medicine - Abstract
Abstract Background Direct cDNA preamplification protocols developed for single-cell RNA-seq have enabled transcriptome profiling of precious clinical samples and rare cell populations without the need for sample pooling or RNA extraction. We term the use of single-cell chemistries for sequencing low numbers of cells limiting-cell RNA-seq (lcRNA-seq). Currently, there is no customized algorithm to select robust/low-noise transcripts from lcRNA-seq data for between-group comparisons. Methods Herein, we present CLEAR, a workflow that identifies reliably quantifiable transcripts in lcRNA-seq data for differentially expressed genes (DEG) analysis. Total RNA obtained from primary chronic lymphocytic leukemia (CLL) CD5+ and CD5− cells were used to develop the CLEAR algorithm. Once established, the performance of CLEAR was evaluated with FACS-sorted cells enriched from mouse Dentate Gyrus (DG). Results When using CLEAR transcripts vs. using all transcripts in CLL samples, downstream analyses revealed a higher proportion of shared transcripts across three input amounts and improved principal component analysis (PCA) separation of the two cell types. In mouse DG samples, CLEAR identifies noisy transcripts and their removal improves PCA separation of the anticipated cell populations. In addition, CLEAR was applied to two publicly-available datasets to demonstrate its utility in lcRNA-seq data from other institutions. If imputation is applied to limit the effect of missing data points, CLEAR can also be used in large clinical trials and in single cell studies. Conclusions lcRNA-seq coupled with CLEAR is widely used in our institution for profiling immune cells (circulating or tissue-infiltrating) for its transcript preservation characteristics. CLEAR fills an important niche in pre-processing lcRNA-seq data to facilitate transcriptome profiling and DEG analysis. We demonstrate the utility of CLEAR in analyzing rare cell populations in clinical samples and in murine neural DG region without sample pooling.
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- 2020
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23. Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia
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Ola A. Elgamal, Abeera Mehmood, Jae Yoon Jeon, Bridget Carmichael, Amy Lehman, Shelley J. Orwick, Jean Truxall, Virginia M. Goettl, Ronni Wasmuth, Minh Tran, Shaneice Mitchell, Rosa Lapalombella, Sudharshan Eathiraj, Brian Schwartz, Kimberly Stegmaier, Sharyn D. Baker, Erin Hertlein, and John C. Byrd
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Acute myeloid leukemia ,Multi-kinase inhibitor ,ArQule 531 ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Acute myeloid leukemia (AML) is the most common type of adult leukemia. Several studies have demonstrated that oncogenesis in AML is enhanced by kinase signaling pathways such as Src family kinases (SFK) including Src and Lyn, spleen tyrosine kinase (SYK), and bruton’s tyrosine kinase (BTK). Recently, the multi-kinase inhibitor ArQule 531 (ARQ 531) has demonstrated potent inhibition of SFK and BTK that translated to improved pre-clinical in vivo activity as compared with the irreversible BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) models. Given the superior activity of ARQ 531 in CLL, and recognition that this molecule has a broad kinase inhibition profile, we pursued its application in pre-clinical models of AML. Methods The potency of ARQ 531 was examined in vitro using FLT3 wild type and mutated (ITD) AML cell lines and primary samples. The modulation of pro-survival kinases following ARQ 531 treatment was determined using AML cell lines. The effect of SYK expression on ARQ 531 potency was evaluated using a SYK overexpressing cell line (Ba/F3 murine cells) constitutively expressing FLT3-ITD. Finally, the in vivo activity of ARQ 531 was evaluated using MOLM-13 disseminated xenograft model. Results Our data demonstrate that ARQ 531 treatment has anti-proliferative activity in vitro and impairs colony formation in AML cell lines and primary AML cells independent of the presence of a FLT3 ITD mutation. We demonstrate decreased phosphorylation of oncogenic kinases targeted by ARQ 531, including SFK (Tyr416), BTK, and fms-related tyrosine kinase 3 (FLT3), ultimately leading to changes in down-stream targets including SYK, STAT5a, and ERK1/2. Based upon in vitro drug synergy data, we examined ARQ 531 in the MOLM-13 AML xenograft model alone and in combination with venetoclax. Despite ARQ 531 having a less favorable pharmacokinetics profile in rodents, we demonstrate modest single agent in vivo activity and synergy with venetoclax. Conclusions Our data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.
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- 2020
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24. Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3‐ITD AML
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Daelynn R. Buelow, Stanley B. Pounds, Yong‐Dong Wang, Lei Shi, Yongjin Li, David Finkelstein, Sheila Shurtleff, Geoffrey Neale, Hiroto Inaba, Raul C. Ribeiro, Reid Palumbo, Dominique Garrison, Shelley J. Orwick, James S. Blachly, Karl Kroll, John C. Byrd, Tanja A. Gruber, Jeffrey E. Rubnitz, and Sharyn D. Baker
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Fms‐like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3‐ITD+ AML. Using RNA sequencing and a next‐generation targeted gene panel, we broadly characterize the co‐occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3‐ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0–3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1, NPM1, SMARCA2, RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3‐ITD+ AML and could help stratify future targeted treatment strategies.
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- 2019
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25. Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice
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Susan M. O’Brien, Jennifer R. Brown, John C. Byrd, Richard R. Furman, Paolo Ghia, Jeff P. Sharman, and William G. Wierda
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acalabrutinib ,adverse events ,Bruton tyrosine kinase inhibitor ,chronic lymphocytic leukemia ,ibrutinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - 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.
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- 2021
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26. TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion
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Eric D. Eisenmann, Jack C. Stromatt, Sydney Fobare, Kevin M. Huang, Daelynn R. Buelow, Shelley Orwick, Jae Yoon Jeon, Robert H. Weber, Bill Larsen, Alice S. Mims, Erin Hertlein, John C. Byrd, and Sharyn D. Baker
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TP53 ,AML ,TP-0903 ,decitabine ,multikinase ,aurora kinase ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene TP53 confers a dismal prognosis with 3-year overall survival of TP53 mutant cancers, this strategy has not been evaluated in mutant TP53 AML. Previously, we demonstrated that TP-0903 is a novel multikinase inhibitor with low nM activity against AURKA/B, Chk1/2, and other cell cycle regulators. Here, we evaluated the preclinical activity of TP-0903 in TP53 mutant AML cell lines, including a single-cell clone of MV4-11 containing a TP53 mutation (R248W), Kasumi-1 (R248Q), and HL-60 (TP 53 null). TP-0903 inhibited cell viability (IC50, 12–32 nM) and induced apoptosis at 50 nM. By immunoblot, 50 nM TP-0903 upregulated pChk1/2 and pH2AX, suggesting induction of DNA damage. The combination of TP-0903 and decitabine was additive in vitro, and in vivo significantly prolonged median survival compared to single-agent treatments in mice xenografted with HL-60 (vehicle, 46 days; decitabine, 55 days; TP-0903, 63 days; combination, 75 days) or MV4-11 (R248W) (51 days; 62 days; 81 days; 89 days) (p < 0.001). Together, these results provide scientific premise for the clinical evaluation of TP-0903 in combination with decitabine in TP53 mutant AML.
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- 2022
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27. Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential
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Max Yano, John C. Byrd, and Natarajan Muthusamy
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cancer ,leukemia ,CLL ,chronic lymphocytic leukemia ,NK cell ,natural killer cell ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. Chronic lymphocytic leukemia (CLL), the most prevalent form of leukemia in Western countries, is a very immunosuppressive disease but still shows significant potential as a target of immunotherapy, including NK-based therapies. In addition to their antileukemia potential, NK cells are important immune effectors in the response to infections, which represent a major clinical concern for CLL patients. Here, we review the interactions between NK cells and CLL, describing functional changes and mechanisms of CLL-induced NK suppression, interactions with current therapeutic options, and the potential for therapeutic benefit using NK cell therapies.
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- 2022
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28. Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients
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Jennifer R. Brown, John C. Byrd, Paolo Ghia, Jeff P. Sharman, Peter Hillmen, Deborah M. Stephens, Clare Sun, Wojciech Jurczak, John M. Pagel, Alessandra Ferrajoli, Priti Patel, Lin Tao, Nataliya Kuptsova-Clarkson, Javid Moslehi, and Richard R. Furman
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with highrisk CLL (clinicaltrials gov. Identifier: NCT02477696) prospectively assess differences in CV toxicity between the two agents.
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- 2021
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29. Optimizing extracellular vesicles’ isolation from chronic lymphocytic leukemia patient plasma and cell line supernatant
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Sara Elgamal, Emanuele Cocucci, Ellen J. Sass, Xiaokui M. Mo, Angela R. Blissett, Edward P. Calomeni, Kerry A. Rogers, Jennifer A. Woyach, Seema A. Bhat, Natarajan Muthusamy, Amy J. Johnson, Karilyn T. Larkin, and John C. Byrd
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Hematology ,Oncology ,Medicine - Abstract
In chronic lymphocytic leukemia (CLL) and very likely all cancer types, extracellular vesicles (EVs) are a common mechanism by which intercellular messages are communicated between normal, diseased, and transformed cells. Studies of EVs in CLL and other cancers have great variability and often lack reproducibility. For CLL patient plasma and cell lines, we sought to characterize current approaches used in isolating EV products and understand whether cell culture–conditioned media or complex biological fluids confound results. Utilizing nanoparticle tracking analysis, protein quantification, and electron microscopy, we show that ultracentrifugation with an OptiPrep cushion can effectively minimize contaminants from starting materials including plasma and conditioned media of CLL cell lines grown in EV-depleted complete RPMI media but not grown in the serum-free media AIM V commonly used in CLL experimental work. Moreover, we confirm the benefit of including 25 mM trehalose in PBS during EV isolation steps to reduce EV aggregation, to preserve function for downstream applications and characterization. Furthermore, we report the highest particles/μg EVs were obtained from our CLL cell lines utilizing the CELLine bioreactor flask. Finally, we optimized a proliferation assay that offers a functional evaluation of our EVs with minimal sample requirements.
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- 2021
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30. Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia
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Dimitrios Papaioannou, Hatice G. Ozer, Deedra Nicolet, Amog P. Urs, Tobias Herold, Krzysztof Mrózek, Aarif M.N. Batcha, Klaus H. Metzeler, Ayse S. Yilmaz, Stefano Volinia, Marius Bill, Jessica Kohlschmidt, Maciej Pietrzak, Christopher J. Walker, Andrew J. Carroll, Jan Braess, Bayard L. Powell, Ann-Kathrin Eisfeld, Geoffrey L. Uy, Eunice S. Wang, Jonathan E. Kolitz, Richard M. Stone, Wolfgang Hiddemann, John C. Byrd, Clara D. Bloomfield, and Ramiro Garzon
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged
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- 2021
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31. Pevonedistat with azacitidine in older patients with TP53-mutated AML: a phase 2 study with laboratory correlates
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Antoine N. Saliba, Scott H. Kaufmann, Eytan M. Stein, Prapti A. Patel, Maria R. Baer, Wendy Stock, Michael Deininger, William Blum, Gary J. Schiller, Rebecca L. Olin, Mark R. Litzow, Tara L. Lin, Brian J. Ball, Michael M. Boyiadzis, Elie Traer, Olatoyosi Odenike, Martha L. Arellano, Alison Walker, Vu H. Duong, Tibor Kovacsovics, Robert H. Collins, Abigail B. Shoben, Nyla A. Heerema, Matthew C. Foster, Kevin L. Peterson, Paula A. Schneider, Molly Martycz, Theophilus J. Gana, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Alice S. Mims, Uma Borate, Amy Burd, Brian J. Druker, Ross L. Levine, John C. Byrd, and James M. Foran
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Hematology - Published
- 2023
32. Inequities in Alliance Acute Leukemia Clinical Trial and Biobank Participation: Defining Targets for Intervention
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Andrew Hantel, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Wendy Stock, Sawyer Jacobson, Sumithra Mandrekar, Richard A. Larson, Richard M. Stone, Christopher S. Lathan, Daniel J. DeAngelo, John C. Byrd, and Gregory A. Abel
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Adult ,Cancer Research ,Leukemia ,Oncology ,Asian People ,Neoplasms ,Ethnicity ,Humans ,Hispanic or Latino ,United States ,Biological Specimen Banks - Abstract
PURPOSE Representativeness in acute leukemia clinical research is essential for achieving health equity. The National Cancer Institute's mandate for Comprehensive Cancer Centers (CCCs) to define and assume responsibility for cancer control and treatment across a geographic catchment area provides an enforceable mechanism to target and potentially remediate participatory inequities. METHODS We examined enrollee characteristics across 15 Cancer and Leukemia Group B/Alliance cooperative group adult acute leukemia clinical trials (N = 3,734) from 1998 to 2013, including participation in optional companion biobanks. We determined enrollment odds by race-ethnicity for all participants adjusted for national incidence, and for those enrolled at CCCs adjusted for catchment area incidence. We modeled biobank participation by sociodemographics using logistic regression. RESULTS Non-Hispanic (NH)-White patients were more likely to be enrolled than NH-Black, NH-Asian, or Hispanic patients (odds ratio [OR], 0.75, 0.48, and 0.44, respectively; all P < .001), but less likely than NH-Native American patients (OR, 1.91; P < .001), adjusted for national incidence. Enrollment odds were lower for NH-Black, NH-Asian, and Hispanic patients at CCCs adjusted for catchment area incidence (OR, 0.57, 0.26, and 0.32, respectively; P < .001); differences were driven by overenrollment of NH-White patients from outside self-defined catchment areas (18.1% v 12.3%; χ2 P = .01) and by CCCs with less absolute enrollee diversity (rank sum P = .03). Among all enrollees, NH-White race-ethnicity and lower neighborhood deprivation correlated with biobank participation (OR, 1.81 and 1.45, respectively; P = .01 and .03). For CCC enrollees, the correlation of race-ethnicity with biobank participation was attenuated by a measure accounting for their site's degree of enrollment disparity but not neighborhood deprivation. CONCLUSION Acute leukemia clinical research disparities are substantial and driven by structural trial enrollment barriers at CCCs. Real-time CCC access and enrollment monitoring is needed to better align research participation with local populations.
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- 2023
33. Challenges and approaches to implementing master/basket trials in oncology
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Amy Burd, Richard L. Schilsky, John C. Byrd, Ross L. Levine, Vassiliki A. Papadimitrakopoulou, Roy S. Herbst, Mary W. Redman, Brian J. Druker, and David R. Gandara
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: The appetite for cutting-edge cancer research, across medical institutions, scientific researchers, and health care providers, is increasing based on the promise of true breakthroughs and cures with new therapeutics available for investigation. At the same time, the barriers for advancing clinical research are impacting how quickly drug development efforts are conducted. For example, we know now that under a microscope, patients with the same type of cancer and histology might look the same; however, the reality is that most cancers are driven by genomic, transcriptional, and epigenetic changes that make each patient unique. Additionally, the immunologic reaction to different tumor types is distinct among patients. The challenge for researchers developing new therapies today is vastly different than it was in the era of cytotoxics. Today, we must identify a sufficient number of patients harboring a rare mutation or other characteristic and match this to the right therapeutic option. This summary provides a guide to help inform the scientific cancer community about the benefits and challenges of conducting umbrella or basket trials (master trials), and to create a roadmap to help make this new and evolving form of clinical trial design as effective as possible.
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- 2019
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34. Outcome prediction by the 2022 European LeukemiaNet genetic-risk classification for adults with acute myeloid leukemia: an Alliance study
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Krzysztof Mrózek, Jessica Kohlschmidt, James S. Blachly, Deedra Nicolet, Andrew J. Carroll, Kellie J. Archer, Alice S. Mims, Karilyn T. Larkin, Shelley Orwick, Christopher C. Oakes, Jonathan E. Kolitz, Bayard L. Powell, William G. Blum, Guido Marcucci, Maria R. Baer, Geoffrey L. Uy, Wendy Stock, John C. Byrd, and Ann-Kathrin Eisfeld
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Cancer Research ,Oncology ,Hematology - Abstract
Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML). We categorized 1637 adults with AML treated with cytarabine/anthracycline regimens according to the 2022 and 2017 ELN classifications. Compared with the 2017 ELN classification, 2022 favorable group decreased from 40% to 35% and adverse group increased from 37% to 41% of patients. The 2022 genetic-risk groups seemed to accurately reflect treatment outcomes in all patients and patients aged CEBPAbZIP mutations or core-binding factor AML, but changed risk assignment of NPM1-mutated/FLT3-ITD-negative patients to intermediate. NPM1-mutated patients with adverse-risk cytogenetic abnormalities were closer prognostically to the intermediate than adverse group. Our analyses both confirm and challenge prognostic significance of some of the newly added markers.
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- 2023
35. TP-0903 is active in models of drug-resistant acute myeloid leukemia
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Jae Yoon Jeon, Daelynn R. Buelow, Dominique A. Garrison, Mingshan Niu, Eric D. Eisenmann, Kevin M. Huang, Megan E. Zavorka Thomas, Robert H. Weber, Clifford J. Whatcott, Steve L. Warner, Shelley J. Orwick, Bridget Carmichael, Emily Stahl, Lindsey T. Brinton, Rosa Lapalombella, James S. Blachly, Erin Hertlein, John C. Byrd, Bhavana Bhatnagar, and Sharyn D. Baker
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Hematology ,Oncology ,Medicine - Abstract
Effective treatment for AML is challenging due to the presence of clonal heterogeneity and the evolution of polyclonal drug resistance. Here, we report that TP-0903 has potent activity against protein kinases related to STAT, AKT, and ERK signaling, as well as cell cycle regulators in biochemical and cellular assays. In vitro and in vivo, TP-0903 was active in multiple models of drug-resistant FLT3 mutant AML, including those involving the F691L gatekeeper mutation and bone marrow microenvironment–mediated factors. Furthermore, TP-0903 demonstrated preclinical activity in AML models with FLT3-ITD and common co-occurring mutations in IDH2 and NRAS genes. We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL-PTD, ASXL1, SRSF2, and WT1, which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML.
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- 2020
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36. Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration
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Deborah M. Stephens, Ken Boucher, Elizabeth Kander, Sameer A. Parikh, Erin M. Parry, Mazyar Shadman, John M. Pagel, Jennifer Cooperrider, Joanna Rhodes, Anthony Mato, Allison Winter, Brian Hill, Sameh Gaballa, Alexey Danilov, Tycel Phillips, Danielle M. Brander, Sonali M. Smith, Matthew Davids, Kerry Rogers, Martha J. Glenn, and John C. Byrd
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of two therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was one (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95% Confidence Interval: 62-83). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; P=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.
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- 2020
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37. Ventricular arrhythmias and sudden death events following acalabrutinib initiation
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Seema A. Bhat, John Gambril, Leylah Azali, Sunnia T. Chen, Lindsay Rosen, Marilly Palettas, Tracy E. Wiczer, Sujay Kalathoor, Qiuhong Zhao, Kerry A. Rogers, Adam Kittai, Michael Grever, Farrukh Awan, Patrick Ruz, John C. Byrd, Jennifer Woyach, and Daniel Addison
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Heart Failure ,Death, Sudden ,Pyrazines ,Benzamides ,Immunology ,Humans ,Arrhythmias, Cardiac ,Cell Biology ,Hematology ,Biochemistry ,Aged - Abstract
Acalabrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, unexplained ventricular arrhythmias (VAs) with next-generation BTKi-therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow-up is unknown. Leveraging a large-cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence of VAs. The primary-endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability-scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as function of time-on-therapy were calculated. Weighted average observed incidence rates were compared with expected population rates using relative-risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1063 person-years of follow-up, there were 8 cases of incident-VAs, including 6 in those without coronary disease (CAD) or heart failure (HF) and 1 sudden-death; median time-to-event 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100 000 person years compared with a reported incidence of 48.1 among similar-aged non–BTKi-treated subjects (relative risk, 8.2; P
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- 2022
38. Sex-Associated Differences in Frequencies and Outcome Prognostication of Recurrent Molecular Features in Adults with Acute Myeloid Leukemia (AML) (AMLCG, CALGB [Alliance])
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Michael P. Ozga, Deedra Nicolet, Krzysztof Mrózek, Selen Yilmaz, Jessica Kohlschmidt, Karilyn T. Larkin, James S. Blachly, Christopher C. Oakes, Jill Buss, Christopher J. Walker, Shelley Orwick, Vindi Jurinovic, Maja Rothenberg-Thurley, Annika Maria Dufour, Stephanie Schneider, Maria Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E. Berdel, Bernhard Josef Woermann, Wolfgang Hiddemann, Jan Braess, Marion Subklewe, Karsten Spiekermann, Andrew J. Carroll, William G. Blum, Bayard L. Powell, Jonathan E. Kolitz, Joseph O. Moore, Robert James Mayer, Richard M. Stone, Geoffrey L. Uy, Wendy Stock, Klaus H. Metzeler, H. Leighton Grimes, John C. Byrd, Nathan Salomonis, Tobias Herold, Alice S. Mims, and Ann-Kathrin Eisfeld
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
39. A Risk-Adapted Study to Assess the Efficacy of Enasidenib and Subsequent Response-Driven Addition of Azacitidine for Newly Diagnosed IDH2-Mutant AML Patients: 3-Year Follow-up
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Eytan Stein, Sheng F Cai, Ying Huang, Andrew Dunbar, Maria R. Baer, Wendy Stock, Tibor Kovacsovics, William G. Blum, Gary J. Schiller, Rebecca L. Olin, James M. Foran, Mark R. Litzow, Tara L. Lin, Prapti A. Patel, Matthew C. Foster, Michael M. Boyiadzis, Robert H. Collins, Jordan Chervin, Abigail B. Shoben, Jo-Anne Vergilio, Nyla A. Heerema, Leonard Rosenberg, Timothy Chen, Ashley O. Yocum, Franchesca Druggan, Sonja Marcus, Mona Stefanos, Molly Martycz, Brian J. Druker, Alice S. Mims, Uma Borate, Amy Burd, John C. Byrd, and Ross L. Levine
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
40. A Phase 1b Dose Escalation and Expansion Study of SNDX-5613, Azacitidine (AZA) and Venetoclax (VEN) in Newly Diagnosed, Patients ≥ 60 Years with Untreated NPM1-Mutated/ FLT3-Wild Type AML or KMT2A-Rearranged Acute Myeloid Leukemia (AML)
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Joshua F. Zeidner, Matthew C. Foster, Mary Johnson, Ying Huang, Ronan T. Swords, Eytan Stein, James M. Foran, Maria R. Baer, Wendy Stock, Yazan F. Madanat, Tibor Kovacsovics, Rebecca L. Olin, William G. Blum, Gary J. Schiller, Tara L. Lin, Robert L. Redner, Zeina Al-Mansour, Emily K Curran, Nyla A. Heerema, Molly Martycz, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Franchesca Druggan, Amy Burd, Ross L. Levine, Brian J. Druker, Uma Borate, John C. Byrd, and Alice S. Mims
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
41. Entospletinib (ENTO) in Combination with Cytarabine (Ara-C) and Daunorubicin (DNR) in Newly Diagnosed (ND) Adult Patients with NPM1-Mutated and FLT3-ITD Wild-Type Acute Myeloid Leukemia (AML) Is Associated with Good Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial
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Uma Borate, Rui Li, Ying Huang, Ronan T. Swords, Elie Traer, Eytan Stein, James M. Foran, Maria R. Baer, Vu H. Duong, Wendy Stock, Olatoyosi Odenike, Prapti Patel, Robert H. Collins, Yazan F. Madanat, Tibor Kovacsovics, Michael W. Deininger, Catherine Smith, Rebecca L. Olin, Martha L. Arellano, William G. Blum, Gary J. Schiller, Tara L. Lin, Matthew C. Foster, Michael M. Boyiadzis, Robert L. Redner, Zeina Al-Mansour, Emily K Curran, Nyla A. Heerema, Theophilus J Gana, Molly Martycz, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Franchesca Druggan, Amy Burd, Ross L. Levine, Brian J. Druker, John C. Byrd, and Alice S. Mims
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
42. VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia
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Steven Sher, Ethan Whipp, Janek Walker, Pu Zhang, Larry Beaver, Katie Williams, Shelley Orwick, Janani Ravikrishnan, Brandi Walker, Elizabeth Perry, Charles Gregory, Matthew Purcell, Alexander Pan, Pearlly Yan, Lapo Alinari, Amy J. Johnson, Melanie M. Frigault, Joy M. Greer, Ahmed Hamdy, Raquel Izumi, Xiaokui Mo, Deepa Sampath, Jennifer Woyach, James Blachly, John C. Byrd, and Rosa Lapalombella
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Cancer Research ,Oncology ,Hematology - Abstract
Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
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- 2022
43. Principles of Medical Oncology
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Apostolia M. Tsimberidou, Robert C. Bast, Fadlo R. Khuri, and John C. Byrd
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- 2022
44. Drug Development of Small Molecule Cancer Therapeutics in an Academic Cancer Center
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Christopher C. Coss, Jeffrey T. Patrick, Damien Gerald, Gerard Hilinski, Reena Shakya, and John C. Byrd
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- 2022
45. Evaluation of allogeneic and autologous membrane-bound IL-21–expanded NK cells for chronic lymphocytic leukemia therapy
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Max Yano, Chia Sharpe, J. Rachel Lance, Janani Ravikrishnan, Kevan Zapolnik, Xiaokui Mo, Jennifer A. Woyach, Deepa Sampath, Adam S. Kittai, Sumithira Vasu, Seema Bhat, Kerry A. Rogers, Dean A. Lee, Natarajan Muthusamy, and John C. Byrd
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Killer Cells, Natural ,Mice ,immune system diseases ,hemic and lymphatic diseases ,Hematopoietic Stem Cell Transplantation ,Animals ,Humans ,Antineoplastic Agents ,Hematology ,Leukemia, Lymphocytic, Chronic, B-Cell - Abstract
Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with anti-CD20 antibodies significantly enhances NK recognition and killing of CLL targets. As any CLL immune therapy would likely be given in combination, we assess commonly used treatments and demonstrate that ibrutinib has mixed suppressive and protective effects on expanded NK cells, whereas expanded NKs are highly resistant to venetoclax. We demonstrate efficacy in vivo in 2 xenograft mouse models of human CLL that support building upon a regimen of venetoclax and obinutuzumab with mbIL-21–expanded NK cells. Collectively, these data support development of mbIL-21–expanded NKs combined with the CD20 antibody obinutuzumab and venetoclax in the treatment of CLL.
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- 2022
46. High early death rates, treatment resistance, and short survival of Black adolescents and young adults with AML
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Karilyn T. Larkin, Deedra Nicolet, Benjamin J. Kelly, Krzysztof Mrózek, Stephanie LaHaye, Katherine E. Miller, Saranga Wijeratne, Gregory Wheeler, Jessica Kohlschmidt, James S. Blachly, Alice S. Mims, Christopher J. Walker, Christopher C. Oakes, Shelley Orwick, Isaiah Boateng, Jill Buss, Adrienne Heyrosa, Helee Desai, Andrew J. Carroll, William Blum, Bayard L. Powell, Jonathan E. Kolitz, Joseph O. Moore, Robert J. Mayer, Richard A. Larson, Richard M. Stone, Electra D. Paskett, John C. Byrd, Elaine R. Mardis, and Ann-Kathrin Eisfeld
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Adult ,Proto-Oncogene Proteins p21(ras) ,Cytogenetics ,Leukemia, Myeloid, Acute ,Young Adult ,Adolescent ,Drug Resistance, Neoplasm ,Antineoplastic Combined Chemotherapy Protocols ,Remission Induction ,Black People ,Humans ,Hematology - Abstract
Survival of patients with acute myeloid leukemia (AML) is inversely associated with age, but the impact of race on outcomes of adolescent and young adult (AYA; range, 18-39 years) patients is unknown. We compared survival of 89 non-Hispanic Black and 566 non-Hispanic White AYA patients with AML treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. Samples of 327 patients (50 Black and 277 White) were analyzed via targeted sequencing. Integrated genomic profiling was performed on select longitudinal samples. Black patients had worse outcomes, especially those aged 18 to 29 years, who had a higher early death rate (16% vs 3%; P=.002), lower complete remission rate (66% vs 83%; P=.01), and decreased overall survival (OS; 5-year rates: 22% vs 51%; P
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- 2022
47. Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma
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Youssef Youssef, Vrajesh Karkhanis, Wing Keung Chan, Frankie Jeney, Alessandro Canella, Xiaoli Zhang, Shelby Sloan, Alexander Prouty, JoBeth Helmig-Mason, Liudmyla Tsyba, Walter Hanel, Xuguang Zheng, Pu Zhang, Ji-Hyun Chung, David M. Lucas, Zachary Kauffman, Karilyn Larkin, Anne M. Strohecker, Hatice G. Ozer, Rosa Lapalombella, Hui Zhou, Zijun Y. Xu-Monette, Ken H. Young, Ruolan Han, Elmar Nurmemmedov, Gerard Nuovo, Kami Maddocks, John C. Byrd, Robert A. Baiocchi, and Lapo Alinari
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common non- Hodgkin lymphoma and is characterized by a remarkable heterogeneity with diverse variants that can be identified histologically and molecularly. Large-scale gene expression profiling studies have identified the germinal center B-cell (GCB-) and activated B-cell (ABC-) subtypes. Standard chemo-immunotherapy remains standard front-line therapy, curing approximately two thirds of patients. Patients with refractory disease or those who relapse after salvage treatment have an overall poor prognosis highlighting the need for novel therapeutic strategies. Transducin b-like protein 1 (TBL1) is an exchange adaptor protein encoded by the TBL1X gene and known to function as a master regulator of the Wnt signaling pathway by binding to β-CATENIN and promoting its downstream transcriptional program. Here, we show that, unlike normal B cells, DLBCL cells express abundant levels of TBL1 and its overexpression correlates with poor clinical outcome regardless of DLBCL molecular subtype. Genetic deletion of TBL1 and pharmacological approach using tegavivint, a first-in-class small molecule targeting TBL1 (Iterion Therapeutics), promotes DLBCL cell death in vitro and in vivo. Through an integrated genomic, biochemical, and pharmacologic analyses, we characterized a novel, β-CATENIN independent, post-transcriptional oncogenic function of TBL1 in DLBCL where TBL1 modulates the stability of key oncogenic proteins such as PLK1, MYC, and the autophagy regulatory protein BECLIN-1 through its interaction with a SKP1-CUL1-F-box (SCF) protein supercomplex. Collectively, our data provide the rationale for targeting TBL1 as a novel therapeutic strategy in DLBCL.
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- 2020
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48. How We Manage Patients With Chronic Lymphocytic Leukemia During the SARS-CoV-2 Pandemic
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Davide Rossi, Mazyar Shadman, Adalgisa Condoluci, Jennifer R. Brown, John C. Byrd, Gianluca Gaidano, Michael Hallek, Peter Hillmen, Anthony Mato, Emili Montserrat, and Paolo Ghia
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract. Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). These can be exacerbated by anti-leukemic treatments. In addition, the typical patients with CLL already have fragilities and background risk factors that apply to the general population for severe COVID-19. On these bases, patients with CLL may experience COVID-19 morbidity and mortality. Recurrent seasonal epidemics of SARS-CoV-2 are expected, and doctors taking care of patients with CLL must be prepared for the possibility of substantial resurgences of infection and adapt their approach to CLL management accordingly. In this Guideline Article, we aim at providing clinicians with a literature-informed expert opinion on the management of patients with CLL during SARS-CoV-2 epidemic.
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- 2020
- Full Text
- View/download PDF
49. Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia
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Nyla A. Heerema, Natarajan Muthusamy, Qiuhong Zhao, Amy S. Ruppert, Heather Breidenbach, Leslie A. Andritsos, Michael R. Grever, Kami J. Maddocks, Jennifer Woyach, Farrukh Awan, Meixiao Long, Amber Gordon, Caitlin Coombes, and John C. Byrd
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p
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- 2020
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50. Mutations associated with a 17-gene leukemia stem cell score and the score’s prognostic relevance in the context of the European LeukemiaNet classification of acute myeloid leukemia
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Marius Bill, Deedra Nicolet, Jessica Kohlschmidt, Christopher J. Walker, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Dimitrios Papaioannou, Xiaoqing Rong-Mullins, Zachary Brannan, Jonathan E. Kolitz, Bayard L. Powell, Kellie J. Archer, Adrienne M. Dorrance, Andrew J. Carroll, Richard M. Stone, John C. Byrd, Ramiro Garzon, and Clara D. Bloomfield
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Leukemia stem cells (LSC) are more resistant to standard chemotherapy and their persistence during remission can cause relapse, which is still one of the major clinical challenges in the treatment of acute myeloid leukemia (AML). A better understanding of the mutational patterns and the prognostic impact of molecular markers associated with stemness could lead to better clinical management and improve patients’ outcomes. We applied a previously described 17-gene expression score comprising genes differently expressed between LSC and leukemic bulk blasts, for 934 adult patients with de novo AML, and studied associations of the 17-gene LSC score with clinical data and mutation status of 81 genes recurrently mutated in cancer and leukemia. We found that patients with a high 17-gene score were older and had more mutations. The 17-gene score was found to have a prognostic impact in both younger (aged
- Published
- 2020
- Full Text
- View/download PDF
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