249 results on '"Katherine R. Calvo"'
Search Results
2. A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome
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David H. McDermott, Daniel Velez, Elena Cho, Edward W. Cowen, John J. DiGiovanna, Diana V. Pastrana, Christopher B. Buck, Katherine R. Calvo, Pamela J. Gardner, Sergio D. Rosenzweig, Pamela Stratton, Melissa A. Merideth, H. Jeffrey Kim, Carmen Brewer, James D. Katz, Douglas B. Kuhns, Harry L. Malech, Dean Follmann, Michael P. Fay, and Philip M. Murphy
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Clinical trials ,Immunology ,Medicine - Abstract
BACKGROUND Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODS In this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTS Plerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSION Plerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATION Clinicaltrials.gov NCT02231879.FUNDING This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.
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- 2023
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3. Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
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Adriana A. de Jesus, Guibin Chen, Dan Yang, Tomas Brdicka, Natasha M. Ruth, David Bennin, Dita Cebecauerova, Hana Malcova, Helen Freeman, Neil Martin, Karel Svojgr, Murray H. Passo, Farzana Bhuyan, Sara Alehashemi, Andre T. Rastegar, Katsiaryna Uss, Lela Kardava, Bernadette Marrero, Iris Duric, Ebun Omoyinmi, Petra Peldova, Chyi-Chia Richard Lee, David E. Kleiner, Colleen M. Hadigan, Stephen M. Hewitt, Stefania Pittaluga, Carmelo Carmona-Rivera, Katherine R. Calvo, Nirali Shah, Miroslava Balascakova, Danielle L. Fink, Radana Kotalova, Zuzana Parackova, Lucie Peterkova, Daniela Kuzilkova, Vit Campr, Lucie Sramkova, Angelique Biancotto, Stephen R. Brooks, Cameron Manes, Eric Meffre, Rebecca L. Harper, Hyesun Kuehn, Mariana J. Kaplan, Paul Brogan, Sergio D. Rosenzweig, Melinda Merchant, Zuoming Deng, Anna Huttenlocher, Susan L. Moir, Douglas B. Kuhns, Manfred Boehm, Karolina Skvarova Kramarzova, and Raphaela Goldbach-Mansky
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Science - Abstract
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.
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- 2023
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4. The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort
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Karyl S. Barron, Ivona Aksentijevich, Natalie T. Deuitch, Deborah L. Stone, Patrycja Hoffmann, Ryan Videgar-Laird, Ariane Soldatos, Jenna Bergerson, Camilo Toro, Cornelia Cudrici, Michele Nehrebecky, Tina Romeo, Anne Jones, Manfred Boehm, Jennifer A. Kanakry, Dimana Dimitrova, Katherine R. Calvo, Hawwa Alao, Devika Kapuria, Gil Ben-Yakov, Dominique C. Pichard, Londa Hathaway, Alessandra Brofferio, Elisa McRae, Natalia Sampaio Moura, Oskar Schnappauf, Sofia Rosenzweig, Theo Heller, Edward W. Cowen, Daniel L. Kastner, and Amanda K. Ombrello
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deficiency of adenosine deaminase 2 (DADA2) ,ADA2 ,lacunar strokes ,immune dysregulation ,hematopoietic cell transplantation (HCT) ,vasculopathy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort’s experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.
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- 2022
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5. Persistence of skewed X-chromosome inactivation in pre-B acute lymphoblastic leukemia of a female ATRX mutation carrier
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Christian P. Bradley, Cai Chen, Karolyn A. Oetjen, Cheng Yan, Reema Panjwani, Sara Hauffe, Katherine R. Calvo, Constance Yuan, Prapti Arvind Patel, Nathan D. Montgomery, Matthew C. Foster, Minoo Battiwalla, A.John Barrett, Richard J. Gibbons, and Sawa Ito
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Specialties of internal medicine ,RC581-951 - Published
- 2019
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6. An immune-based biomarker signature is associated with mortality in COVID-19 patients
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Michael S. Abers, Ottavia M. Delmonte, Emily E. Ricotta, Jonathan Fintzi, Danielle L. Fink, Adriana A. Almeida de Jesus, Kol A. Zarember, Sara Alehashemi, Vasileios Oikonomou, Jigar V. Desai, Scott W. Canna, Bita Shakoory, Kerry Dobbs, Luisa Imberti, Alessandra Sottini, Eugenia Quiros-Roldan, Francesco Castelli, Camillo Rossi, Duilio Brugnoni, Andrea Biondi, Laura Rachele Bettini, Mariella D’Angio’, Paolo Bonfanti, Riccardo Castagnoli, Daniela Montagna, Amelia Licari, Gian Luigi Marseglia, Emily F. Gliniewicz, Elana Shaw, Dana E. Kahle, Andre T. Rastegar, Michael Stack, Katherine Myint-Hpu, Susan L. Levinson, Mark J. DiNubile, Daniel W. Chertow, Peter D. Burbelo, Jeffrey I. Cohen, Katherine R. Calvo, John S. Tsang, NIAID COVID-19 Consortium, Helen C. Su, John I. Gallin, Douglas B. Kuhns, Raphaela Goldbach-Mansky, Michail S. Lionakis, and Luigi D. Notarangelo
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COVID-19 ,Immunology ,Medicine - Abstract
Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN–, type II IFN–, and NF-κB–dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients’ first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
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- 2021
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7. Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome
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Alana Vicente, Bhavisha A. Patel, Fernanda Gutierrez-Rodrigues, Emma Groarke, Valentina Giudice, Jennifer Lotter, Xingmin Feng, Sachiko Kajigaya, Barbara Weinstein, Evette Barranta, Matthew J. Olnes, Ankur R. Parikh, Maher Albitar, Colin O. Wu, Ruba Shalhoub, Katherine R. Calvo, Danielle M. Townsley, Phillip Scheinberg, Cynthia E. Dunbar, Neal S. Young, and Thomas Winkler
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by cytopenia and a propensity to develop acute myeloid leukemia (AML). The management of lower-risk (LR) MDS with persistent cytopenias remains suboptimal. Eltrombopag (EPAG), a thrombopoietin receptor agonist, can improve platelet counts in LR-MDS and tri-lineage hematopoiesis in aplastic anemia (AA). We conducted a phase 2 dose modification study to investigate the safety and efficacy of EPAG in LR-MDS. EPAG dose was escalated from 50 mg/day, to a maximum of 150 mg/day over a period of 16 weeks. The primary efficacy endpoint was hematologic response at 16-20 weeks. Eleven of 25 (44%) patients responded; five and six patients had uni- or bi-lineage hematologic responses, respectively. The predictors of response were presence of a PNH clone, marrow hypocellularity, thrombocytopenia with or without other cytopenia, and elevated plasma thrombopoietin levels at study entry. The safety profile was consistent with previous EPAG studies in AA; no patients discontinued drug due to adverse events. Three patients developed reversible grade-3 liver toxicity and one patient had increased reticulin fibrosis. Ten patients discontinued EPAG after achieving a robust response (median time 16 months); four of them reinitiated EPAG due to declining counts, and all attained a second robust response. Six patients had disease progression not associated with expansion of mutated clones and no patient progressed to AML on study. In conclusion, EPAG was well-tolerated and effective in restoring hematopoiesis in patients with low to intermediate-1 risk MDS. This study was registered at clinicaltrials.gov as #NCT00932156.
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- 2020
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8. Predisposition to hematologic malignancies in patients with xeroderma pigmentosum
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Karolyn A. Oetjen, Melissa A. Levoska, Deborah Tamura, Sawa Ito, Dorothea Douglas, Sikandar G. Khan, Katherine R. Calvo, Kenneth H. Kraemer, and John J. DiGiovanna
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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9. Myelodysplasia in the setting of paroxysmal nocturnal hemoglobinuria: Interpretation of blast percentage in a marrow with erythroid hyperplasia
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Emma M. Groarke, Bhavisha A. Patel, Alina Dulau‐Florea, Irina Maric, Neal S. Young, and Katherine R. Calvo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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10. Rapid progression to AML in a patient with germline GATA2 mutation and acquired NRAS Q61K mutation
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Lisa J. McReynolds, Yubo Zhang, Yanqin Yang, Jingrong Tang, Matthew Mulé, Amy P. Hsu, Danielle M. Townsley, Robert R. West, Jun Zhu, Dennis D. Hickstein, Steven M. Holland, Katherine R. Calvo, and Christopher S. Hourigan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
GATA2 deficiency syndrome is caused by autosomal dominant, heterozygous germline mutations with widespread effects on immune, pulmonary and vascular systems. Patients commonly develop hematological abnormalities including bone marrow failure, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We present a patient with GATA2 mutation and MDS who progressed to AML over four months. Whole exome and targeted deep sequencing identified a new p.Q61K NRAS mutation in the bone marrow at the time of AML development. Rapid development of AML is possible in the setting of germline GATA2 mutation despite stable MDS, supporting close monitoring and consideration of early allogeneic transplantation.
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- 2019
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11. A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma
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Neha Korde, Mattias Carlsten, Min-Jung Lee, Alex Minter, Esther Tan, Mary Kwok, Elisabet Manasanch, Manisha Bhutani, Nishant Tageja, Mark Roschewski, Adriana Zingone, Rene Costello, Marcia Mulquin, Diamond Zuchlinski, Irina Maric, Katherine R. Calvo, Raul Braylan, Prashant Tembhare, Constance Yuan, Maryalice Stetler-Stevenson, Jane Trepel, Richard Childs, and Ola Landgren
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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12. MonoMAC and GATA2 deficiency: overlapping clinical and pathological features with aplastic anemia and idiopathic CD4+ lymphocytopenia. Reply to Haematologica 2012;97(4):058669
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Katherine R. Calvo, Dennis D. Hickstein, and Steven M. Holland
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2012
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13. MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response
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Weixin Wang, Meghan Corrigan-Cummins, Justin Hudson, Irina Maric, Olga Simakova, Sattva S. Neelapu, Larry W. Kwak, John E. Janik, Barry Gause, Elaine S. Jaffe, and Katherine R. Calvo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma.Design and Methods MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human microRNAs. Tandem gene expression profiles were obtained for predicting microRNA targets.Results The expression of 133 microRNAs was significantly different (> 2-fold; P
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- 2012
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14. Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications
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Katherine R. Calvo, Donald C. Vinh, Irina Maric, Weixin Wang, Pierre Noel, Maryalice Stetler-Stevenson, Diane C. Arthur, Mark Raffeld, Amalia Dutra, Evgenia Pak, Kyungjae Myung, Amy P. Hsu, Dennis D. Hickstein, Stefania Pittaluga, and Steven M. Holland
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
A novel, genetic immunodeficiency syndrome has been recently described, herein termed “MonoMAC”. It is characterized by severe circulating monocytopenia, NK- and B-lymphocytopenia, severe infections with M. avium complex (MAC), and risk of progression to myelodysplasia/acute myelogenous leukemia. Detailed bone marrow analyses performed on 18 patients further define this disorder. The majority of patients had hypocellular marrows with reticulin fibrosis and multilineage dysplasia affecting the myeloid (72%), erythroid (83%) and megakaryocytic (100%) lineages. Cytogenetic abnormalities were present in 10 of 17 (59%). Despite B-lymphocytopenia, plasma cells were present but were abnormal (e.g. CD56+) in nearly half of cases. Increased T-cell large granular lymphocyte populations were present in 28% of patients. Chromosomal breakage studies, cell cycle checkpoint functions, and sequencing of TERT and K-RAS genes revealed no abnormalities. MonoMAC appears to be a unique, inherited syndrome of bone marrow failure. We describe distinctive bone marrow features to help in its recognition and diagnosis. (Clinicaltrials.gov identifiers: NCT00018044, NCT00923364, NCT01212055)
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- 2011
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15. Pediatric myelodysplastic syndrome
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Stephen Babcock, Katherine R. Calvo, and Robert P. Hasserjian
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Pathology and Forensic Medicine - Published
- 2023
16. Spectrum of clonal hematopoiesis in VEXAS syndrome
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Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna Fernandez, Terra L Lasho, Ruba N Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy M. Finke, Matthew J. Koster, Abhishek A. Mangaonkar, Kenneth J Warrington, Kebede Begna, Zhuoer Xie, Amanda K Ombrello, David S Viswanatha, Marcela A. Ferrada, Lorena Wilson, Ronald S. Go, Taxiarchis V. Kourelis, Kaaren K Reichard, Horatiu Olteanu, Ivana Darden, Dalton Hironaka, Lemlem Alemu, Sachiko Kajigaya, Rodrigo T. Calado, Emma M. Groarke, Sofia Rosenzweig, Daniel L Kastner, Katherine R Calvo, Colin O. Wu, Peter C. Grayson, Neal S Young, David B. Beck, Bhavisha A. Patel, and Mrinal M. Patnaik
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.
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- 2023
17. Supplementary Data from Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Nonmalignant Clonal Hematopoiesis
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Christopher S. Hourigan, Yuesheng Li, Patrick Burr, J. Philip McCoy, Pradeep K. Dagur, Aik Ooi, Shu Wang, Saurabh Gulati, Aaron Llanso, Robert Durruthy-Durruthy, Adam Sciambi, Catherine Lai, Christin B. DeStefano, Janet Valdez, Julie Thompson, Clifton L. Dalgard, Gauthaman Sukumar, Anthony R. Soltis, Matthew D. Wilkerson, Karolyn A. Oetjen, Katherine E. Lindblad, Katherine R. Calvo, Meghali Goswami, Gege Gui, Chidera Nosiri, Jack Ghannam, and Laura W. Dillon
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Supplementary Data
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- 2023
18. Data from Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Nonmalignant Clonal Hematopoiesis
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Christopher S. Hourigan, Yuesheng Li, Patrick Burr, J. Philip McCoy, Pradeep K. Dagur, Aik Ooi, Shu Wang, Saurabh Gulati, Aaron Llanso, Robert Durruthy-Durruthy, Adam Sciambi, Catherine Lai, Christin B. DeStefano, Janet Valdez, Julie Thompson, Clifton L. Dalgard, Gauthaman Sukumar, Anthony R. Soltis, Matthew D. Wilkerson, Karolyn A. Oetjen, Katherine E. Lindblad, Katherine R. Calvo, Meghali Goswami, Gege Gui, Chidera Nosiri, Jack Ghannam, and Laura W. Dillon
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Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML posttreatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody–oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A- and TET2-mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts.Significance:This study offers a proof of principle of patient-personalized customized single-cell proteogenomics in AML including whole-genome sequencing–defined structural variants, currently unmeasurable by commercial “off-the-shelf” panels. This approach allows for the definition of genetic and immunophenotype features for an individual patient that would be best suited for measurable residual disease tracking.
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- 2023
19. Supplementary Table 1 from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
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Supplementary Table 1. Characteristics of all patients studied.
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- 2023
20. Supplementary materials-Neutrophil chemotaxis videos from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
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Neutrophils chemotaxis video
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- 2023
21. Data from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
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Purpose: Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAb) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in preclinical studies, in vitro ibrutinib was reported to decrease CD20 expression and inhibit cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox.Experimental Design: Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs.Results: We demonstrate that CD20 expression on ibrutinib was rapidly and persistently downregulated (median reduction 74%, day 28, P < 0.001) compared with baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and downregulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pretreatment cells (median reduction 75%, P < 0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay-accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. In addition, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy.Conclusions: Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal antitumor effects of such combinations requires further investigation. Clin Cancer Res; 22(1); 86–95. ©2015 AACR.
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- 2023
22. Supplementary Figures from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
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Supplementary Figure 1. Uniform CD20 loss from the surface of primary CLL cells after in vivo exposure to ibrutinib. Supplementary Figure 2. Loss of CD20 on ibrutinib and basal CD20 expression levels do not correlate with high risk prognostic factors. Supplementary Figure 3. Selective NF-κB inhibitor diminishes CD20 cell surface expression. Supplementary Figure 4. Complement regulatory proteins membrane cofactor protein and protectin are not consistently inhibited by ibrutinib.
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- 2023
23. Supplementary materials-Clinical trial protocol from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
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Clinical trial protocol
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- 2023
24. Supplementary figures S1-S5 from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
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Supplementary Figure S1. Ibrutinib alters the absolute expression of inflammatory cytokines and chemokines in serum from patients with CLL. Supplementary Figure S2. Ibrutinib treatment reduces tumor burden. Supplementary Figure S3. Both CD4+ and CD8+ T cell subsets are decreased on ibrutinib. Supplementary Figure S4. Grading of macrophage interaction with CLL cells in bone marrow specimens. Supplementary Figure S5. Ibrutinib alters the absolute expression of chemokines in bone marrow supernatant from patients with CLL.
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- 2023
25. Data from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
- Abstract
Purpose: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment.Experimental Design: Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed.Results: Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4+ T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4+ T cells in vitro. Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells.Conclusions: In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. Clin Cancer Res; 22(7); 1572–82. ©2015 AACR.See related commentary by Bachireddy and Wu, p. 1547
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- 2023
26. Supplementary tables and figure legends from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
- Author
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
- Abstract
Supplementary Table S1: Evaluation of serum cytokine levels on ibrutinib Supplementary Table S2: Evaluation of chemoattractant levels in bone marrow supernatant on ibrutinib supplementary figure legends for supplementary figures S1-S5
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- 2023
27. Supplementary Table S1 from Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
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Zhong Chen, Carter Van Waes, Katherine R. Calvo, John C. Morris, Xiaojiang Xu, Gerhard S. Mundinger, Kunal Saigal, Bhavana Dabir, Jay Friedman, Bin Yan, Mary E. Winters, Clint T. Allen, and Francisco G. Pernas
- Abstract
Supplementary Table S1 from Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
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- 2023
28. Conflict of Interest Form from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
- Author
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
- Abstract
Conflict of Interest Form from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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- 2023
29. Data from Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
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Zhong Chen, Carter Van Waes, Katherine R. Calvo, John C. Morris, Xiaojiang Xu, Gerhard S. Mundinger, Kunal Saigal, Bhavana Dabir, Jay Friedman, Bin Yan, Mary E. Winters, Clint T. Allen, and Francisco G. Pernas
- Abstract
Purpose: Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment.Experimental Design: The IC50 of gefitinib for HNSCC cell lines were determined using 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial.Results:In vitro, gefitinib inhibited cell proliferation with differing IC50, and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor κB. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients.Conclusions: Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKT and p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC.
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- 2023
30. Supplementary Figures Legends from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
- Abstract
Supplementary Figures Legends from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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- 2023
31. Supplementary Data from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
- Abstract
Supplementary Figures and Tables
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- 2023
32. Data from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
- Abstract
Purpose:To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.Patients and Methods:This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.Results:Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.Conclusions:Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
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- 2023
33. ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
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Robert R. West, Dennis D. Hickstein, Desiree Tillo, Amy P. Hsu, Weixin Wang, Thomas R. Bauer, Katherine R. Calvo, Stephenie Droll, Justin B. Lack, Laura M. Tuschong, Lisa J. Embree, and Steven M. Holland
- Subjects
Myeloid ,GATA2 Deficiency ,Cell Cycle Proteins ,Disease ,medicine.disease_cause ,Trisomy 8 ,Germline mutation ,Neoplasms ,medicine ,Humans ,Chromosome 7 (human) ,Mutation ,Myeloproliferative Disorders ,business.industry ,Hematology ,medicine.disease ,GATA2 Transcription Factor ,Repressor Proteins ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,Immunology ,Disease Progression ,Female ,Bone marrow ,business - Abstract
Patients with GATA2 deficiencyharbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic syndrome (MDS) was the most common diagnosis (∼44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID; ∼37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (∼43%), notably trisomy 8 (∼23%) and monosomy 7 (∼12%), but the changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ∼25% of patients, although the mutations were rarely concomitant. Mutations in DNMT3A were found in ∼10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 deficiency.
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- 2022
34. Classification of rare pediatric myeloid neoplasia—Quo vadis?
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Charlotte M. Niemeyer, Martina Rudelius, Akiko Shimamura, Christian Flotho, Henrik Hasle, Elliot Stieglitz, Brigitte Strahm, Lucy A. Godley, Olga K. Weinberg, Attilio Orazi, and Katherine R. Calvo
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
35. The Spectrum of GATA2 Deficiency Syndrome
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Katherine R. Calvo and Dennis D. Hickstein
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of clinical features including nontuberculous mycobacterial, bacterial, fungal, and human papillomavirus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor that gives rise to B lymphocytes, monocytes, natural killer cells, and dendritic cells, leading to cytopenias of these lineages and subsequent infections. The bone marrow failure is typically characterized by hypocellularity. Dysplasia may either be absent or subtle but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelomonocytic leukemia. The latter 3 malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or in STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency, including the following: (1) Why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2? (2) What are the genetic changes that lead to myeloid progression? (3) What causes the apparent genetic anticipation? (4) What is the role of preemptive HSCT?
- Published
- 2022
36. A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies
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Byung-Chul Lee, Yifan Zhou, Erica Bresciani, Neval Ozkaya, Alina Dulau-Florea, Blake Carrington, Tae-Hoon Shin, Valentina Baena, Zulfeqhar A. Syed, So Gun Hong, Tao Zhen, Katherine R. Calvo, Paul Liu, and Cynthia E. Dunbar
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Germ line loss-of-function heterozygous mutations in the RUNX1 gene cause familial platelet disorder with associated myeloid malignancies (FPDMM) characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant hematopoietic stem and progenitor cells (HSPCs) in vivo long term. We generated a rhesus macaque with an FPDMM competitive repopulation model using CRISPR/Cas9 nonhomologous end joining editing in the RUNX1 gene and the AAVS1 safe-harbor control locus. We transplanted mixed populations of edited autologous HSPCs and tracked mutated allele frequencies in blood cells. In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells. Platelet counts remained below the normal range in the long term. Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization. In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous–mutated HSPCs long term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse myelodysplastic syndrome/ acute myeloid leukemia predisposition and thrombopoietic defects.
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- 2022
37. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS
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Wanxia L. Tsai, Robert A. Colbert, Marcus Y Chen, Arlene Sirajuddin, Ryan S. Laird, Peter C. Grayson, Patrycja Hoffmann, Sinisa Savic, Marcela A. Ferrada, Emma M. Groarke, Kristina V. Wells, Massimo Gadina, Bhavisha A Patel, Mariana J. Kaplan, Keith A. Sikora, Emily Rose, Lorena Wilson, Daniel L. Kastner, Gustaf Wigerblad, Zuoming Deng, Amanda K. Ombrello, Oskar Schnappauf, Emily Rominger, Kaitlin A. Quinn, Daniela Ospina Cardona, Jeff Kim, Ivona Aksentijevich, Neal S. Young, David B. Beck, Wendy Goodspeed, Clint T. Allen, Mimi T. Le, Katherine R. Calvo, Yiming Luo, and Anne Jones
- Subjects
030203 arthritis & rheumatology ,0301 basic medicine ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Costochondritis ,Mortality rate ,Immunology ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,Internal medicine ,medicine ,Immunology and Allergy ,Chondritis ,Macrocytic anemia ,business ,Exome ,Mean corpuscular volume ,Relapsing polychondritis ,Multiple myeloma - Abstract
Objective Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Methods Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Results Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count
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- 2021
38. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1
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Fernanda Gutierrez-Rodrigues, Daniel L. Kastner, David B. Beck, Patrycja Hoffmann, Marcela A. Ferrada, Bhavisha A Patel, Nisha Patel, Megan Trick, Neal S. Young, Peter C. Grayson, Zhijie Wu, Ifeyinwa Emmanuela Obiorah, Daniela Ospina Cardona, Alina Dulau-Florea, Lorena Wilson, Emma M. Groarke, Weixin Wang, Katherine R. Calvo, Jennifer Lotter, and Amanda K. Ombrello
- Subjects
Male ,medicine.medical_specialty ,Myeloid ,Neutropenia ,Monoclonal Gammopathy of Undetermined Significance ,Gastroenterology ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,Myeloid Neoplasia ,business.industry ,Myelodysplastic syndromes ,Hematology ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Hematologic disease ,Myelodysplastic Syndromes ,Mutation ,Macrocytic anemia ,Multiple Myeloma ,business ,Monoclonal gammopathy of undetermined significance - Abstract
Somatic mutations in UBA1 involving hematopoietic stem and myeloid cells have been reported in patients with the newly defined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Here, we report clinical hematologic manifestations and unique bone marrow (BM) features in 16 patients with VEXAS. All patients were male and had a history of severe autoinflammatory and rheumatologic manifestations and a somatic UBA1 mutation (p.Met41). Ten patients had hematologic disorders: myelodysplastic syndrome (MDS; 6 of 16), multiple myeloma (2 of 16), monoclonal gammopathy of undetermined significance (2 of 16), and monoclonal B-cell lymphocytosis (2 of 16), and a few of those patients had 2 co-existing clonal processes. Although macrocytic anemia (100%) and lymphopenia (80%) were prevalent in all patients with VEXAS, thrombocytopenia and neutropenia were more common in patients with progression to MDS. All BMs in VEXAS patients had prominent cytoplasmic vacuoles in myeloid and erythroid precursors. In addition, most BMs were hypercellular with myeloid hyperplasia, erythroid hypoplasia, and varying degrees of dysplasia. All patients diagnosed with MDS were lower risk (low blast count, very good to intermediate cytogenetics) according to standard prognostic scoring with no known progression to leukemia. In addition, 10 of 16 patients had thrombotic events, including venous thromboembolism and arterial stroke. Although VEXAS presents symptomatically as a rheumatologic disease, morbidity and mortality are associated with progression to hematologic disease. Given the increased risk of developing MDS and multiple myeloma, surveillance for disease progression is important.
- Published
- 2021
39. miR-181c regulates MCL1 and cell survival in GATA2 deficient cells
- Author
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Stephenie Droll, Rui Chen, Dennis D. Hickstein, Meghan Corrigan-Cummins, Zhen Zhao, Layla M. Saleh, Emily Barber, Amy P. Hsu, Weixin Wang, Katherine R. Calvo, Donald C. Vinh, Nga Voong Hawk, Steven M. Holland, Vollter Anastas, and Megan Trick
- Subjects
Myeloid ,Cell Survival ,GATA2 Deficiency ,Immunology ,Cell ,GATA2 ,Myeloid leukemia ,Cell Biology ,Transfection ,Biology ,medicine.disease ,Molecular biology ,GATA2 Transcription Factor ,MicroRNAs ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,medicine ,Humans ,Myeloid Cell Leukemia Sequence 1 Protein ,Immunology and Allergy ,B cell - Abstract
GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N = 13) in comparison to controls (N = 10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N = 29; P
- Published
- 2021
40. The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia
- Author
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Martina, Rudelius, Olga K, Weinberg, Charlotte M, Niemeyer, Akiko, Shimamura, and Katherine R, Calvo
- Abstract
Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200-1228, 2022).
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- 2022
41. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data
- Author
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Daniel A. Arber, Attilio Orazi, Robert P. Hasserjian, Michael J. Borowitz, Katherine R. Calvo, Hans-Michael Kvasnicka, Sa A. Wang, Adam Bagg, Tiziano Barbui, Susan Branford, Carlos E. Bueso-Ramos, Jorge E. Cortes, Paola Dal Cin, Courtney D. DiNardo, Hervé Dombret, Eric J. Duncavage, Benjamin L. Ebert, Elihu H. Estey, Fabio Facchetti, Kathryn Foucar, Naseema Gangat, Umberto Gianelli, Lucy A. Godley, Nicola Gökbuget, Jason Gotlib, Eva Hellström-Lindberg, Gabriela S. Hobbs, Ronald Hoffman, Elias J. Jabbour, Jean-Jacques Kiladjian, Richard A. Larson, Michelle M. Le Beau, Mignon L.-C. Loh, Bob Löwenberg, Elizabeth Macintyre, Luca Malcovati, Charles G. Mullighan, Charlotte Niemeyer, Olatoyosi M. Odenike, Seishi Ogawa, Alberto Orfao, Elli Papaemmanuil, Francesco Passamonti, Kimmo Porkka, Ching-Hon Pui, Jerald P. Radich, Andreas Reiter, Maria Rozman, Martina Rudelius, Michael R. Savona, Charles A. Schiffer, Annette Schmitt-Graeff, Akiko Shimamura, Jorge Sierra, Wendy A. Stock, Richard M. Stone, Martin S. Tallman, Jürgen Thiele, Hwei-Fang Tien, Alexandar Tzankov, Alessandro M. Vannucchi, Paresh Vyas, Andrew H. Wei, Olga K. Weinberg, Agnieszka Wierzbowska, Mario Cazzola, Hartmut Döhner, Ayalew Tefferi, Arber, Daniel A, Orazi, Attilio, Hasserjian, Robert P, Borowitz, Michael J, Branford, Susan, Tefferi, Ayalew, and Hematology
- Subjects
Consensus ,Leukemia ,Myeloproliferative Disorders ,Immunology ,Genomics ,Cell Biology ,Hematology ,Settore MED/08 - Anatomia Patologica ,World Health Organization ,Biochemistry ,Hematologic Neoplasms ,Acute Disease ,Humans ,myeloid neoplasia ,lymphoid neoplasia - Abstract
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
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- 2022
42. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia
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Emma M. Groarke, Bhavisha A. Patel, Ruba Shalhoub, Fernanda Gutierrez-Rodrigues, Parth Desai, Harshraj Leuva, Yoshitaka Zaimoku, Casey Paton, Nina Spitofsky, Jennifer Lotter, Olga Rios, Richard W. Childs, David J. Young, Alina Dulau-Florea, Cynthia E. Dunbar, Katherine R. Calvo, Colin O. Wu, and Neal S. Young
- Subjects
Immunosuppression Therapy ,Cancer Research ,Myeloproliferative Disorders ,Anemia, Aplastic ,Hematology ,Middle Aged ,Article ,Clonal Evolution ,Leukemia, Myeloid, Acute ,Oncology ,Core Binding Factor Alpha 2 Subunit ,Humans ,RNA Splicing Factors ,Immunosuppressive Agents - Abstract
Predictors, genetic characteristics, and long-term outcomes of patients with SAA who clonally evolved after immunosuppressive therapy (IST) were assessed. SAA patients were treated with IST from 1989–2020. Clonal evolution was categorized as “high-risk” (overt myeloid neoplasm [meeting WHO criteria for dysplasia, MPN or acute leukemia] or isolated chromosome-7 abnormality/complex karyotype without dysplasia or overt myeloid neoplasia) or “low-risk” (non-7 or non-complex chromosome abnormalities without morphological evidence of dysplasia or myeloid neoplasia). Univariate and multivariable analysis using Fine-Gray competing risk regression model determined predictors. Long-term outcomes included relapse, overall survival (OS) and hematopoietic stem cell transplant (HSCT). Somatic mutations in myeloid cancer genes were assessed in evolvers and in 407 patients 6 months after IST. Of 663 SAA patients, 95 developed clonal evolution. Pre-treatment age >48 years and ANC >0.87×10(9)/L were strong predictors of high-risk evolution. OS was 37% in high-risk clonal evolution by 5 years compared to 94% in low-risk. High-risk patients who underwent HSCT had improved OS. Eltrombopag did not increase high-risk evolution. Splicing factors and RUNX1 somatic variants were detected exclusively at high-risk evolution; DNMT3A, BCOR/L1 and ASXL1 were present in both. RUNX1, splicing factors and ASXL1 mutations detected at 6 months after IST predicted high-risk evolution.
- Published
- 2022
43. Classification of rare pediatric myeloid neoplasia-Quo vadis?
- Author
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Charlotte M, Niemeyer, Martina, Rudelius, Akiko, Shimamura, Christian, Flotho, Henrik, Hasle, Elliot, Stieglitz, Brigitte, Strahm, Lucy A, Godley, Olga K, Weinberg, Attilio, Orazi, and Katherine R, Calvo
- Subjects
Myeloproliferative Disorders ,Neoplasms ,Humans ,Syndrome ,Child - Published
- 2022
44. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis
- Author
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Marcela A. Ferrada, Sinisa Savic, Daniela Ospina Cardona, Jason C. Collins, Hugh Alessi, Fernanda Gutierrez-Rodrigues, Dinesh Babu Uthaya Kumar, Lorena Wilson, Wendy Goodspeed, James S. Topilow, Julie J. Paik, James A. Poulter, Tanaz A. Kermani, Matthew J. Koster, Kenneth J. Warrington, Catherine Cargo, Rachel S. Tattersall, Christopher J. A. Duncan, Anna Cantor, Patrycja Hoffmann, Elspeth M. Payne, Hanna Bonnekoh, Karoline Krause, Edward W. Cowen, Katherine R. Calvo, Bhavisha A. Patel, Amanda K. Ombrello, Daniel L. Kastner, Neal S. Young, Achim Werner, Peter C. Grayson, and David B. Beck
- Subjects
Nucleotides ,Mutation ,Immunology ,Ubiquitination ,Codon, Initiator ,Humans ,Ubiquitin-Activating Enzymes ,Cell Biology ,Hematology ,Biochemistry - Abstract
Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.
- Published
- 2022
45. Skin in the game: the emergence of myelodysplasia cutis
- Author
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Katherine R, Calvo
- Subjects
Myelodysplastic Syndromes ,Immunology ,Humans ,Cell Biology ,Hematology ,Biochemistry ,Skin - Published
- 2022
46. Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Nonmalignant Clonal Hematopoiesis
- Author
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Shu Wang, Robert Durruthy-Durruthy, Karolyn A. Oetjen, Jack Ghannam, Catherine Lai, Julie Thompson, Katherine E. Lindblad, Katherine R. Calvo, Adam Sciambi, Aaron Llanso, Gege Gui, Chidera Nosiri, Yuesheng Li, Aik Ooi, Janet Valdez, Meghali Goswami, Pradeep K. Dagur, Matthew D. Wilkerson, Anthony R. Soltis, Patrick Burr, Gauthaman Sukumar, Christopher S. Hourigan, Clifton L. Dalgard, Christin B. DeStefano, Laura W. Dillon, Saurabh Gulati, and J. Philip McCoy
- Subjects
Neoplasm, Residual ,medicine.diagnostic_test ,business.industry ,Hybridization probe ,Myeloid leukemia ,General Medicine ,Computational biology ,Biology ,Precision medicine ,Malignancy ,medicine.disease ,Proteogenomics ,Article ,DNA sequencing ,Clone Cells ,Flow cytometry ,Leukemia, Myeloid, Acute ,hemic and lymphatic diseases ,medicine ,Humans ,Personalized medicine ,Clonal Hematopoiesis ,business - Abstract
Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML posttreatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody–oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A- and TET2-mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts. Significance: This study offers a proof of principle of patient-personalized customized single-cell proteogenomics in AML including whole-genome sequencing–defined structural variants, currently unmeasurable by commercial “off-the-shelf” panels. This approach allows for the definition of genetic and immunophenotype features for an individual patient that would be best suited for measurable residual disease tracking.
- Published
- 2021
47. Clonal Hematopoiesis in Vexas Syndrome
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Bhavisha A. Patel, Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna A. Fernandez, Terra Lasho, Ruba Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy Finke, Matthew Koster, Abhishek A. Mangaonkar, Kenneth Warrington, Kebede H. Begna, Zhuoer Xie, Amanda Ombrello, David S. Viswanatha, Marcela Ferrada, Lorena Wilson, Ronald Go, Taxiarchis Kourelis, Kaaren K. Reichard, Horatiu Olteanu, Emma M. Groarke, Ivana Darden, Dalton Hironaka, Sofia Rosenzweig, Daniel L. Kastner, Katherine R. Calvo, Colin O. Wu, Peter C. Grayson, David B. Beck, Mrinal M.M. Patnaik, and Neal S. Young
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
48. Abnormal Cytotoxic T-Cell Expansion in the Bone Marrow of Patients with SASH3 Deficiency and Cytopenias
- Author
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Saber Tadros, Shamik Majumdar, Ottavia Delmonte, Jenna Bergerson, Irene Cortese, David H. McDermott, Jaspal Khillan, Kyoungin Cho, Luigi D. Notarangelo, Philip M. Murphy, and Katherine R. Calvo
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
49. Thrombotic Manifestations in Patients with Vexas Syndrome
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Pedro E. Alcedo Andrade, Ruba Shalhoub, Alina Dulau-Florea, Khanh Nghiem, Marcela Ferrada, Lorena Wilson, Ivana Darden, Wendy Goodspeed, Katherine R. Calvo, David B. Beck, Daniel L. Kastner, Peter C. Grayson, Neal S. Young, Colin O. Wu, Yogendra Kanthi, Bhavisha A. Patel, and Emma M. Groarke
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
50. Spatial-Temporal Multiomic Analysis of Tumor-Immune Interactions in Patients with AML Receiving Pembrolizumab and Decitabine
- Author
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Gege Gui, Abigail Wong-Rolle, Laura W. Dillon, Meghali Goswami, Eddie Martin, Prajan Divakar, Jason Reeves, Katherine R. Calvo, Kasper D. Hansen, Christopher S. Hourigan, and Chen Zhao
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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