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1. Incidence of Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma in the targeted therapy era: CHRONIC LYMPHOCYTIC LEUKEMIA

Author

Hampel, Paul J., Rabe, Kari G., Wang, Yucai, Hwang, Steven R., Kenderian, Saad S., Muchtar, Eli, Leis, Jose F., Koehler, Amber B., Tsang, Mazie, Hilal, Talal, Parrondo, Ricardo, Bailen, Rachel J., Schwager, Susan M., Hanson, Curtis A., Braggio, Esteban, Slager, Susan L., Shi, Min, Zepeda-Mendoza, Cinthya J., Van Dyke, Daniel L., Shanafelt, Tait D., King, Rebecca L., Call, Timothy G., Kay, Neil E., Ding, Wei, and Parikh, Sameer A.

Published
2024
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2. The non-canonical BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia

Author

Hägerstrand, Daniel, Oder, Blaž, Cortese, Diego, Qu, Ying, Binzer-Panchal, Amrei, Österholm, Cecilia, Del Peso Santos, Teresa, Rabbani, Leily, Asl, Hassan Foroughi, Skaftason, Aron, Ljungström, Viktor, Lundholm, August, Koutroumani, Maria, Haider, Zahra, Jylhä, Cecilia, Mollstedt, John, Mansouri, Larry, Plevova, Karla, Agathangelidis, Andreas, Scarfò, Lydia, Armand, Marine, Muggen, Alice F., Kay, Neil E., Shanafelt, Tait, Rossi, Davide, Orre, Lukas M., Pospisilova, Sarka, Barylyuk, Konstantin, Davi, Frederic, Vesterlund, Mattias, Langerak, Anton W., Lehtiö, Janne, Ghia, Paolo, Stamatopoulos, Kostas, Sutton, Lesley-Ann, and Rosenquist, Richard

Published
2024
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3. Defining precancer: a grand challenge for the cancer community

Author

Faupel-Badger, Jessica, Kohaar, Indu, Bahl, Manisha, Chan, Andrew T., Campbell, Joshua D., Ding, Li, De Marzo, Angelo M., Maitra, Anirban, Merrick, Daniel T., Hawk, Ernest T., Wistuba, Ignacio I., Ghobrial, Irene M., Lippman, Scott M., Lu, Karen H., Lawler, Mark, Kay, Neil E., Tlsty, Thea D., Rebbeck, Timothy R., and Srivastava, Sudhir

Published
2024
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7. IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

Author

Bordini, Jessica, Lenzi, Chiara, Frenquelli, Michela, Morabito, Alessia, Pseftogas, Athanasios, Belloni, Daniela, Mansouri, Larry, Tsiolas, George, Perotta, Eleonora, Ranghetti, Pamela, Gandini, Francesca, Genova, Francesca, Hägerstrand, Daniel, Gavriilidis, Georgios, Keisaris, Sofoklis, Pechlivanis, Nikolaos, Davi, Frederic, Kay, Neil E., Langerak, Anton W., Pospisilova, Sarka, Scarfò, Lydia, Makris, Antonios, Psomopoulos, Fotis E., Stamatopoulos, Kostas, Rosenquist, Richard, Campanella, Alessandro, and Ghia, Paolo

Published
2024
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9. Incidence, risk factors, and outcomes of patients with monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia who develop venous thromboembolism

Author

Koehler, Amber B., Rabe, Kari G., Crusan, Daniel J., Call, Timothy G., Achenbach, Sara J., Hampel, Paul J., Kenderian, Saad S., Leis, Jose F., Wang, Yucai, Muchtar, Eli, Tsang, Mazie, Hilal, Talal, Parrondo, Ricardo, Bailey, Kent R., Ding, Wei, Bailen, Rachel, Schwager, Susan M., Shi, Min, Hanson, Curtis A., Slager, Susan L., Kay, Neil E., Ashrani, Aneel A., and Parikh, Sameer A.

Published
2025
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10. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Author

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

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

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

Published
2023

11. Relationship among three common hematological premalignant conditions

Author

Boddicker, Nicholas J., Parikh, Sameer A., Norman, Aaron D., Rabe, Kari G., Griffin, Rosalie, Call, Timothy G., Robinson, Dennis P., Olson, Janet E., Dispenzieri, Angela, Rajkumar, Vincent, Kumar, Shaji, Kay, Neil E., Hanson, Curtis A., Cerhan, James R., Murray, David, Braggio, Esteban, Shanafelt, Tait D., Vachon, Celine M., and Slager, Susan L.

Published
2023
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12. Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis

Author

Kleinstern, Geffen, Boddicker, Nicholas J., O’Brien, Daniel R., Allmer, Cristine, Rabe, Kari G., Norman, Aaron D., Griffin, Rosalie, Yan, Huihuang, Ma, Tao, Call, Timothy G., Bruins, Laura, Brown, Sochilt, Bonolo de Campos, Cecilia, Hanson, Curtis A., Leis, Jose F., Ding, Wei, Vachon, Celine M., Kay, Neil E., Oakes, Christopher C., Parker, Alexander S., Brander, Danielle M., Weinberg, J. Brice, Furman, Richard R., Shanafelt, Tait D., Cerhan, James R., Parikh, Sameer A., Braggio, Esteban, and Slager, Susan L.

Published
2024
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13. Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans

Author

Kleinstern, Geffen, Weinberg, J Brice, Parikh, Sameer A, Braggio, Esteban, Achenbach, Sara J, Robinson, Dennis P, Norman, Aaron D, Rabe, Kari G, Boddicker, Nicholas J, Vachon, Celine M, Lesnick, Connie E, Call, Timothy G, Brander, Danielle M, Rassenti, Laura Z, Kipps, Thomas J, Olson, Janet E, Cerhan, James R, Kay, Neil E, Furman, Richard R, Hanson, Curtis A, Shanafelt, Tait D, and Slager, Susan L

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Health Disparities, Genetics, Hematology, Cancer, Human Genome, Lymphoma, Rare Diseases, Lymphatic Research, Minority Health, Adult, Black or African American, Aged, Aged, 80 and over, B-Lymphocytes, Biomarkers, Tumor, Case-Control Studies, Clone Cells, Female, Follow-Up Studies, Humans, Immunoglobulins, Immunophenotyping, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytosis, Male, Middle Aged, Prognosis, Risk Factors, United States, White People, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10-29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10-63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10-5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

Published
2022

14. Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia

Author

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

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Lymphoma, Lymphatic Research, Rare Diseases, Cancer, Hematology, 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.

Published
2022

15. Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

Author

Walker, Janek S, Hing, Zachary A, Harrington, Bonnie, Baumhardt, Jordan, Ozer, Hatice Gulcin, Lehman, Amy, Giacopelli, Brian, Beaver, Larry, Williams, Katie, Skinner, Jordan N, Cempre, Casey B, Sun, Qingxiang, Shacham, Sharon, Stromberg, Benjamin R, Summers, Matthew K, Abruzzo, Lynne V, Rassenti, Laura, Kipps, Thomas J, Parikh, Sameer, Kay, Neil E, Rogers, Kerry A, Woyach, Jennifer A, Coppola, Vincenzo, Chook, Yuh Min, Oakes, Christopher, Byrd, John C, and Lapalombella, Rosa

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Lymphatic Research, Lymphoma, Genetics, Cancer, Hematology, 2.1 Biological and endogenous factors, Animals, Epigenesis, Genetic, Female, Gene Expression Regulation, Leukemic, Humans, Karyopherins, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Mice, Inbred C57BL, Models, Molecular, Mutation, Receptors, Cytoplasmic and Nuclear, Retrospective Studies, Transcriptome, Exportin 1 Protein, Mice, XPO1, Chronic lymphocytic leukemia, Mouse model, Selinexor, Sines, Expression profiling, Mutation analysis, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology, Oncology and carcinogenesis
Abstract

BackgroundExportin 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.MethodsWe 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).ResultsWe 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.ConclusionsThese 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.

Published
2021

16. Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation in Patients With Chronic Lymphocytic Leukemia

Author

Christopoulos, Georgios, Attia, Zachi I., Achenbach, Sara J., Rabe, Kari G., Call, Timothy G., Ding, Wei, Leis, Jose F., Muchtar, Eli, Kenderian, Saad S., Wang, Yucai, Hampel, Paul J., Koehler, Amber B., Kay, Neil E., Kapoor, Prashant, Slager, Susan L., Shanafelt, Tait D., Noseworthy, Peter A., Friedman, Paul A., Herrmann, Joerg, and Parikh, Sameer A.

Published
2024
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17. CD19 occupancy with tafasitamab increases therapeutic index of CART19 cell therapy and diminishes severity of CRS

Author

Sakemura, R. Leo, Manriquez Roman, Claudia, Horvei, Paulina, Siegler, Elizabeth L., Girsch, James H., Sirpilla, Olivia L., Stewart, Carli M., Yun, Kun, Can, Ismail, Ogbodo, Ekene J., Adada, Mohamad M., Bezerra, Evandro D., Kankeu Fonkoua, Lionel Aurelien, Hefazi, Mehrdad, Ruff, Michael W., Kimball, Brooke L., Mai, Long K., Huynh, Truc N., Nevala, Wendy K., Ilieva, Kristina, Augsberger, Christian, Patra-Kneuer, Maria, Schanzer, Jürgen, Endell, Jan, Heitmüller, Christina, Steidl, Stefan, Parikh, Sameer A., Ding, Wei, Kay, Neil E., Nowakowski, Grzegorz S., and Kenderian, Saad S.

Published
2024
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19. Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy

Author

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
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Lymphoma, Cancer Genomics, Rare Diseases, Lymphatic Research, Human Genome, Hematology, Genetics, Cancer, 2.1 Biological and endogenous factors, CpG Islands, DNA Methylation, Disease Progression, Epigenome, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Biochemistry and cell biology, 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.

Published
2021

20. Mortality Rates Among Hospitalized Patients With COVID-19 Treated With Convalescent Plasma: A Systematic Review and Meta-Analysis

Author

Senefeld, Jonathon W., Gorman, Ellen K., Johnson, Patrick W., Moir, M. Erin, Klassen, Stephen A., Carter, Rickey E., Paneth, Nigel S., Sullivan, David J., Morkeberg, Olaf H., Wright, R. Scott, Fairweather, DeLisa, Bruno, Katelyn A., Shoham, Shmuel, Bloch, Evan M., Focosi, Daniele, Henderson, Jeffrey P., Juskewitch, Justin E., Pirofski, Liise-Anne, Grossman, Brenda J., Tobian, Aaron A.R., Franchini, Massimo, Ganesh, Ravindra, Hurt, Ryan T., Kay, Neil E., Parikh, Sameer A., Baker, Sarah E., Buchholtz, Zachary A., Buras, Matthew R., Clayburn, Andrew J., Dennis, Joshua J., Diaz Soto, Juan C., Herasevich, Vitaly, Klompas, Allan M., Kunze, Katie L., Larson, Kathryn F., Mills, John R., Regimbal, Riley J., Ripoll, Juan G., Sexton, Matthew A., Shepherd, John R.A., Stubbs, James R., Theel, Elitza S., van Buskirk, Camille M., van Helmond, Noud, Vogt, Matthew N.P., Whelan, Emily R., Wiggins, Chad C., Winters, Jeffrey L., Casadevall, Arturo, and Joyner, Michael J.

Published
2023
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21. Differential prognosis of single and multiple TP53 abnormalities in high-count MBL and untreated CLL

Author

Griffin, Rosalie, Wiedmeier-Nutor, Julia E., Parikh, Sameer A., McCabe, Chantal E., O'Brien, Daniel R., Boddicker, Nicholas J., Kleinstern, Geffen, Rabe, Kari G., Bruins, Laura, Brown, Sochilt, Bonolo de Campos, Cecilia, Ding, Wei, Leis, Jose F., Hampel, Paul J., Call, Timothy G., Van Dyke, Daniel L., Kay, Neil E., Cerhan, James R., Yan, Huihuang, Slager, Susan L., and Braggio, Esteban

Published
2023
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23. Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia

Author

Shanafelt, Tait D, Wang, Xin V, Kay, Neil E, Hanson, Curtis A, O'Brien, Susan, Barrientos, Jacqueline, Jelinek, Diane F, Braggio, Esteban, Leis, Jose F, Zhang, Cong C, Coutre, Steven E, Barr, Paul M, Cashen, Amanda F, Mato, Anthony R, Singh, Avina K, Mullane, Michael P, Little, Richard F, Erba, Harry, Stone, Richard M, Litzow, Mark, and Tallman, Martin

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Orphan Drug, Clinical Research, Clinical Trials and Supportive Activities, Hematology, Rare Diseases, Cancer, Lymphoma, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Adenine, Aged, Antineoplastic Combined Chemotherapy Protocols, Cyclophosphamide, Female, Humans, Immunotherapy, Intention to Treat Analysis, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperidines, Progression-Free Survival, Pyrazoles, Pyrimidines, Rituximab, Vidarabine, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundData regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.MethodsIn a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.ResultsA total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P

Published
2019

25. GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity

Author

Cox, Michelle J., Manriquez Roman, Claudia, Tapper, Erin E., Siegler, Elizabeth L., Chappell, Dale, Durrant, Cameron, Ahmed, Omar, Sinha, Sutapa, Mwangi, Raphael, Scott, Nancy S., Hefazi, Mehrdad, Schick, Kendall J., Horvei, Paulina, Ruff, Michael W., Can, Ismail, Adada, Mohamad, Bezerra, Evandro, Kankeu Fonkoua, Lionel Aurelien, Parikh, Sameer A., Kay, Neil E., Sakemura, Reona, and Kenderian, Saad S.

Published
2022
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27. Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial

Author

Shanafelt, Tait D., Wang, Xin Victoria, Hanson, Curtis A., Paietta, Elisabeth M., O'Brien, Susan, Barrientos, Jacqueline, Jelinek, Diane F., Braggio, Esteban, Leis, Jose F., Zhang, Cong Christine, Coutre, Steven E., Barr, Paul M., Cashen, Amanda F., Mato, Anthony R., Singh, Avina K., Mullane, Michael P., Little, Richard F., Erba, Harry, Stone, Richard M., Litzow, Mark, Tallman, Martin, and Kay, Neil E.

Published
2022
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30. Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma

Author

Sakemura, Reona, Hefazi, Mehrdad, Siegler, Elizabeth L., Cox, Michelle J., Larson, Daniel P., Hansen, Michael J., Manriquez Roman, Claudia, Schick, Kendall J., Can, Ismail, Tapper, Erin E., Horvei, Paulina, Adada, Mohamad M., Bezerra, Evandro D., Kankeu Fonkoua, Lionel Aurelien, Ruff, Michael W., Nevala, Wendy K., Walters, Denise K., Parikh, Sameer A., Lin, Yi, Jelinek, Diane F., Kay, Neil E., Bergsagel, P. Leif, and Kenderian, Saad S.

Published
2022
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31. 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

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.

Published
2018

33. Efficacy of pembrolizumab monotherapy and in combination with BCR inhibitors for Richter transformation of chronic lymphocytic leukemia (CLL).

Author

Wang, Yucai, primary, LaPlant, Betsy R., additional, Parikh, Sameer Ashok, additional, Leis, Jose Francisco, additional, Call, Timothy G., additional, Shanafelt, Tait D., additional, He, Rong, additional, Micallef, Ivana N., additional, Nowakowski, Grzegorz S., additional, Habermann, Thomas Matthew, additional, Witzig, Thomas E., additional, Koehler, Amber B., additional, Hampel, Paul Joseph, additional, Kenderian, Saad, additional, Muchtar, Eli, additional, Aitken, Casey N., additional, Sinha, Sutapa, additional, Kay, Neil E., additional, Ansell, Stephen M., additional, and Ding, Wei, additional

Published
2024
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34. Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib

Author

Wang, Xin Victoria, Hanson, Curtis A., Tschumper, Renee C., Lesnick, Connie E., Braggio, Esteban, Paietta, Elisabeth M., O'Brien, Susan, Barrientos, Jacqueline C., Leis, Jose Francisco, Zhang, Cong Christine, Coutre, Steven E., Barr, Paul M., Cashen, Amanda F., Mato, Anthony R., Singh, Avina K., Mullane, Michael P., Erba, Harry, Stone, Richard, Litzow, Mark R., Tallman, Martin S., Shanafelt, Tait D., and Kay, Neil E.

Published
2021
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36. Clinical outcomes in patients with chronic lymphocytic leukemia with disease progression on ibrutinib

Author

Hampel, Paul J., Rabe, Kari G., Call, Timothy G., Ding, Wei, Leis, Jose F., Chanan-Khan, Asher A., Kenderian, Saad S., Muchtar, Eli, Wang, Yucai, Ailawadhi, Sikander, Koehler, Amber B., Parrondo, Ricardo, Schwager, Susan M., Sher, Taimur, Hanson, Curtis A., Shi, Min, Van Dyke, Daniel L., Braggio, Esteban, Slager, Susan L., Kay, Neil E., and Parikh, Sameer A.

Published
2022
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38. Precancer Atlas to Drive Precision Prevention Trials

Author

Spira, Avrum, Yurgelun, Matthew B, Alexandrov, Ludmil, Rao, Anjana, Bejar, Rafael, Polyak, Kornelia, Giannakis, Marios, Shilatifard, Ali, Finn, Olivera J, Dhodapkar, Madhav, Kay, Neil E, Braggio, Esteban, Vilar, Eduardo, Mazzilli, Sarah A, Rebbeck, Timothy R, Garber, Judy E, Velculescu, Victor E, Disis, Mary L, Wallace, Douglas C, and Lippman, Scott M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Rare Diseases, Cancer, Aging, Cancer Genomics, Digestive Diseases, Women's Health, Clinical Research, Colo-Rectal Cancer, Human Genome, Breast Cancer, Prevention, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Animals, Cancer Vaccines, Cellular Microenvironment, DNA, Mitochondrial, Epigenesis, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Mitochondria, Neoplasms, Precancerous Conditions, Precision Medicine, Single-Cell Analysis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity - basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA - an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510-41. ©2017 AACR.

Published
2017

39. Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families

Author

Slager, Susan L., Lanasa, Mark C., Marti, Gerald E., Achenbach, Sara J., Camp, Nicola J., Abbasi, Fatima, Kay, Neil E., Vachon, Celine M., Cerhan, James R., Johnston, James B., Call, Timothy G., Rabe, Kari G., Kleinstern, Geffen, Boddicker, Nicholas J., Norman, Aaron D., Parikh, Sameer A., Leis, Jose F., Banerji, Versha, Brander, Danielle M., Glenn, Martha, Ferrajoli, Alessandra, Curtin, Karen, Braggio, Esteban, Shanafelt, Tait D., McMaster, Mary L., Weinberg, J. Brice, Hanson, Curtis A., and Caporaso, Neil E.

Published
2021
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40. Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia

Author

Cox, Michelle J., Lucien, Fabrice, Sakemura, Reona, Boysen, Justin C., Kim, Yohan, Horvei, Paulina, Manriquez Roman, Claudia, Hansen, Michael J., Tapper, Erin E., Siegler, Elizabeth L., Forsman, Cynthia, Crotts, Sydney B., Schick, Kendall J., Hefazi, Mehrdad, Ruff, Michael W., Can, Ismail, Adada, Mohamad, Bezerra, Evandro, Kankeu Fonkoua, Lionel Aurelien, Nevala, Wendy K., Braggio, Esteban, Ding, Wei, Parikh, Sameer A., Kay, Neil E., and Kenderian, Saad S.

Published
2021
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42. Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy

Author

Ioannou, Nikolaos, Hagner, Patrick R., Stokes, Matt, Gandhi, Anita K., Apollonio, Benedetta, Fanous, Mariam, Papazoglou, Despoina, Sutton, Lesley-Ann, Rosenquist, Richard, Amini, Rose-Marie, Chiu, Hsiling, Lopez-Girona, Antonia, Janardhanan, Preethi, Awan, Farrukh T., Jones, Jeffrey, Kay, Neil E., Shanafelt, Tait D., Tallman, Martin S., Stamatopoulos, Kostas, Patten, Piers E.M., Vardi, Anna, and Ramsay, Alan G.

Published
2021
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47. Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19

Author

Ripoll, Juan G., primary, Tulledge-Scheitel, Sidna M., additional, Stephenson, Anthony A., additional, Ford, Shane, additional, Pike, Marsha L., additional, Gorman, Ellen K., additional, Hanson, Sara N., additional, Juskewitch, Justin E., additional, Miller, Alex J., additional, Zaremba, Solomiia, additional, Ovrom, Erik A., additional, Razonable, Raymund R., additional, Ganesh, Ravindra, additional, Hurt, Ryan T., additional, Fischer, Erin N., additional, Derr, Amber N., additional, Eberle, Michele R., additional, Larsen, Jennifer J., additional, Carney, Christina M., additional, Theel, Elitza S., additional, Parikh, Sameer A., additional, Kay, Neil E., additional, Joyner, Michael J., additional, and Senefeld, Jonathon W., additional

Published
2024
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48. Real‐world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres

Author

Mato, Anthony, Nabhan, Chadi, Kay, Neil E, Weiss, Mark A, Lamanna, Nicole, Kipps, Thomas J, Grinblatt, David L, Flinn, Ian W, Kozloff, Mark F, Flowers, Christopher R, Farber, Charles M, Kiselev, Pavel, Swern, Arlene S, Sullivan, Kristen, Flick, E Dawn, and Sharman, Jeff P

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Precision Medicine, Clinical Research, Hematology, Lymphoma, Lymphatic Research, Cancer, Rare Diseases, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Chromosome Aberrations, Disease Management, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Practice Patterns, Physicians', Prognosis, Prospective Studies, Registries, Treatment Outcome, Young Adult, chronic lymphocytic leukaemia, practice patterns, patient characteristics, Connect((R)) CLL Registry, chemoimmunotherapy, Connect® CLL Registry, Cardiorespiratory Medicine and Haematology, Immunology, Cardiovascular medicine and haematology
Abstract

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.

Published
2016

49. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience

Author

Van Dyke, Daniel L, Werner, Lillian, Rassenti, Laura Z, Neuberg, Donna, Ghia, Emanuella, Heerema, Nyla A, Dal Cin, Paola, Aquila, Marie Dell, Sreekantaiah, Chandrika, Greaves, Andrew W, Kipps, Thomas J, and Kay, Neil E

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Hematology, Rare Diseases, Genetics, Lymphoma, Cancer, Lymphatic Research, Chromosome Deletion, Chromosomes, Human, Disease-Free Survival, Female, Follow-Up Studies, Humans, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Survival Rate, chronic lymphocytic leukaemia, cytogenetics, leukaemia, fluorescence insitu hybridization, fluorescence in situ hybridization, Cardiorespiratory Medicine and Haematology, Immunology, Cardiovascular medicine and haematology
Abstract

This study revisited the Dohner prognostic hierarchy in a cohort of 1585 well-documented patients with chronic lymphocytic leukaemia. The duration of both time to first treatment (TTFT) and overall survival (OS) were significantly longer than observed previously, and this is at least partly due to improved therapeutic options. Deletion 13q remains the most favourable prognostic group with median TTFT and OS from fluorescence in situ hybridization (FISH) testing of 72 months and >12 years, respectively. Deletion 11q had the poorest median TTFT (22 months) and 17p deletion the poorest median OS (5 years). The percentages of abnormal nuclei were significantly associated with differential TTFT for the trisomy 12, 13q and 17p deletion cohorts but not for the 11q deletion cohort. From the date of the first FISH study, patients with >85% 13q deletion nuclei had a notably shorter TTFT (24 months). Patients with ≤20% 17p deletion nuclei had longer median TTFT and OS from the date of the first FISH study (44 months and 11 years), and were more likely to be IGHV mutated.

Published
2016

50. Tolerability and long-term disease control by IGHV mutation status among patients with CLL on ibrutinib arm of E1912

Author

Shanafelt, Tait D., Wang, Xin Victoria, Hanson, Curtis A., Paietta, Elisabeth, O’Brien, Susan, Barrientos, Jacqueline, Jelinek, Diane F., Braggio, Esteban, Leis, Jose F., Zhang, Cong Christine, Barr, Paul M., Cashen, Amanda F., Mato, Anthony R., Singh, Avina K., Mullane, Michael P., Little, Richard F., Erba, Harry, Stone, Richard M., Litzow, Mark, Tallman, Martin, and Kay, Neil E.

Published
2025
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